Search Results - EGA European Genome-Phenome Archive

Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk paediatric cancer

Zero Childhood Cancer is a precision medicine program to benefit children with poor-outcome, rare, relapsed or refractory cancer. Utilising tumour and germline whole genome sequencing (WGS) and RNA sequencing (RNAseq) across 252 tumours from high-risk paediatric cancer patients, we identified 968 reportable molecular aberrations (39.9% in WGS and RNAseq, 35.1% WGS-only, 25.0% RNAseq-only). 93.7% of patients had at least one germline or somatic aberration, 71.4% had therapeutic targets and 5.2% had a change in diagnosis. WGS identified pathogenic cancer-predisposing variants in 16.2% of patients. In 76 CNS tumours, methylome analysis confirmed diagnosis in 71.1% and contributed to a change of diagnosis in two cases (2.6%). To date 43 patients have received a recommended therapy, 38 of whom could be evaluated. A small but encouraging proportion of 31% showed some evidence of clinical benefit. Comprehensive molecular profiling resolved the molecular basis of virtually all high-risk cancers, which in some cases has significant clinical impact.

Study EGAS00001004572

HCA_Placental_Infection_Atlas

HCA Placental Infection Atlas Self-renewing human trophoblast stem cells (hTSC) can give rise to major trophoblast lineages, including syncytiotrophoblast (SCT) and extravillous trophoblast (EVT). hTSC has facilitated the study of placental development and function in vitro. Here, we aim to utilise the hTSC line (HMDMC 20/0005) to study human placental infection and inflammation. This study will provide the opportunity to better understand the pathogenesis of human placenta in the event of infection and inflammation. In brief, differentiated hTSC will be infected with relevant pathogens and stimulated with a panel of inflammatory cytokines. We will use single-cell genomic and spatial approaches to characterise cellular heterogeneity in response to infection or cytokines stimulus. In parallel, we will investigate the interaction between iPSC-derived macrophages with different trophoblast lineages during the course of infection using single-cell genomic and spatial methods. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

Study EGAS00001004722

WGS of T-cell and NK-cell lymphoma for ICGC (NKTL-SG)

Lymphomas are malignancies originating from the lymphatic system and there is a worldwide significant increase in incidences of this cancer. Lymphomas can be further classified into 2 categories namely Hodgkinâ€™s (HL), and Non-Hodgkinâ€™s lymphoma (NHL). The latter can be divided further into B, T and NK cell NHL. Peripheral T-cell lymphoma (PTCL) and Natural Killer/ T-cell lymphoma (NKTL) arise from mature T lymphocytes and NK cells. The more common subtypes include NKTL, PTCL not-otherwise-specified (PTCL-NOS), systemic anaplastic large cell lymphoma (ALCL), follicular PTCL (F-PTCL), angioimmunoblastic T-cell lymphoma (AITL) and enteropathy-associated T-cell lymphoma (EATL). Whole genome analyses on T-cell and NK-cell lymphoma samples from various countries to gain a better understanding of the pathogenesis and biology of these tumors. The comprehensive profiling and comparison among patients from various countries with different etiopathogenesis will hopefully facilitate the elucidation of key pathways and underlying molecular mechanisms driving these cancers, opening up novel therapeutic strategies in the future.

Study EGAS00001002398

Cell-free DNA TAPS for early cancer detection

Multimodal, genome-wide characterization of epigenetic and genetic information in circulating cell-free DNA (cfDNA) could enable more sensitive early cancer detection. However, due to technological challenges associated with DNA methylation sequencing in low input cfDNA samples, most studies have been limited by DNA damage caused by bisulfite sequencing, or the qualitative nature of enrichment-based sequencing. Recently, we developed TET-assisted Pyridine Borane Sequencing (TAPS), which is a mild, bisulfite-free method for base-resolution direct DNA methylation sequencing. Here we optimized TAPS for cfDNA (cfTAPS) to provide high-quality and high-depth whole-genome cell-free methylomes. We applied cfTAPS to 85 cfDNA samples from patients with hepatocellular carcinoma (HCC) or pancreatic ductal adenocarcinoma (PDAC) and non-cancer controls. From just 10 ng cfDNA (1-3 mL of plasma), we generated the most comprehensive cfDNA methylome to date. We demonstrated that cfTAPS provides multimodal information about cfDNA characteristics, including DNA methylation, tissue of origin, and DNA fragmentation. Integrated analysis of these epigenetic and genetic features enables accurate identification of early HCC and PDAC.

Study EGAS00001004962

A combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancer

The earlier diagnosis of cancer is one of the keys to reducing future cancer deaths. Here we describe our efforts to develop a non-invasive, blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinoma and 185 control patients without known cancers. KRAS mutations were detected in the plasma of 66 patients (30%) and every mutation found in the plasma was identical to that subsequently found in the patients' primary tumor (100% concordance). The use of KRAS in conjunction with two thresholded protein biomarkers (CA19-9 and prolactin) increased the sensitivity to 67%. Only one of the 185 plasma samples from the control cohort were positive for any of the three markers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types.

Study EGAS00001002444

Description and determinants of the faecal resistome and microbiome of farmers and slaughterhouse workers: a metagenome-wide cross-sectional study.

Within this study, we extracted DNA of 194 stool samples of persons living or working on pig and broiler farms (54 pig farmers, 24 broiler farmers), 70 pig slaughterhouse workers and 46 control subjects (Lifelines population living in the Northern parts of the Netherlands, and without recent antimicrobial use and occupational livestock contact). Total DNA was sequenced and metagenomic analysis was performed. Subsequently, the faecal resistomes and microbiomes were described and analysed (doi: 10.1016/j.envint.2020.105939). Highlights study: • Food chain workers are exposed to antimicrobial resistant (AMR) bacteria in livestock. • We describe faecal resistomes and microbiomes of farmers and slaughterhouse workers. • Faecal AMR gene loads in pork exposed workers exceed those in broiler farmers/controls. • Resistome and microbiome differences are shown between and within occupational groups. • On-farm working hours and working/living on a pig farm determine the faecal resistome. • Contact with livestock may be a determinant for human AMR gene carriage. This study is part of the EFFORT project: http://www.effort-against-amr.eu/.

Study EGAS00001003944

Integrative genomic analysis identifies multiple subtypes and therapeutic targets in acute erythroid leukemia

Acute erythroid leukemia (AEL) is a high risk leukemia of poorly understood genetic basis, and controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic and clinical features of 159 childhood and adult AEL cases to non-AEL myeloid disorders, and identified patterns of mutation that describe 5 age-related subgroups with distinct transcriptional profiles: adult, TP53-mutated; NPM1-mutated; KMT2A-mutated/rearranged; adult, DDX41-mutated; and pediatric, NUP98-rearranged. Mutational spectra were age-dependent and significantly associated with outcome, with NPM1 mutations and high HOXB9 expression being associated with favorable prognosis, and TP53, FLT3 and RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases, and include recurrent mutations of ALK and NTRK1, the latter of which drive erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this form of leukemia that has hitherto and dismal outcome.

Study EGAS00001002537

Kalirin-RAC controls nucleokinetic migration in ADRN-type neuroblastoma

The migrational propensity of neuroblastoma is affected by cell identity, but the mechanisms behind the divergence remain unknown. Using RNAi and time-lapse imaging, we show that ADRN-type NB cells exhibit RAC1- and kalirin-dependent nucleokinetic (NUC) migration that relies on several integral components of neuronal migration. Inhibition of NUC migration by RAC1 and kalirin-GEF1 inhibitors occurs without hampering cell proliferation and ADRN identity. Using three clinically-relevant expression dichotomies, we reveal that most of up-regulated mRNAs in RAC1- and kalirin-GEF1-suppressed ADRN-type NB cells are associated with low-risk characteristics. The computational analysis shows that, in a context of overall gene set poverty, the upregulomes in RAC1- and kalirin-GEF1-suppressed ADRN-type cells are a batch of AU-rich elements (ARE)-containing mRNAs, which suggests a link between NUC migration and mRNA stability. GSEA-based search for vulnerabilities reveals prospective weak points in RAC1- and kalirin-GEF1-suppressed ADRN-type NB cells, including activities of H3K27- and DNA methyltransferases. Altogether, these data support the introduction of NUC inhibitors into cancer treatment research.

Study EGAS00001005023

Somatic_mutation_profiling_of_intestinal_crypts_from_IBD

In this project we want to investigate the role that somatic mutations in intestinal stem cells play in IBD. We will use laser capture microdissection to ascertain epithelial cells from an individual crypts/vilus. We will extract DNA from these and use a new low-input material library prep methods to make accurate libraries for sequencing. In this pilot phase of the project we will perform 15X whole-genome sequencing of a small number of crypts biopsied from four patients. Biopsies have been taken from inflammed and noninflammed patches to compare mutation rates and mutational signatures. We will also test if crypts from inflammed patches of a single patient are clonal (either within a given inflammed patch or across inflammed patches). We will quantify the rate of cancer driver mutations in inflammed and non-inflammed crypts. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

Study EGAS00001002896

Interferon lambda 4 impairs viral antigen presentation and attenuates T cell responses

Genetic variants of the interferon lambda (IFNL) gene locus are strongly associated with spontaneous and IFN treatment induced clearance of hepatitis C virus (HCV) infections. Individuals with the ancestral IFNL4-dG allele are not able to clear HCV in the acute phase and develop chronic hepatitis C (CHC) with more than 90% probability. Paradoxically, the IFNL4-dG allele encodes a fully functional IFNλ4 protein with antiviral activity against HCV and coronavirus. Here we describe a hitherto unknown effect of IFNλ4 on HCV antigen presentation. Only minor amounts of IFNλ4 are secreted, because the protein is largely retained in the endoplasmic reticulum (ER) where it induces ER stress. Stressed cells were significantly weaker activators of HCV specific CD8+ T cells. This was not due to reduced MHC I surface presentation or extracellular IFNλ4 effects, since T cell responses could be restored by exogenous loading of MHC with HCV antigens. Rather, IFNλ4 induced ER stress impaired HCV antigen processing and/or loading onto the MHC I complex. Our results provide a potential explanation for the IFNλ4 – HCV paradox.

Study EGAS00001005396

An instructive role for IL7RA in the development of human B-cell precursor leukemia

Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Yet its role in leukemia initiation is unclear and has not been shown in primary human hematopoietic cells. We previously described activating mutations in interleukin-7 receptor alpha (IL7RA) in poor-prognosis “ph-like” BCP-ALL. Here we show that expression of activated mutant IL7RA in human CD34+ hematopoietic cells creates a preleukemic state in transplanted NOD/LtSz-scid IL2Rγnull mice, characterized by persistence of self-renewing Pro-B cells with non-productive V(D)J gene rearrangements. Preleukemic CD34+CD10highCD19+ cells evolved to a BCP-ALL with spontaneously acquired CDKN2A deletions as commonly observed in primary human BCP-ALL. CRISPR mediated silencing of CDKN2A in primary human CD34+ cells transduced with activated IL7RA resulted in robust development of BCP-ALLs in-vivo. Thus, we demonstrate for the first time that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.

Study EGAS00001005347

DERMATLAS__Hidradenoma_papilliferum_RNAseq

Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are hidradenoma papilliferums.

Study EGAS00001005715

DERMATLAS__Porocarcinoma_RNAseq

Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are porocarcinomas.

Study EGAS00001005721

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity

Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease. To advance this, we present a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity revealed cells, their inflammatory mediators and networks as potential therapeutic targets, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Tensor and matrix decomposition of the overall dataset revealed feature groupings linked with disease severity and specificity. Our systems-based integrative approach and blood atlas will inform future drug development, clinical trial design and personalised medicine approaches for COVID-19.

Study EGAS00001005493

Multi-omic analysis of cell-of-origin and epigenomic state in pediatric H3K27M gliomas

It is not known whether midline pediatric gliomas driven by Histone 3 K27M mutations (oncohistones) or EZHIP expression (oncohistone-mimics) share a common cell-of-origin, or arise from distinct cell types with unique vulnerabilities to PRC2 inhibition and partner alterations. Here, we define the etiological and oncogenic relationship between pediatric midline gliomas characterized by inhibition of K27M and K27M-like oncohistones. We assemble an extensive reference for gliogenesis from the developing mouse and human fetal brain. With bulk and single-cell transcriptomics and epigenomics, we profiled a large cohort of primary tumors comprising H3.1K27M and H3.3K27M pontine gliomas, H3.3K27M thalamic gliomas, and EZHIP+ posterior fossa ependymomas. We focus on differences across axes of location (thalamus vs. pons vs. posterior fossa), tumor type (diffuse midline gliomas vs. ependymomas), and oncohistone (H3.1/2K27M vs. H3.3K27M vs. EZHIP). We use tumor molecular features to delineate transcriptional states and cell-of-origin in each entity. Finally, we use culture models in isogenic contexts to interrogate the effect of each oncohistone or mimic.

Study EGAS00001005773

Molecular origins of mpMRI visibility

Multiparametric magnetic resonance imaging (mpMRI) has transformed the landscape of prostate cancer (PCa) management. Prostate Imaging Reporting and Data System (PI-RADSv2) scores reflect function and correlate phenotypic features with tumor aggressiveness, is an independent predictor of biochemical recurrence, and may distinguish low-risk tumors requiring no treatment from high-risk tumors requiring aggressive management. We hypothesize that differences in functional mpMRI of prostate tumors reflect the genetic and epigenetic heterogeneity of PCa. We profiled the genomes and transcriptomes of 40 Gleason score 3+4 tumors, of which 20 tumors were mpMRI invisible (not PI-RADSv2 3-5) and 20 tumors were visible (PI-RADSv2 5). Genomes of visible tumors were more unstable than those of invisible tumors. We identified 62 enriched transcripts, including numerous snoRNAs, Relaxin 1 and SCHLAP1, in visible tumors. These data suggest a confluence of aggressive pathological and microenvironmental phenomenon in PI-RADSv2 5 tumors reminiscent of nimbosus, while linking the molecular profiles of tumor aggressiveness with their functional features on mpMRI.

Study EGAS00001003179

Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosissusceptibility

Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG)and associated myelin by immune cells, which are thought to be the main drivers of MS susceptibility. Assessing chromatin accessibility and the transcriptome simultaneously at the single cell level, we found that immune genes exhibit a primedchromatin state in mouse and human OLG in a non-disease context, compatible withrapid transitions to immune-competent states in MS. We identified transcription factors as BACH1 and STAT1 involved in immune gene regulation in oligodendrocyteprecursor cells (OPCs). A subset of immune genes present bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon-gamma (IFNg) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse andhuman OLG, and treatment of mouse OPCs with IFNg leads to chromatin architecture remodeling at these loci and altered expression of interacting genes. Our data indicates that susceptibility for MS may involve OLG, which therefore constitute novel targets for immunological-based therapies for MS.

Study EGAS00001005911

Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer

The vast majority of colorectal cancer (CRC) patients fail to respond to immune checkpoint inhibitors (ICI). Understanding tumor-intrinsic determinants of immunotherapy resistance is critical to improve CRC patient outcomes. Here, we demonstrate that transcript levels of the core autophagy gene ATG16L1 are prognostic of poor outcome and predictive of ICI resistance in late-stage CRC. Deletion of Atg16l1 in murine CRC organoids markedly inhibited tumor growth in primary and metastatic niches in syngeneic hosts. ATG16L1 deficiency rendered CRC organoids more responsive to interferon (IFN) signaling and enhanced programmed cell death while decreasing tumor stem-like populations. IFN hypersensitivity consequently promoted cytotoxic anti-tumor immunity in vivo. In IMblaze370, a large phase III clinical trial of anti-PD-L1 in advanced metastatic CRC, low ATG16L1 levels identified patients with increased lymphocyte infiltration and improved outcome in a KRAS mutant setting. This work reveals autophagy as a clinically relevant immunosuppressive mechanism in CRC and provides a rationale for autophagy inhibition to boost immunotherapy responses in the clinic.

Study EGAS00001005952

Whole-exome sequencing of glioblastomas with long-term relapse interval

Treatment options for GBM patients have not changed over the last 15 years, and the success of targeted therapy or immunotherapy has been disappointinglimited. Thus, the standard of care for GBM patients remains surgical resection followed by concomitant DNA alkylating agent therapy with temozolomide (TMZ) and radiation therapy (RT). However, the time to relapse is generally short (6.9 months on average) owing to the tumor’s ability to infiltrate normal parenchyma and its intrinsic resistance to radio-chemotherapy. Due to the lack of alternative treatment options, elucidating underlying resistance mechanism has come into major focus of research, with the hope for opening new ways of therapeutic intervention overcoming resistance. To explore therapy resistance driving events, we performed a study using a single-centric collective of matched pairs of therapy-naïve and post-therapeuticc tissue from GBM patients, selected based on a maximally long interval between resections of the initial and the recurrent tumors. This rare collective was analyzed by whole exome sequencing (WES), mRNA expression and miRNA expression profiling.

Study EGAS00001006022

Tumour gene expression signature in primary melanoma predicts long-term outcomes: A prospective multicentre study

Adjuvant systemic therapies are now routinely used following resection of stage III melanoma, however accurate prognostic information is needed to better stratify patients. We used differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR=1.63, p=5.24x10-5) and overall survival (HR=1.61, p=1.67x10-4), and validated in 177 regional lymph nodes metastasis as well as two externally ascertained datasets. The machine learning classification models trained using the signature genes performed significantly better in predicting metastases than models trained with clinical covariates (pAUROC=0.02), or published prognostic signatures. The signature score negatively correlated with measures of immune cell infiltration (ρ=-0.75, p<2.2x10-16), with a higher score representing reduced lymphocyte infiltration and a higher 5-year risk of death in stage II melanoma. Our expression signature identifies melanoma patients at higher risk of metastases and warrants further evaluation in adjuvant clinical trials.

Study EGAS00001004664

RNA-seq of M-CSF differentiated human peripheral monocyte-derived macrophages (MDMs) - Validation macIDR

Macrophages represent multifunctional leukocytes defined by their stimulus-specific transcriptional reprogramming. As in vivo macrophages are often difficult to obtain, in vitro macrophage models are often used. We aggregated public expression data to define consensus expression profiles for eight commonly-used in vitro macrophage models and built the classifier macIDR, capable of distinguishing macrophage subsets with high accuracy (>0.95). Classification of in vivo macrophages suggested that alveolar macrophages resembled interleukin-10 activated macrophages in general whereas chronic obstructive pulmonary disease patients displayed decreased similarity to interferon-γ stimulated macrophages. Adipose tissue-derived macrophages were classified as unstimulated macrophages, but would resemble LPS-stimulated macrophages more in diabetic-obese patients. Rheumatoid arthritic synovial macrophages were similar to macrophages stimulated with interleukin-10 or interferon-γ. Altogether, our results suggest that macIDR is capable of identifying in vitro macrophages. By projecting in vivo macrophages onto the in vitro macrophages, we were capable of elucidating macrophage-specific changes as a result of tissue and disease.

Study EGAS00001003451

Genetic and epigenetic variation at regulatory regions contribute to cancer evolution under endocrine treatment

Comprehensive profiling of hormone-dependent breast cancer (HDBC) has identified hundreds of protein-coding alterations contributing to cancer initiation, but only a handful have been linked to endocrine therapy resistance, potentially contributing to 40% of relapses. If other mechanisms underlie the evolution of HDBC under adjuvant therapy is currently unknown. In this work, we employ integrative functional genomics to dissect the contribution of cis-regulatory elements (CREs) to cancer evolution by focusing on 12 megabases of non-coding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Massive parallel perturbation in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance9. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies non-coding changes involved in therapy resistance. Overall, our data uncover actionable transient transcriptional programs critical for dormant persister cells and unveil new regulatory nodes driving evolutionary trajectories towards disease progression.

Study EGAS00001006340

Proteogenomics reveals two distinct biological pilocytic astrocytoma subgroups

Pilocytic astrocytoma (PA) is the most common pediatric brain tumor and driven by aberrant MAPK signaling, typically mediated by BRAF alterations. While five-year overall survival rates exceed 95%, tumor recurrence constitutes a major clinical challenge in incompletely resected tumors despite chemotherapeutic or radiation based therapies. Therefore, we used proteogenomics to discern the biological heterogeneity of PA to improve classification of this tumor entity and identify novel therapeutic targets. Our proteogenomics approach integrates RNA sequencing and LC/MS-based proteomic profiling data from a cohort of 58 confirmed, primary PA samples. An integrative genomics approach was conducted to discern the biological heterogeneity of PA and to identify aberrant pathway activation in these biological subgroups. In summary, Pilocytic astrocytomas segregate into two groups where younger patients are significantly associated with Group 1. Importantly, we validate the two distinct biological subgroups in two non-overlapping cohorts. The biological heterogeneity seen here may improve biological classification and reveal novel therapeutic targets specifically useful for non-resectable tumors with high risk of recurrent or progressive disease.

Study EGAS00001006402

Multi-focal genomic dissection of synchronous primary and metastatic tissue from de novo metastatic prostate cancer

De novo metastatic prostate cancer is highly aggressive, but the paucity of routinely-collected tissue in this setting has hindered genomic stratification and jeopardizes precision oncology efforts. Here, we leveraged a rare study of surgical intervention in 43 de novo metastatic prostate cancers to assess somatic genotype across 607 synchronous primary and metastatic tissue foci plus circulating tumor DNA. Intra-prostate heterogeneity was pervasive and impacted clinically-relevant genes, resulting in frequent discordance between select primary-restricted foci and synchronous metastases. Additional complexity was driven in several instances by polyclonal metastatic seeding from the reservoir of phylogenetically-related primary populations. When simulating standard clinical practice relying on a single tissue focus, genomic heterogeneity plus highly variable per-sample tumor fraction caused false genotyping of dominant disease. However, in silico modeling demonstrated that analysis of multiple biopsy cores can rescue misassigned somatic genotypes. Our results define the relationship between synchronous treatment-naive primary and metastatic lesions in de novo metastatic prostate cancer and provide a framework for implementing genomics-guided patient management.

Study EGAS00001006466

DERMATLAS__Tubular_adenoma

IVirtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are tubular adenomas.

Study EGAS00001006686

DERMATLAS__Tubular_adenoma_RNAseq

IVirtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are tubular adenomas.

Study EGAS00001006685

RNA sequencing of CCO- and CCO+ human hepatocytes

RNAseq data from Passman et al 2023. Clonal CCO-deficient hepatocyte patches and nearby CCO-proficient hepatocytes were identified in morphologically normal human livers and sampled at varying distances along the PT-CV axis. Samples are named according to their location within the liver lobule, with "PT" denoting samples abutting the portal triad, "CV" denoting samples abutting the central hepatic vein, and "Mid" sampled acquired midway between these structures. Normal human liver is thought to be generally quiescent, however clonal hepatocyte expansions have been observed but neither their cellular source nor their expansion dynamics have been determined. Knowing the hepatocyte cell of origin, and their subsequent dynamics and trajectory within the human liver will provide an important basis to understand disease-associated dysregulation. Here we use in vivo lineage tracing and a combination of methylation sequence analysis to demonstrate normal human hepatocyte ancestry. We exploit next generation mitochondrial sequencing to determine hepatocyte clonal expansion dynamics across spatially-distinct areas of laser-capture microdissected clones, in tandem with computational modelling in morphologically-normal human liver.

Study EGAS00001006984

Modulation of the peripheral blood immune cell transcriptome by vitamin D3 supplementation in people with a first demyelinating event: a randomized placebo-controlled trial

Vitamin D deficiency is a risk factor for developing multiple sclerosis (MS). Both in vitro and animal studies suggest an immunomodulatory effect of vitamin D. The PrevANZ trial, a phase IIb randomized placebo-controlled trial of oral vitamin D3 supplementation in people with a first demyelinating event (FDE), was conducted to determine if supplementation can prevent recurrent disease activity in this cohort at high risk of developing definite MS. As a sub-study of this trial, we used whole blood transcriptomic analyses to investigate the effect of vitamin D3 supplementation on peripheral immune cells in people with an FDE, and to gain insight into potential mechanisms by which vitamin D3 may regulate MS risk and disease activity. The PrevANZ trial randomized participants to 1000 IU, 5000 IU or 10,000 IU daily of oral vitamin D3 or placebo. Peripheral blood was collected at baseline and 12 weeks in PAXgene Blood RNA tubes. Transcriptomic datasets were generated by RNA sequencing.

Study EGAS00001007346

DERMATLAS__Leiomyoma_WES

Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyomas.

Study EGAS00001007629

GOSH_Childhood_Leukemia_Behjati_WellcomeCore_RNA

Paediatric single-cell archival project This project is taking sequential samples of children with B-cell acute lymphoblastic leukaemia (B-ALL) treated at Great Ormond Street Hospital (GOSH) between 2011 and the present day. Patients selected, are those that have done badly (e.g. had to escalate treatment, relapsed or died) despite having apparently ""good"" or ""intermediate"" risk cytogenetics, and often also had immunotherapy (e.g., the bi-specific T-cell engager blinatumomab) because of this. Using samples from key treatment-points, we hope to better characterise their disease and treatment response, to re-define understandings of risk for patients who did unexpectedly poorly. Additionally, we hope to define the disease/immunological factors that determine response to increasingly used immunotherapies within the field of paediatric B-ALL. Each of the samples will be viably frozen bone marrow-derived mononuclear cells. They will come in Eppendorf's, frozen and de-anonymised, from GOSH. We plan to primarily do single cell analysis (GEX, BCR +/-TCR), and then tumour-only WGS and bulk-RNA expression on left-over

Study EGAS00001007616

DERMATLAS__Leiomyoma_RNAseq

Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyomas.

Study EGAS00001007630

DERMATLAS__Leiomyosarcoma_RNAseq

Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyosarcomas.

Study EGAS00001007631

Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma

The embryonic transcription factor TBXT (brachyury) drives chordoma, a spinal neoplasm without effective drug therapies. TBXT’s regulatory network is poorly understood, and strategies to disrupt its activity for therapeutic purposes are lacking. We developed designed ankyrin repeat proteins that block TBXT-DNA binding (T-DARPins). In chordoma cells, T-DARPins reduced cell cycle progression, spheroid formation, and tumor growth in mice and induced signs of senescence and differentiation. Transcriptomic and proteomic analyses identified gene networks involved in cell cycle regulation, embryonic cell identity, and interferon response and revealed features of regulome components, such as druggability for future translational studies and the fine-tuning of TBXT downstream effectors through IGFBP3. Finally, we found high interferon signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with sensitivity to JAK2 inhibitors. These findings demonstrate the potential of DARPins for probing nuclear proteins to understand the regulatory networks of transcription factor-driven cancers, including entry points for therapies that warrant testing in patients.

Study EGAS00001008140

Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P-Rex1/Rac1 signalling

The estrogen receptor (ER) drives growth in ~70% of breast cancers, and endocrine therapies prevent recurrence. However, 30% of patients recur, with many fatal cases occurring late (after >5 years), presenting a challenge due to their often non-proliferative nature and limited options. To study this, we generated slow-growing resistant cells that form small primary tumours but readily metastasize. Single-cell RNA sequencing (scRNAseq) revealed that endocrine therapy reprograms these cells, notably upregulating the Rac1 signalling component P-Rex1. We found in clinical cohorts that P-Rex1 in high in ER+ breast cancer. Intravital imaging demonstrated that Rac1 signalling is active in ER+ cells following endocrine therapy. Targeting the Rac1 pathway with small molecule inhibitors (NSC23766, R-ketorolac) reduced survival and motility in resistant cells, inhibited in vivo Rac1 activity, and reduced tumour burden when combined with tamoxifen in a drug-refractory patient-derived xenograft. This work identifies the P-Rex1/Rac1 axis, as a potential therapeutic target for late recurring ER+ breast cancer.

Study EGAS00001008353

Somatic mutation and selection at epidemiological scale - Sanger_NanoSeq_RandD

Bottleneck sequencing of human tissue including neurons, cord blood, sperm This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/. As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations. Some of these clones represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding of the clonal landscapes of human tissues, and their impact on cancer risk, ageing and disease, remains limited due to the challenge of detecting somatic mutations present in small numbers of cells. Here, we introduce a new version of nanorate sequencing (NanoSeq), a duplex sequencing method with error rates of less than 5 per billion base pairs, which is compatible with whole-exome and targeted gene sequencing. Deep sequencing of polyclonal samples with single-molecule sensitivity enables the simultaneous detection of mutations in large numbers of clones, yielding accurate somatic mutation rates, mutational signatures and driver mutation frequencies in any tissue. Applying targeted NanoSeq to 1,042 non-invasive samples of oral epithelium and 371 samples of blood from a twin cohort, we found an unprecedentedly rich landscape of selection, with 46 genes under positive selection driving clonal expansions in the oral epithelium, over 62,000 driver mutations, and evidence of negative selection in some genes. The high number of positively selected mutations in multiple genes provides high-resolution maps of selection across coding and non-coding sites, a form of in vivo saturation mutagenesis. Multivariate regression models enable mutational epidemiology studies on how carcinogenic exposures and cancer risk factors, such as age, tobacco or alcohol, alter the acquisition and selection of somatic mutations. Accurate single-molecule sequencing has the potential to unveil the polyclonal landscape of any tissue, providing a powerful tool to study early carcinogenesis, cancer prevention and the role of somatic mutations in ageing and disease.

Dataset EGAD00001015624

Action to Control Cardiovascular Risk in Diabetes (ACCORD - Imaging)

Available DataAction to Control Cardiovascular Risk in Diabetes (ACCORD-Imaging), provides access to ECG signals data from the ACCORD clinical trial. The clinical phenotyping and outcomes data from the trial are associated with ACCORD-BioLINCC, phs003551.ObjectivesThe purpose of this study was to determine if intensive glycemic control, multiple lipid management and intensive blood pressure control could prevent major cardiovascular events (myocardial infarction, stroke or cardiovascular death) in adults with type 2 diabetes mellitus. Secondary hypotheses included treatment differences in other cardiovascular outcomes, total mortality, microvascular outcomes, health-related quality of life and cost-effectiveness.BackgroundGlycemia Trial:Patients with type 2 diabetes mellitus die of cardiovascular disease (CVD) at rates two to four times higher than non-diabetic populations of similar demographic characteristics. They also experience increased rates of nonfatal myocardial infarction and stroke. With the growing prevalence of obesity in the United States, CVD associated with type 2 diabetes is expected to become an even greater public health challenge in the coming decades than it is now. Expected increases in event rates will be associated with a concomitant rise in suffering and resource utilization.The ACCORD study investigated whether intensive therapy to target normal glycated hemoglobin (HbA1c) levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors when compared to standard therapy (HbA1c between 7.0% and 7.9%). A separate analysis investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in these patients.Lipid Therapy Trial:Patients with type 2 diabetes mellitus have an increased incidence of atherosclerotic cardiovascular disease attributable, in part, to associated risk factors such as dyslipidemia. This is characterized by elevated plasma triglyceride levels, low levels of high-density lipoprotein (HDL) cholesterol and small, dense low-density lipoprotein (LDL) particles. The ACCORD Lipid Therapy trial was designed to test the effect of a therapeutic strategy that uses a fibrate to raise HDL-C and lower triglyceride levels and uses a statin for treatment of LDL-C reduce the rate of CVD events compared to a strategy that only uses a statin for treatment of LDL-C on cardiovascular outcomes in patients with type 2 diabetes that were at high risk for cardiovascular disease.Blood Pressure Trial:Diabetes mellitus increases the risk of cardiovascular disease at every level of systolic blood pressure. Because cardiovascular risk in patients with diabetes is graded and continuous across the entire range of levels of systolic blood pressure, even at prehypertensive levels, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended beginning drug treatment in patients with diabetes who have systolic blood pressures of 130 mm Hg or higher, with a treatment goal of reducing systolic blood pressure to below 130 mm Hg. There is, however, a paucity of evidence from randomized clinical trials to support these recommendations. The ACCORD Blood Pressure trial tested the effect of a target systolic blood pressure below 120 mm Hg on major cardiovascular events among high-risk persons with type 2 diabetes compared to a strategy that targeted a SBP of EYE Substudy:Diabetic retinopathy, an important microvascular complication of diabetes, is a leading cause of blindness in the United States. Randomized, controlled clinical trials in cohorts of patients with type 1 diabetes and those with type 2 diabetes have shown the beneficial effects of intensive glycemic control and intensive treatment of elevated blood pressure on the progression of diabetic retinopathy. Elevated serum cholesterol and triglyceride levels have been implicated, in observational studies and small trials, as additional risk factors for the development of diabetic retinopathy and visual loss. The ACCORD EYE Substudy evaluated the effects of the ACCORD medical strategies on the progression of diabetic retinopathy in a subgroup of trial patients.MIND Substudy:Studies suggest that older persons with type 2 diabetes have at least twice the likelihood of developing late-life cognitive impairment or dementia compared to those without. The mechanisms underlying these cognitive disorders are increasingly thought to reflect a mixed pathology pattern with contributions from vascular, neurodegenerative and neurovascular processes. Pathophysiological mechanisms that have been described include inflammation, oxidative stress, energy imbalance, protein misfolding, glucocorticoid-mediated effects and differences in genetic susceptibilities. The ACCORD MIND substudy took as a premise that early intervention with the ACCORD therapeutic strategies to improve glycemic control could mitigate the adverse effects of type 2 diabetes on the brain.Subjects10,251 patients with type 2 diabetes and HbA1c concentrations of 7.5% or more participated in the trial. Of these patients, 5518 were assigned to the lipid therapy arm and 4733 to the blood pressure arm. EYE Substudy:A subgroup of 2856 patients was evaluated for the effects of the ACCORD interventions at 4 years on the progression of diabetic retinopathy. Patients who, at baseline, had a history of proliferative diabetic retinopathy that had been treated with laser photocoagulation or vitrectomy were excluded.MIND Substudy:A subgroup of 2977 patients was evaluated for cognitive function and brain volume. The ACCORD MIND substudy excluded patients aged DesignPatients were randomly assigned to undergo either intensive glycemic control (targeting a glycated hemoglobin level EYE Substudy:EYE Substudy patients were evaluated at two standardized and comprehensive eye examinations for the effects of the ACCORD interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy.MIND Substudy:The cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, was assessed at baseline, 20 and 40 months. Total brain volume (TBV), the primary brain structure outcome, was assessed with MRI at baseline and 40 months in a sub-set of 632 patients. All patients with follow-up data were included in the primary analyses.ConclusionsGlycemia Trial:As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. (NEJM. 2008; 358(24): 2545-59).Microvascular Outcomes of the Glycemia Trial:Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Microvascular benefits of intensive therapy should be weighed against the risk of increased total and cardiovascular disease-related mortality, increased weight gain, and higher risk for severe hypoglycemia. (Lancet. 2010; 376(9739): 419-30)Lipid Therapy Trial:The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes (NEJM. 2010; 362(17): 1563–1574).Blood Pressure Trial:In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events (NEJM. 2010; 362: 1575-1585).EYE Substudy:Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy (NEJM. 2010; 363: 233-244).MIND Substudy:Although significant differences in TBV favored the intensive therapy, cognitive outcomes were not different. Combined with the unfavorable effects on other ACCORD outcomes, MIND findings do not support using intensive therapy to reduce the adverse effects of diabetes on the brain in patients similar to MIND patients (Lancet Neurol. 2011; 10(11): 969–977).

Study phs003562

Framingham Cohort

Startup of Framingham Heart Study. Cardiovascular disease (CVD) is the leading cause of death and serious illness in the United States. In 1948, the Framingham Heart Study (FHS) -- under the direction of the National Heart Institute (now known as the National Heart, Lung, and Blood Institute, NHLBI) -- embarked on a novel and ambitious project in health research. At the time, little was known about the general causes of heart disease and stroke, but the death rates for CVD had been increasing steadily since the beginning of the century and had become an American epidemic. The objective of the FHS was to identify the common factors or characteristics that contribute to CVD by following its development over a long period of time in a large group of participants who had not yet developed overt symptoms of CVD or suffered a heart attack or stroke. Design of Framingham Heart Study. In 1948, the researchers recruited 5,209 men and women between the ages of 30 and 62 from the town of Framingham, Massachusetts, and began the first round of extensive physical examinations and lifestyle interviews that they would later analyze for common patterns related to CVD development. Since 1948, the subjects have returned to the study every two years for an examination consisting of a detailed medical history, physical examination, and laboratory tests, and in 1971, the study enrolled a second-generation cohort -- 5,124 of the original participants' adult children and their spouses -- to participate in similar examinations. The second examination of the Offspring cohort occurred eight years after the first examination, and subsequent examinations have occurred approximately every four years thereafter. In April 2002 the Study entered a new phase: the enrollment of a third generation of participants, the grandchildren of the original cohort. The first examination of the Third Generation Study was completed in July 2005 and involved 4,095 participants. Thus, the FHS has evolved into a prospective, community-based, three generation family study. The FHS is a joint project of the National Heart, Lung and Blood Institute and Boston University. Research Areas in the Framingham Heart Study. Over the years, careful monitoring of the FHS population has led to the identification of the major CVD risk factors -- high blood pressure, high blood cholesterol, smoking, obesity, diabetes, and physical inactivity -- as well as a great deal of valuable information on the effects of related factors such as blood triglyceride and HDL cholesterol levels, age, gender, and psychosocial issues. Risk factors have been identified for the major components of CVD, including coronary heart disease, stroke, intermittent claudication, and heart failure. It is also clear from research in the FHS and other studies that substantial subclinical vascular disease occurs in the blood vessels, heart and brain that precedes clinical CVD. With recent advances in technology, the FHS has enhanced its research capabilities and capitalized on its inherent resources by the conduct of high resolution imaging to detect and quantify subclinical vascular disease in the major blood vessels, heart and brain. These studies have included ultrasound studies of the heart (echocardiography) and carotid arteries, computed tomography studies of the heart and aorta, and magnetic resonance imaging studies of the brain, heart, and aorta. Although the Framingham cohort is primarily white, the importance of the major CVD risk factors identified in this group have been shown in other studies to apply almost universally among racial and ethnic groups, even though the patterns of distribution may vary from group to group. In the past half century, the Study has produced approximately 1,200 articles in leading medical journals. The concept of CVD risk factors has become an integral part of the modern medical curriculum and has led to the development of effective treatment and preventive strategies in clinical practice. In addition to research studies focused on risk factors, subclinical CVD and clinically apparent CVD, Framingham investigators have also collaborated with leading researchers from around the country and throughout the world on projects involving some of the major chronic illnesses in men and women, including dementia, osteoporosis and arthritis, nutritional deficiencies, eye diseases, hearing disorders, and chronic obstructive lung diseases. Genetic Research in the Framingham Heart Study. While pursuing the Study's established research goals, the NHLBI and the Framingham investigators has expanded its research mission into the study of genetic factors underlying CVD and other disorders. Over the past two decades, DNA has been collected from blood samples and from immortalized cell lines obtained from Original Cohort participants, members of the Offspring Cohort and the Third Generation Cohort. Several large-scale genotyping projects have been conducted in the past decade. Genome-wide linkage analysis has been conducted using genotypes of approximately 400 microsatellite markers that have been completed in over 9,300 subjects in all three generations. Analyses using microsatellite markers completed in the original cohort and offspring cohorts have resulted in over 100 publications, including many publications from the Genetics Analysis Workshop 13. Several other recent collaborative projects have completed thousands of SNP genotypes for candidate gene regions in subsets of FHS subjects with available DNA. These projects include the Cardiogenomics Program of the NHLBI's Programs for Genomics Applications, the genotyping of ~3000 SNPs in inflammation genes, and the completion of a genome-wide scan of 100,000 SNPs using the Affymetrix 100K Genechip. Framingham Cohort Phenotype Data. The phenotype database contains a vast array of phenotype information available in all three generations. These will include the quantitative measures of the major risk factors such as systolic blood pressure, total and HDL cholesterol, fasting glucose, and cigarette use, as well as anthropomorphic measures such as body mass index, biomarkers such as fibrinogen and CRP, and electrocardiography measures such as the QT interval. Many of these measures have been collected repeatedly in the original and offspring cohorts. Also included in the SHARe database will be an array of recently collected biomarkers, subclinical disease imaging measures, clinical CVD outcomes as well as an array of ancillary studies. The phenotype data is located here in the top-level study phs000007 Framingham Cohort. To view the phenotype variables collected from the Framingham Cohort, please click on the "Variables" tab above. The Framingham Cohort is utilized in the following dbGaP substudies. To view genotypes, analysis, expression data, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" section of this top-level study page phs000007 Framingham Cohort. phs000342 Framingham SHARe phs000282 Framingham CARe phs000363 Framingham SABRe phs000307 Framingham Medical Resequencing phs000401 Framingham ESP Heart-GO phs000651 Framingham CHARGE-S phs000724 Framingham DNA Methylation phs001610 Framingham T2D-GENES phs002558 Framingham ADSP phs002559 Framingham BRIDGET phs002560 Framingham Cholesterol phs002611 Framingham Post-Mortem Brain Tissue phs002938 Framingham Molecular QTL The unflagging commitment of the research participants in the NHLBI FHS has made more than a half century of research success possible. For decades, the FHS has made its data and DNA widely available to qualified investigators throughout the world through the Limited Access Datasets and the FHS DNA Committee, and the SHARe database will continue that tradition by allowing access to qualified investigators who agree to the requirements of data access. With the SHARe database, we continue with an ambitious research agenda and look forward to new discoveries in the decades to come.

Study phs000007

National Human Genome Research Institute (NHGRI) GENEVA Genome-Wide Association Study of Venous Thrombosis (GWAS of VTE)

Overview: Our overall long-term goal is to determine risk factors for the complex (multifactorial) disease, venous thromboembolism (VTE), that will allow physicians to stratify individual patient risk and target VTE prophylaxis to those who would benefit most. In this genome-wide association case-control study (1300 cases and 1300 controls) we hope to identify susceptibility variants for VTE. Mutations within genes encoding for important components of the anticoagulant, procoagulant, fibrinolytic, and innate immunity pathways are risk factors for VTE. We hypothesize that other genes within these four pathways or within other pathways also are VTE disease-susceptibility genes. Therefore, we performed a genome wide association (GWA) screen and analysis using the Illumina 660W platform to identify SNPs within 1,300 clinic-based, non-cancer VTE cases primarily from Minnesota and the upper Midwest USA, and 1300 clinic-based, unrelated controls frequency-matched on patient age, gender, myocardial infarction/stroke status and state of residence. This is a subset of a slightly larger candidate gene study using 1500 case-control pairs to identify haplotype-tagging SNPs (ht-SNPs) in a large set of candidate genes (n~750) within the anticoagulant, procoagulant, fibrinolytic, and innate immunity pathways. Study Populations. Cases. VTE cases were consecutive Mayo Clinic outpatients with objectively-diagnosed deep vein thrombosis (DVT) and/or pulmonary embolism (PE) residing in the upper Midwest and referred by Mayo Clinic physician to the Mayo Clinic Special Coagulation Laboratory for clinical diagnostic testing to evaluate for an acquired or inherited thrombophilia, or to the Mayo Clinic Thrombophilia Center. Any person contacted to be a control but discovered to have had a VTE was evaluated for inclusion as a case. Cases were primarily residents from Minnesota, Wisconsin, Iowa, Michigan, Illinois, North or South Dakota, Nebraska, Kansas, Missouri and Indiana. A DVT or PE was categorized as objectively diagnosed when (a) confirmed by venography or pulmonary angiography, or pathology examination of thrombus removed at surgery, or (b) if at least one non-invasive test (compression duplex ultrasonography, lung scan, computed tomography scan, magnetic resonance imaging) was positive. A VTE was defined as: Proximal leg deep vein thrombosis (DVT), which includes the common iliac, internal iliac, external iliac, common femoral, superficial [now termed "femoral"] femoral, deep femoral [sometimes referred to as "profunda" femoral] and/or popliteal veins. (Note: greater and lesser saphenous veins, or other superficial or perforator veins, were not included as proximal or distal leg DVT). Distal leg DVT (or "isolated calf DVT"), which includes the anterior tibial, posterior tibial and/or peroneal veins. (Note: gastrocnemius, soleal and/or sural [e.g., "deep muscular veins" of the calf] vein thrombosis was not included as distal leg DVT). Arm DVT, which includes the axillary, subclavian and/or innominate (brachiocephalic) veins. (Note: jugular [internal or external], cephalic and brachial vein thrombosis was not included in "arm DVT"). Hepatic, portal, splenic, superior or inferior mesenteric, and/or renal vein thrombosis. (Note: ovarian, testicular, peri-prostatic and/or pelvic vein thrombosis was not included). Cerebral vein thrombosis (includes cerebral or dural sinus or vein, saggital sinus or vein, and/or transverse sinus or vein thrombosis). Inferior vena cava (IVC) thrombosis Superior vena cava (SVC) thrombosis Pulmonary embolism Patients with VTE related to active cancer, antiphospholipid syndrome, inflammatory bowel disease, vasculitis, a rheumatoid or other autoimmune disorder, a vascular anomaly (e.g., Klippel-Trénaunay syndrome, etc.), heparin-induced thrombocytopenia, or a mechanical cause for DVT (e.g., arm DVT or SVC thrombosis related to a central venous catheter or transvenous pacemaker, portal and/or splenic vein thrombosis related to liver cirrhosis, IVC thrombosis related to retroperitoneal fibrosis, etc.), with hemodialysis arteriovenous fistula thrombosis, or with prior liver or bone marrow transplantation were excluded. Controls. A Mayo Clinic outpatient control group was prospectively recruited for this study. Controls were frequency-matched on the age group (18-29, 30-39, 40-49, 50-59, 60-69, 70-79, and 80+ years), sex, myocardial infarction/stroke status, and state of residence distribution of the cases. We selected clinic-based controls using a controls' database of persons undergoing general medical examinations in the Mayo Clinic Departments of General Internal Medicine or Primary Care Internal Medicine. Additionally persons undergoing evaluation at the Mayo Clinic Sports Medicine Center, and the Department of Family Medicine were screened for inclusion as controls. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to venous thrombosis through large-scale genome-wide association studies of 1,300 clinic-based, VTE cases and 1300 clinic-based, unrelated controls. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

Study phs000289

Incentives and Case Management to Improve Cardiac Care: Healthy Lifestyle Program (HeLP)

Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this study.Objectives: The HeLP study assessed how early case management, financial incentives contingent on cardiac-rehabilitation attendance, or both impacted adherence to cardiac rehabilitation among patients with lower socioeconomic status (SES) who had a cardiac-rehabilitation-qualifying diagnosis. Background:Cardiovascular disease (CVD) is the leading cause of death in the United States. Regular attendance at cardiac rehabilitation (CR) is the number one recommendation for patients who have experienced a recent cardiac event. CR is a secondary prevention outpatient program involving an individually tailored structured exercise program along with counseling and encouragement regarding lifestyle changes to reduce the recurrence of major cardiac events.Despite the benefits of CR attendance, enrollment and adherence to the program are low. This is particularly true of individuals of lower socioeconomic status (SES), who also generally suffer a higher burden from CVD on account of higher-risk cardiac profiles. As these profiles are the result of modifiable behavior targeted by CR (i.e., smoking, obesity, lack of physical activity), methods of increasing CR attendance among this population are necessary.Case management and financial incentives contingent on CR attendance are two potential strategies for addressing this issue. Previous studies have shown how trained case managers can support and assist patients with attending CR and improving their cardiac health, and how financial incentives can promote various types of health-related behavior. The purpose of the present study was to evaluate how these two interventions, individually and in tandem, fared at improving CR adherence among individuals of lower SES specifically. Participants:A total of 314 participants were screened, and 209 were randomized. All consented to have their data shared for research purposes. Design:Eligible patients were approached either while still in the hospital or during initial visits to CR. After obtaining informed consent, clinical and demographic characteristics (i.e., age, sex, education, race and ethnicity, smoking status, and CR-qualifying diagnosis) and depressive symptoms were collected. Participants then were randomized 2:3:3:3 to usual care (UC), case management starting in hospital (CM), financial incentives for attending CR (FI), or financial incentives plus case management (FICM). For all participants regardless of condition, an appropriate referral for CR was confirmed after randomization. Over the course of the study participants completed three assessments – one at intake, one after four months, and one after one year. Clinical (i.e., cardiorespiratory fitness, body composition, and cardiac-related quality of life) and sociocognitive (i.e., Beck Depression Inventory, Achenbach System of Empirically Based Assessment, and Behavior Rating Inventory of Executive Function) measures were obtained at each assessment. Participants randomized to the UC condition were contacted weekly by study staff for adverse event checks, but received no additional intervention. Participants randomized to the CM condition were immediately assigned a case manager. Case managers met with their participants, usually within 24 hours of consent while they were still in the hospital, to introduce themselves during an initial check-in. Within the first week of consent they completed a longer, more thorough initial needs assessment with their participant and established behavioral goals. For the next 16 weeks, case managers met with their participants at least once a week, typically over the phone, to discuss progress on these goals and address any problems or barriers that had arisen. Case managers also were available via phone outside of these regular meetings during normal working hours and Saturday mornings. Participants randomized to the FI condition could earn money for completing an initial CR orientation and attending CR sessions. Twenty dollars could be earned for completing the CR orientation session. CR attendance was reinforced on an escalating schedule starting at $10. Payments increased by $2 for each successive session attended, and capped out at a maximum of $40 per session. Unexcused absences resulted in the incentives for that session not being earned, and the potential earnings for the next scheduled session being reset to $10. Successful participation of two consecutive sessions following the reset resulted in the incentives being returned to the amount prior to the reset. In total, participants could earn $1220 for attending the initial orientation and all 36 sessions of CR. The primary outcome of interest was the percentage of participants who completed at least 30 sessions of CR. Secondary outcomes included the number of sessions completed, cardiorespiratory fitness (peak VO2 and estimated metabolic equivalents (METs)), body composition (waist circumference and BMI), depression scores, and both general and cardiac-related qualify of life. Conclusions:The two interventions involving financial incentives (i.e., financial incentives alone and financial incentives plus case management) significantly improved CR adherence compared to usual care. Subsequent analyses revealed that the combination of financial incentives and case management led to greater improvements in CR attendance than financial incentives alone.

Study phs003737

Sleep Heart Health Study (SHHS-BioLINCC)

Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.Related StudiesParent cohort phenotype data can be accessed through ARIC-BioLINCC, Framingham-BioLINCC, and CHS-BioLINCC. Objectives To determine the cardiovascular and other consequences of sleep-disordered breathing and to test whether sleep-disordered breathing is associated with an increased risk of coronary heart disease, stroke, all-cause mortality and hypertension by examining subjects from well-characterized and established epidemiologic cohorts. Background Obstructive sleep apnea syndrome (OSA) is a potentially debilitating condition characterized by repetitive episodes of apnea while asleep, nocturnal oxygen desaturation, excessive daytime sleepiness, and loud disruptive snoring. Epidemiologic data from middle-aged adults indicate that OSA is common, with prevalence rates of 4% in men and 2% in women. Prior studies implicated OSA as a risk factor for the development of hypertension, ischemic heart disease, congestive heart failure, stroke and consequently premature death. Questions arose as to whether an increased propensity for cardiovascular and cerebrovascular diseases was limited to only those with frank OSA or whether more subtle forms of sleep-disordered breathing (SDB) would also confer elevated risk. Further evidence was also needed to clarify whether, SDB, including OSA, is an independent risk factor for the development of cardiovascular or cerebrovascular disease. Known cardiovascular and cerebrovascular disease risk factors such as obesity and smoking are commonly present in those with SDB; therefore, apparent associations between SDB and cardiovascular and cerebrovascular diseases may have resulted from the effects of these concomitant risk factors. Moreover, there was no understanding as to whether such factors as race, age, gender, and prevalent cardiovascular or cerebrovascular disease might interact with SDB to alter future cardiovascular and cerebrovascular disease risk. Mechanisms underlying any propensity to develop cardiovascular or cerebrovascular disease with SDB had not been firmly established (Quan, et al., 1997, PMID: 9493915). Participants Participants in SHHS were recruited from nine existing NHLBI epidemiological studies in which data on cardiovascular risk factors had been collected previously. The “parent” cohorts included: Two sites of the Atherosclerosis Risk in Communities Study (ARIC) Three sites of the Cardiovascular Health Study (CHS) The Framingham Offspring Cohort The Strong Heart Study (SHS) sites in South Dakota, Oklahoma, and Arizona The New York Hypertension Cohorts The Tucson Epidemiologic Study of Airways Obstructive Diseases and the Health and Environment Study From these parent cohorts, a sample of participants who met the inclusion criteria (age 40 years or older; no history of treatment of sleep apnea; no tracheostomy; no current home oxygen therapy) was invited to participate in the baseline examination of the SHHS, which included an initial polysomnogram (SHHS-1). Several cohorts over-sampled snorers in order to increase the study-wide prevalence of sleep-disordered breathing. In all, 6441 individuals were enrolled between November 1, 1995 and January 31, 1998. During exam cycle 3 (January 2001-June 2003), a second polysomnogram (SHHS-2) was obtained in 3295 of the participants. Due to sovereignty issues, Strong Heart Study participants are not included in the shared SHHS data. Data from a total of 5839 participants (1920 ARIC, 1249 CHS, 997 Framingham Offspring and OMNI 1, and 1673 from other studies), consenting to share data are available. Design The Sleep Heart Health Study added in-home polysomnography to the data collected in each of the parent studies at a baseline SHHS exam and a follow-up approximately 4 years later. Using the Compumedics PS polysomnograph, sleep studies were obtained in an unattended setting, usually in the homes of the participants, by trained and certified technicians. The recording montage consisted of: C3/A2 and C4/A1 EEGs, sampled at 125 Hz right and left electrooculograms (EOGs), sampled at 50 Hz a bipolar submental electromyogram (EMG), sampled at 125 Hz thoracic and abdominal excursions (THOR and ABDO), recorded by inductive plethysmography bands and sampled at 10 Hz "airflow" detected by a nasal-oral thermocouple (Protec, Woodinville, WA), sampled at 10 Hz finger-tip pulse oximetry (Nonin, Minneapolis, MN) sampled at 1 Hz ECG from a bipolar lead, sampled at 125 Hz for most SHHS-1 studies and 250 Hz for SHHS-2 studies Heart rate (PR) derived from the ECG and sampled at 1 Hz body position (using a mercury gauge sensor) ambient light (on/off, by a light sensor secured to the recording garment)This montage provides data on the occurrence of sleep-disordered breathing, sleep stages, heart rate, oximetry and on arousals. Each participant in the parent studies was also asked to complete the Sleep Habits Questionnaire which covers usual sleep pattern, snoring, and sleepiness.

Study phs003637

HELIUS DAC The HELIUS data are owned by the Amsterdam University Medical Centers, location AMC in Amsterdam, The Netherlands. To allow sharing of microbiome data collected in HELIUS with (inter)national researchers, 16s rRNA sequence analysis has been stored at the European genome-phenome archive (EGA; accession code EGAD00001004106). This requires that access needs to be granted, also because the HELIUS data are stored with relevant phenotypical variables. Access is granted to all researchers affiliated with an internationally recognized research institution who request to use the HELIUS data within the EGA context, after having signed the data transfer agreement. Any researcher can request the data by submitting a proposal to the HELIUS Executive Board as outlined at http://www.heliusstudy.nl/en/researchers/collaboration, by email: heliuscoordinator at amsterdamumc dot nl. The HELIUS Executive Board will check proposals if they do not conflict with ethical approvals and informed consent forms of the HELIUS study.

Dac EGAC00001000895

RNA-Seq of human longitudinal whole blood samples from PCR-positive and PCR-negative recent household contacts of COVID-19 index cases.

Little is known about the transcriptomic profile of individuals who are exposed to SARS-CoV-2 yet resist becoming PCR positive. To investigate this, longitudinal whole-blood samples were taken (0, 7, 14, and 28 days after enrolment) from PCR positive and PCR negative SARS-CoV-2-naïve household contacts who were recently exposed to a COVID-19 index. Samples were also taken from pre- and post-pandemic unexposed controls. Total RNA was extracted from PAXgene tubes before undergoing poly(A) selection followed by globin and rRNA depletion. DNA libraries were constructed using the NEBNext® Ultra™ II Directional RNA Library Prep Kit for Illumina. All samples were then sequenced across 2 flowcells of an Illumina HiSeq 4000.

Dataset EGAD50000000684

Whole Exome Sequencing of controls performed at the Broad Institute on a cohort from Bristol, UK

These data were generated as part of a collaboration between University of Bristol, UK and the Stanley Center at the Broad Institute. This project sequenced and analysed the whole exomes of 2969 samples from the Avon Longitudinal Study of Parents and Children (ALSPAC). ALSPAC is a population-based pregnancy cohort with participants acting as ‘controls’ for this project. Genomic DNA from each sample was sequenced to a mean depth of 20x. The exome used Twist capture and samples were sequenced on Illumina NovaSeq 6000 machines producing CRAM files. ALSPAC recruited pregnant women in the Avon County of south-west England between 1991 and 1992. Of the 15,447 pregnancies, 14,901 children were alive at 1 year of age. DNA was extracted from child blood samples taken between ages 7 and 24.

Dataset EGAD50000000716

ProstOmics - Spatial Transcriptomics

Spatial transcriptomics data (ST) from 32 human prostate tissue samples originating from 8 prostate cancer patients (5 patients with post-surgery relapse). The ST data was acquired using the Visium Spatial Gene Expression kit which resulted in over 20 000 spatially defined spots for the 32 tissue samples. The raw transcriptomics data is RNA-seq. The individual samples have information on patient origin and sample type (cancer, cancer-adjacent field-effect normal or normal sample far from cancer). Each ST spot has metadata such as sample origin, histology class (stroma, normal epithelium, cancer of various grading etc), number of cells and estimated cell type fractions. Patient metadata include information of age at surgery, time (months) until reported relapse, total follow-up time, pre-surgery PSA, post-surgery T-stage and metastasis status.

Dataset EGAD50000000603

Low T cell diversity is associated with poor outcome in bladder cancer - Single cell RNAseq and TCRseq data

T cells are crucial effector cells in the endogenous defense against cancer, yet the clinical impact of their quantity, diversity, and dynamics remains underexplored. In this study we performed single cell RNAseq paired with single cell TCR-seq on tumor and blood samples from 4 patients (n samples = 8). The goal was to investigate T cell subtypes of expanded and non-expanded T cell clones in blood and in tumors.

Study EGAS50000000938

Emirati Genome Project Population Variome (MAF Table)

The Emirati Genome Project (EGP) Variome comprises allele frequency data derived from 43,608 individuals sequenced as part of the national genome program in the United Arab Emirates. Samples were processed at the M42 EGP Facility and sequenced to a minimum of 30x coverage using Illumina NovaSeq 6000 short-read technology. Variant calling and alignment were performed using the DRAGEN pipeline (v3.9) against the GRCh38 reference genome. This dataset contains a total of 421,605,069 short variants (SNVs and indels), stored in VCF format. Each variant is annotated with population-level metrics in the INFO field, including: AC (alternate allele count) AF (alternate allele frequency) RC (reference allele count) RF (reference allele frequency) For convenience, VCF files are split by chromosome (chr1–22, X, Y), compressed and indexed using bgzip and tabix.

Dataset EGAD50000001558

RNA sequencing of untreated head and neck cancer patient-derived xenografts (PDXs) and matched patient tumor tissue.

RNA sequencing was performed on untreated patient tumor tissue and matched patient-derived xenograft (PDX) models of primary head and neck squamous cell carcinoma (HNSCC). The aim of this analysis was to characterize the transcriptional landscape of the tumors in the in vivo setting. 117 total samples were sequenced with paired reads on 10 lanes from different flowcells. They were loaded as 2400 separate files to maintain the data as it was received from BGI - each sample is therefore composed of 5 separate EGAN with 4 files each, adding a 0.1 - .. - 0.5 to each BioSample ID to generate sample aliases. All R1 (and R2, separately) files referring to a BioSample ID should be concatenated to obtain fastq files corresponding to single patients or PDXs.

Dataset EGAD50000002278

Whole-exome sequencing (WES) analysis of untreated head and neck cancer patient-derived xenografts (PDXs) matched patient tumor tissue and normal mucosa tissue.

WES analysis was performed on untreated patient tumor/normal mucosa tissue and matched patient-derived xenograft (PDX) models of primary head and neck squamous cell carcinoma (HNSCC) to investigate the preservation of tumor-specific genomic alterations in the in vivo context. 183 total samples were sequenced with paired reads on 8-10 lanes from different flowcells. They were loaded as 3538 separate files to maintain the data as it was received from BGI - each sample is therefore composed of 5 separate EGAN with 2-4 files each, adding a 0.1 - .. - 0.5 to each BioSample ID to generate sample aliases. All R1 (and R2, separately) files referring to a BioSample ID should be concatenated to obtain fastq files corresponding to single patients or PDXs.

Dataset EGAD50000002325

Evaluation of protocols for rRNA depletion-based RNA sequencing of nanogram inputs of mammalian total RNA

Next generation RNA-Sequencing (RNA-seq) is a flexible approach that can be applied to e.g. global quantification of transcript expression, the characterization of RNA structure such as splicing patterns and profiling of expressed mutations. Many RNA-seq protocols require up to microgram levels of total RNA input amounts to generate high quality data, and thus remain impractical for the limited starting material amounts typically obtained from rare cell populations, such as those from early developmental stages or from laser micro-dissected clinical samples. Here, we present an assessment of the contemporary ribosomal RNA depletion-based protocols, and identify those that are suitable for inputs as low as 1-10 ng of intact total RNA and 100-500 ng of partially degraded RNA from formalin-fixed paraffin-embedded tissues.

Dataset EGAD00001005316

Single nuclei sequencing of early, late-term, and early-onset pre-eclamptic decidua and villi.

Hypertensive disorders in pregnancy, of which the multisystem syndrome pre-eclampsia is the most severe, leading to preterm delivery, maternal mortality, and life-long complications. To elucidate early disease dynamics, we present the first spatio-temporal study comparing single-nuclei transcriptomes of human preterm pre-eclamptic placentae and healthy controls, contextualizing this in a comprehensive study including early and late gestational placentae. This study includes early placentae samples from the fetal part (villi; n=10), maternal part (Decidua; n=3), late placentae samples from healthy pregnancies, villi (n=6), decidua (n=4), and late placentae samples from early-onset preeclamptic pregnancies, villi (n=5) and decidua (n=5).

Dataset EGAD00001008273

Cholangiocarcinoma

Arcagen is an EORTC/SPECTA pan-European project that aims to recruit 1000 rare cancer patients from different tumour domains of EURACAN. This study collected samples from advanced or metastatic rare cancer from patients older than 12, and analysed them using Foundation Medicine next-generation sequencing (NGS) panels (FoundationOne CDx for FFPE samples or FoundationOne Liquid CDx for blood samples). Here we are submitting two datasets that contain NGS files from gastrointestinal rare cancers (n=119): - Dataset 2 (87 patients): Intra-hepatic cholangiocarcinoma (n=47), Extra-hepatic, cholangiocarcinoma (n=16), Not specified Cholangiocarcinoma (n=9), Small bowel adenocarcinoma (n=6) and other rare GI cancer (n=9)

Dataset EGAD00001008968

Systemic mutagen exposures reported by normal kidney cell genomes - peripheral blood samples (NanoSeq)

Lifestyle, environmental and other exposures to exogenous mutagens generate somatic mutations in normal human cells in vivo and increase cancer risk. However, the global repertoire of exogenous mutagen exposures is uncertain. Using single-molecule duplex sequencing of normal kidney (n=319) and blood (n=272) samples from 10 countries, we show that kidney proximal tubule cells exhibit higher mutation rates than most normal cell types despite low cell division rates. Compared to cells from kidney glomeruli, medulla, distal tubules, or peripheral blood, proximal tubule cells show marked enrichment of mutational signatures due to the exogenous carcinogenic mutagens, aristolochic acids, and of several signatures of unknown causes. The results suggest the existence of multiple, common, systemically circulated mutagens affecting human populations and indicate that the genomes of kidney proximal tubule cells report such exposures with high sensitivity.

Dataset EGAD00001015824

Resequencing candidate genes for male spermatogenic impairment

This study aims to identify novel candidate variants from human Y-chromosomal genes DAZ, BPY2 and CDY1/2 by resequencing the coding regions of these genes from male patients with spermatogenic impairment. The coding regions of the genes plus a selection of phylogenetically informative Y-chromosomal markers have been amplified by standard PCR, amplicon lengths range from 178 to 486 bp. Amplicons were quantified by gel electrophoresis and pooled in approx. equimolar concentrations per patient. For each of the 480 submitted samples, approx. 1 microgram of amplified DNA pool was provided in a total volume of 120 microlitres. The samples were indexed and libraries prepared for PE250bp Illumina MiSeq runs. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ .

Dataset EGAD00001006784

Identification of immune mechanisms associated with the high rate of relapse in patient with visceral leishmaniasis and HIV co-infection

RNA-seq transcriptomics of whole blood samples from longitudinal follow-up of a cohort of visceral leishmaniasis (VL) patients with and without HIV coinfection, from active disease through apparent cure and potential relapse. Analysis will identify potential correlates of relapse to identify immune mechanisms underlying the high rate of relapse in HIV/VL coinfection. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ .

Dataset EGAD00001008361

Full blood mRNA sequencing of myotonic dystrophy type 1 patients after cognitive behavioural therapy

This dataset consists of 60 mRNA sequencing runs from full blood of 31 myotonic dystrophy type 1 patients, of which for 27 patients reliable data is available before and after 10 months of cognitive behavioural therapy. >30 million 150 bp paired end reads were obtained with UMI-labeled adapters to facilitate filtering of PCR duplicates. Via UMI-analysis we found samples with the aliases sample_01 and sample_02 to contain a very high number of PCR duplicates and recommend the use of these samples only with highest caution or not at all.

Dataset EGAD00001008383

Low-coverage whole genome sequencing for a highly selective cohort of severe COVID-19 patients

We generated a dataset consisting of 79 VCF files, and respective FASTQ and CRAM files, methodically generated using the GLIMPSE1 imputation algorithm leveraging the 1000 Genomes Project Phase 3 dataset as the reference panel of haplotypes. In total this dataset is composed of approximately 325 GB of FASTQ data, 156 GB of CRAM data, and 6 GB of VCF data. Our samples were specifically derived from sequenced DNA from a highly selective cohort of patients, mostly comprised of Iberian Populations in Spain (IBS) individuals but also containing some individuals with other genetic backgrounds, who presented severe COVID-19 symptoms during the initial wave of the SARS-CoV-2 pandemic in Madrid, Spain. On average, each VCF file in this rich dataset contains 9.49 million high-confidence single nucleotide variants [95%CI: 9.37 million - 9.61 million].

Dataset EGAD00001011363

Genomic Evolution of Breast Cancer Metastasis and Relapse

Recurrent breast cancer is almost universally fatal. We characterize 170 patients locally relapsed or distant metastatic cancers using massively parallel sequencing. We identify that the relapse-seeding clone disseminates late from the primary tumor. TP53 and AKT1 appear to be enriched in ER-positive cancers predisposed to relapse. Mutation acquisition continues at relapse as the same mutation signatures continue to operate and new signatures, such as that caused by radiotherapy appear de novo. In 49% of cases we identify drivers mutations private to the relapse and these are sampled from a wider range of cancer genes, including SWI-SNF complex and JAK-STAT signaling.

Dataset EGAD00001002696

Systemic mutagen exposures reported by normal kidney cell genomes - microdissected kidney samples (NanoSeq)

Lifestyle, environmental and other exposures to exogenous mutagens generate somatic mutations in normal human cells in vivo and increase cancer risk. However, the global repertoire of exogenous mutagen exposures is uncertain. Using single-molecule duplex sequencing of normal kidney (n=319) and blood (n=272) samples from 10 countries, we show that kidney proximal tubule cells exhibit higher mutation rates than most normal cell types despite low cell division rates. Compared to cells from kidney glomeruli, medulla, distal tubules, or peripheral blood, proximal tubule cells show marked enrichment of mutational signatures due to the exogenous carcinogenic mutagens, aristolochic acids, and of several signatures of unknown causes. The results suggest the existence of multiple, common, systemically circulated mutagens affecting human populations and indicate that the genomes of kidney proximal tubule cells report such exposures with high sensitivity.

Dataset EGAD00001015827

Acral Melanoma PDXs from the admixed Brazilian Population- Tumour RNA expression data - htseq count files

Files containing the read counts obtained with obtained with HTSeq for all the genes in Ensembl v103 annotation for GRCh38 human reference genome. This dataset contains the files for all Tumour samples. Acral melanoma (AM) is an aggressive melanoma subtype with limited therapeutic options and poor outcomes. In non-European descent and admixed populations, like in Latin America, it can account for a significant proportion of cutaneous melanoma cases. Here, we performed comprehensive genomic and functional profiling of AM from a uniquely diverse Brazilian cohort. Whole-exome and transcriptome sequencing was performed on both tumours and patient-derived xenograft (PDX) samples. The PDX were obtained from a comprehensive collection of patient-derived xenograft (AM-PDX) models that we established which faithfully retained the histopathological and genomic features of the original tumours.

Dataset EGAD00001015745

A developmental cell atlas of the human thyroid gland

Thyroid hormones are essential for health, but human thyroid development and cellular heterogeneity are poorly understood. We generated a high-resolution, spatiotemporal transcriptional atlas of human fetal thyroid, and examined its perturbations in trisomy 21 (T21), where aberrant thyroid development is associated with congenital hypothyroidism, and in papillary thyroid carcinoma (PTC). Normal tissue revealed two functional follicular cell states (fTFC1, fTFC2) with divergent PAX8 expression levels, persisting into adulthood. Additionally, the rare C-cell population was comprehensively profiled at single-cell resolution for the first time. T21 fetal thyroid was hypoplastic, with disrupted follicular morphology and altered expression of genes mediating cellular topology and extracellular matrix interactions. Finally, the transcriptional signals of both fetal follicular cell states were found to be perturbed in PTC. Overall, we defined a reference atlas for normal human fetal thyrocyte heterogeneity and provided novel insights into thyroid disorders.

Dataset EGAD00001015783

MultiOMICS study of a pair of infant monozygotic twins with concordant B-cell ALL (WGS)

B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common cancer in childhood. Studying identical twins with B-cell ALL provides a unique and tractable model for deciphering the developmental timing of pre- and post-natal mutations contributing to clonal evolution. To date, this has mainly focused on major cytogenetic subgroups of childhood B-cell ALL, including MLL fusions, ETV6-RUNX1, hyperdiploidy, and BCR-ABL1. However, formal demonstration of the prenatal origin and “backtracking” the natural history of the leukemia remains understudied in “B-other”/Normal Karyotype (NK) B-cell ALL. To characterize the genetic landscape of this particular leukemia subtype, we performed whole genome DNA- and B-cell receptor (BCR)- on a pair of 8-month-old monozygotic twins diagnosed with concordant “B-other”/NK B-cell ALL.

Dataset EGAD00001005017

single cell RNA-seq of bone marrow from infants with MLL-rearranged Acute Lymphoblastic Leukemia by single cell RNA-sequencing

This dataset contains two experiments. 1) Single cell RNA-seq of diagnostic samples from patients with MLL-rearranged infant ALL that underwent relapse or not (samples ending in R relapsed, samples ending in N did not). For some of the patients, multiple indipendent plates were produced (each plate is a sample). 2) in vitro prednisolone exposure experiment. diagnostic bone marrow samples from patient 4662R were cultured for three days with and without prednisolone. Single cell experiments were conducted according to Muraro et al (cell systems, 2016, doi:10.1016/j.cels.2016.09.002). Cell barcodes and UMI sequences are embedded in the header of each fastq entry. Cell barcodes irrelevant to this experiment were removed before submission.

Dataset EGAD00001005461

Sequence Data from the phase 2 PrE0505 trial of Durvalumab with First Line Platinum-Pemetrexed for Unresectable Pleural Mesothelioma

Dataset comprises of 84 bam files from exome sequencing data, including 40 tumor-normal pairs and 4 normal files. Each sample is numbered by the patient case ID such as 135, 156 and so on. The filenames are suffixed with "_tumor" and "_normal" to indicate tumor and normal bam files respectively.

Dataset EGAD00001008016

Acral Melanoma PDXs from the admixed Brazilian Population - Patient Derived Xenograft samples VCF files with somatic SNV and INDELs - Whole exome sequencing data

Raw, flagged and annotated VCF files with somatic calls made with CavEMan and Pindel for Patient Derived Xenograft samples. Variant effect prediction was run with Ensembl VEP v103. Acral melanoma (AM) is an aggressive melanoma subtype with limited therapeutic options and poor outcomes. In non-European descent and admixed populations, like in Latin America, it can account for a significant proportion of cutaneous melanoma cases. Here, we performed comprehensive genomic and functional profiling of AM from a uniquely diverse Brazilian cohort. Whole-exome and transcriptome sequencing was performed on both tumours and patient-derived xenograft (PDX) samples. The PDX were obtained from a comprehensive collection of patient-derived xenograft (AM-PDX) models that we established which faithfully retained the histopathological and genomic features of the original tumours.

Dataset EGAD00001015749

A non-canonical lymphoblast in refractory childhood T cell leukaemia

Refractory cancers may arise either through the acquisition of resistance mechanisms by cancer cells or represent distinct diseases. The origin of childhood T-cell acute lymphoblastic leukaemia (T-ALL) that does not respond to initial treatment, i.e. refractory disease, is unknown. Refractory T-ALL carries a poor prognosis and cannot be predicted at diagnosis. Here, we performed single cell mRNA sequencing of T-ALL from children who did or did not respond to initial treatment. We identified a transcriptionally distinctive blast population, exhibiting features of innate-like lymphocytes, as the major source of refractory disease. Evidence of such blasts at diagnosis heralded refractory disease across independent datasets and was associated with survival in a large, contemporary trial cohort. Our findings portray refractory T-ALL as a distinct disease. They may have immediate clinical utility.

Dataset EGAD00001015381

Massive parallel RNA sequencing of highly purified mesenchymal cells derived from bone marrow specimens of 10 healthy donors

Highly purified mesenchymal cells (CD45-/7AAD-/CD235a-/CD31-/CD271+/CD105+) were prospectively FACS-isolated from bone marrow specimens of 10 healthy donors (HDs). This data set is used as a baseline control to observe the differences between gene expression profiles (GEPs) of pre-leukemia cases (45 low-risk myelodysplastic syndrome, 4 Shwachman-Diamond and 3 Diamond-Blackfan anemia patients) and gene expression patterns observed in a normal, healthy context. Through differential expression and gene set enrichment analysis we determined that inflammatory signaling pathways are significantly more active in mesenchymal cells of pre-leukemia cases compared to their healthy counterparts. Finally, we determined through statistical modelling of healthy donor's GEPs which pre-leukemia cases have significantly more active inflammatory signaling and demonstrated a strong relation to survival statistics.

Dataset EGAD00001002659

MultiOMICS study of a pair of infant monozygotic twins with concordant B-cell ALL (WGBS)

B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common cancer in childhood. Studying identical twins with B-cell ALL provides a unique and tractable model for deciphering the developmental timing of pre- and post-natal mutations contributing to clonal evolution. To date, this has mainly focused on major cytogenetic subgroups of childhood B-cell ALL, including MLL fusions, ETV6-RUNX1, hyperdiploidy, and BCR-ABL1. However, formal demonstration of the prenatal origin and “backtracking” the natural history of the leukemia remains understudied in “B-other”/Normal Karyotype (NK) B-cell ALL. To characterize the epigenetic landscape of this particular leukemia subtype, we performed DNA bisulfite-sequencing on a pair of 8-month-old monozygotic twins diagnosed with concordant “B-other”/NK B-cell ALL.

Dataset EGAD00001005018

Single cell resolution landscape of hypomutated childhood cancers

A paradigm of childhood cancers is that they have a low mutation burden, with some ostensibly bearing fewer mutations than the normal tissues from which they derive. We set out to resolve this paradox by examining paediatric renal cancers with exceptionally few mutations using high resolution, high depth sequencing approaches. We found that apparent hypomutation was the result of unusual clonal architecture due to a normal tissue-like mode of tumour evolution, raising the possibility that the mutation burden of some cancers has been systematically misjudged.

Dataset EGAD00001015406

Anaplastic Oligodendroglioma AO Exome-seq data

Anaplastic oligodendrogliomas (AOs) are rare primary brain tumors which are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosome 1p/19q co-deletion and IDH mutation. We analyzed 51 AOs by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall 7.5% of AO are mutated for TCF12, which encodes an oligodendrocyte-related transcription factor. 80% of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frame shift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumor type. Our analysis provides further insights into the unique and shared pathways driving AO.

Dataset EGAD00001001452

Exome sequencing of thyroid disease in Val Borbera

The Val Borbera is a region characterized by low iodine and high prevalence of thyroid disorders, the commonest endocrine disorders in the general population. About 30% of the participants of the Val Borbera Project were affected by such disorders and were characterized by several parameters, TSH level, anti TPO antibodies, echography, family origin. Individuals with extreme phenotypes were identified and could be clustered based on family origin and genotype. We propose to exome sequence 6 of them, affected with true goiter, at high dept (40-60x) to obtain information on exonic rare variants. Due to the family structure and to the availability of whole genome sequence information on 110 individuals from the isolated population we expect to be able to identify putative causative variants for thyroid disorders that may be studied in the remaining affected individuals.

Dataset EGAD00001000729

Genome-Wide Association Study of Hypertriglyceridemia in Mexicans

Coronary artery disease (CAD) is the number one cause of death and mortality world-wide. High levels of serum triglycerides (TGs) and low levels of serum high-density lipoprotein cholesterol (HDL-C) are major risk factors for CAD. Previous epidemiological studies have shown that these two lipid disturbances are highly common dyslipidemias in Mexicans. However, the genetic factors underlying high serum TGs and low HDL-C are underinvestigated and poorly identified in Mexicans. As the Mexican-American and the genetically related Latin-American populations represent the fastest growing minority in the United States, elucidation of the unknown genetic factors influencing the increased susceptibility of Mexicans to these common dyslipidemias is of great relevance to these U.S. minorities and the American healthcare system. This study is a research collaboration between investigators at the University of California, Los Angeles (UCLA) and Instituto Nacional de Ciencias Médicas y Nutrición (INCMN), Mexico City, to perform a two-stage genome-wide association study (GWAS) for hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) in Mexicans (Weissglas-Volkov et al. 2013, PMID: 23505323). This study was funded by an RO1 grant from NIH/NHLBI (PI Paivi Pajukanta; PI of the subaward Teresa Tusie-Luna). In stage 1 of the GWAS, we tested all GWAS SNPs from the Illumina Infinium Human610-Quad platform that passed quality control for association in ~2,200 hypertriglyceridemia cases and controls. In stage 2, we genotyped the ~1,200 positive signals of stage 1 in additional ~2,200 hypertriglyceridemia cases and controls, and performed a combined analysis of the two stages to identify genome-wide significant variants. The subjects were recruited at the INCMN. The DNA isolation and clinical laboratory measurements of the case-control study samples were performed at INCMN using standardized procedures. Genotyping and statistical analyses of the data were performed at UCLA. A summary of this GWAS can be found in Weissglas-Volkov et al. 2013 Journal of Medical Genetics, PMID: 23505323. Briefly, using the two-stage GWAS design, we identified a novel Mexican-specific genome-wide significant locus for serum TG levels close to the Niemann-Pick type C1 protein (NPC1) gene (Weissglas-Volkov et al. 2013, PMID: 23505323). Of the European lipid GWAS loci, three TG loci (APOA5, GCKR, and LPL) and four HDL-C loci (ABCA1, CETP, LIPC and LOC55908) resulted in genome-wide significant signals in Mexicans. Furthermore, our cross-ethnic mapping narrowed three European TG GWAS loci, APOA5, MLXIPL, and CILP2 that exhibited long range LD and a large number of candidate SNPs in the European GWAS scan. In the apolipoprotein A1C3A4A5 gene cluster region, the cross-ethnic fine mapping and LD comparisons reduced the number of candidate variants to one SNP, rs964184. We also found that although 52% of the associations from European lipid GWAS meta-analysis could be generalized to Mexicans, in 82% of the European GWAS loci, a different variant other than the European lead SNP provided the statistically strongest evidence of association in the Mexican scan (Weissglas-Volkov et al. 2013, PMID: 23505323). Taken together, our Mexican GWAS for lipids identified a novel Mexican-specific locus for high serum TGs; restricted three European GWAS loci; and investigated which European lipid GWAS variants extend to the Mexican population (Weissglas-Volkov et al. 2013, PMID: 23505323). This NHLBI sponsored RO1 project aimed to identify genetic variants contributing to serum lipid levels in Mexicans. In addition to de-identified genome wide genotypic data, a selected list of de-identified phenotypic data related to hypertriglyceridemia and related metabolic traits are also available in dbGaP.

Study phs000618

CRU-Ukrainian National Research Center for Radiation Medicine Trio Study

Data on transgenerational effects following nuclear accidents are important for understanding fully the consequences of parental exposure to ionizing radiation. Few studies to date have had adequate statistical power to detect effects of the magnitude expected based on animal data, and most have not been of low-dose, protracted exposures associated with nuclear accidents and their aftermath. Although, to date, scant use has been made of the new genomic technologies, in Chernobyl-exposed areas of Ukraine and Belarus, excess minisatellite mutations have been seen in children born after the accident. We propose a study of parent-child trios in which at least one parent was exposed to Chernobyl radiation as a clean-up worker (mean dose>=100 mGy) and/or evacuee from a contaminated area (mean >=50 mGy). The specific aims are to investigate the transgenerational and de novo mutation rates of the spectrum of genetic variants in trios, in particular looking at effects in children and mapping them to possible parental origin of the chromsoome. Together with long-term collaborators at the Research Center for Radiation Medicine (RCRM) in Kiev, epidemiologic data will be collected for up to 450 trios of parents with preconceptional doses and their unexposed offspring. We will use state-of-the-art genomic technologies to characterize the landscape of the genomes of the trios to determine whether parental radiation exposure is associated with genetic mutations transmitted to the offspring, by examining de novo mutation rates, minisatellite mutations, copy number alterations, and variations in telomere length. The analysis will be conducted in peripheral blood and/or buccal samples (when blood is not available) from complete father-mother-child trios. Doses to the gonads from the time of the accident to the time of conception will be reconstructed for all parents using existing records supplemented by interview data. Trio subjects will be selected from representative populations exposed to radiation from Chernobyl who are under active follow-up in the Clinico-Epidemiologic Registry at RCRM. To help identify specific effects of paternal and maternal radiation exposure, we will initially select sets of trio subjects in five categories: (1) exposed father, unexposed mother; (2) unexposed father, exposed mother; (3) both parents exposed; (4) both parents unexposed; and (5) a group of high dose "emergency workers" with acute radiation syndrome. All trio members will be invited to the RCRM outpatient clinic for collection of a 20 ml blood sample (or buccal cells for those who refuse phlebotomy). Both parents will be asked to complete a general questionnaire to obtain demographic and lifestyle data. Then one or both will complete detailed dosimetry questionnaires, based on forms used in previous collaborations with RCRM and administered by specially trained interviewers. Once 50 trios have been recruited (10 from each of the 5 exposure categories), we will conduct an interim evaluation of participation rates, sample collection and quality, and dose reconstruction in order to modify the protocol as needed. The analytical approach will be to correlate the extent, especially for de novo events of genetic alterations in the offspring with parental pre-conceptional radiation dose overall and by parental origin. The statistical power in relation to de novo mutations is very high, in excess of 90%, but somewhat lower for trends in minisatellite mutations. Study findings will contribute importantly to knowledge of the heritable effects of moderate- and low-dose radiation exposure in humans and to radiation risk projection. Eventually data from the Trio Study may be shared with the international community through dbGap.

Study phs001163

The UCSD / O'Connor "TSP" (Twin/Sibling/Pedigree) Resource in Hypertension

Study Design: The UCSD / O'Connor "TSP" (Twin/Sibling/Pedigree) Resource in Hypertension contains N=797 participants. At the time of recruitment individuals ranged from 15-84 years of age and had varying ethnic backgrounds (Whites, African-Americans and Hispanics). The cohort was developed to study the genetic basis of autonomic dysfunction in human essential hypertension (reviewed in Zhang et al. Curr Hypertens Rep. 2011 13: 36-45. PMID: 21104344) and contains cross-sectionally collected phenotypes related to blood pressure regulation.  Phenotypes: Phenotype data specifically focuses on the sympathetic branch of the autonomic system, which is a key regulator of blood pressure. Data includes circulating concentrations of the secretory "quantum" (catecholamines, neuropeptides, chromogranins) which influence vascular responses to sympatho-adrenal activation resulting in blood pressure. Other measures on the twins and a subset of family members include a standard urine panel with absolute concentrations of potassium, sodium, uric acid, phosphorous; DynaPulse acquired heart rate and blood pressure measures including systolic and diastolic blood pressure, mean arterial pressure, heart rate, Left Ventricular (LV) ejection time, LV contractility, cardiac output, stroke volume data including; and absolute concentrations of plasma aldosterone, endothelin, leptin, and insulin. Phenotype data is included for the 697 individuals sequenced here and 100 family members.  Whole Genome Sequence Data Generation: Whole genome sequencing (20X coverage) was conducted on plasma-derived DNA. The WGS was generated using the Illumina HiSeq X Ten sequencing platform with variants called by Human Longevity, Inc (HLI; Ref 1). Preparation of sample libraries was conducted by mechanical shearing of gDNA (100-800 bp), isolation of DNA fragments 300-500bp in size, followed by library PCR amplification employing high-fidelity, low-bias PCR to amplify library fragments consisting of appropriate adapter sequences on both ends. BAM files were created by alignment of sequence reads to the reference genome (GRCh38) using iSAAC-01.14.02.06 (Python2.7). Note: The user may want to realign the sequence data and recall variants. In total, the WGS dataset contains 30 monozygotic twin pairs represented by one member of the twin pair, 133 monozygotic twin pairs with both individuals sequenced, 7 dizygotic twin pairs represented by one member of the twin pair, 67 dizygotic twin pairs with both individuals sequenced, 8 twin pairs with undetermined zygosity (both individuals sequenced) and 1 triplet with mother (all individuals sequenced). The dataset also contains sequences of 260 family members of twins including their mother, father, non-twin sibling, and offspring. Table 1 describes the composition of families ("sibling" refers to a non-twin sibling in the cohort). Note: We suggest users check gender and family relatedness. Table 1: Description of the families with sequence data                                                                                                               Units with:Twin PairsTwin (no pairs)No twinSibshipsMother and Father511Mother only1222Father only113One or more siblings22133Mother and siblings132Father and siblings(s)211Offspring of twins11Non twin siblings2Sib with unknown relative1Only one member of8The UCSD/O'Connor "TSP" (Twin/Sibling/Pedigree) Resource in Hypertension is now being managed at the UCSD School of Medicine's Institute for Genomic Medicine (IGM). The TSP Resource has collected a wide range of information (phenotypic, genotypic, demographic, metabolomic) and reagents (blood, plasma, urine, DNA, human induced pluripotent stem cells). For additional information about the resource, including other data types available as well as references and links to data from studies with previous collaborators, please go to the resource website at IGM [http://igm.ucsd.edu/research/twins-resource.shtml] or contact Dr. Brinda Rana at UCSD [bkrana@ucsd.edu]. 

Study phs002230

Systolic Blood Pressure Intervention Trial (SPRINT-BioLINCC)

Available DataThe available data include all elements of the previously released SPRINT Primary Outcome Paper (SPRINT-POP) data, the full SPRINT clinical data including the MRI and MIND data, and select ancillary study data (Ambulatory Blood Pressure Monitoring, APOL1, Acute Kidney Injury, ASK, Heart, FAST, PWV, Renal Resistance, Biomarkers, Plasma AD).ObjectiveThe Systolic Blood Pressure Trial (SPRINT) was conducted to test the hypothesis that treating systolic blood pressure to a target of less than 120 mm Hg, as compared to a target of less than 140 mm Hg, would reduce the incidence of cardiovascular disease.BackgroundHypertension is a highly prevalent condition among adults and is a leading risk factor for myocardial infarction and stroke. Further, isolated systolic hypertension is the most common form of hypertension in adults over 50 years of age. Observational studies have shown a monotonic increase in cardiovascular risk with systolic blood pressures above 115 mm Hg; however, general population clinical trials have only documented the benefits of lowering systolic blood pressure to a target of 150 mm Hg. A 2007 expert panel sponsored by the National Heart, Lung, and Blood Institute designated the hypothesis that lowering the systolic blood pressure goal to a level SubjectsA total of 9361 participants were enrolled, with 4,678 randomized to the intensive-treatment group and 4,683 randomized to the standard-treatment group.DesignSPRINT was a randomized, single blinded (outcome adjudicators were blinded to treatment assignment) treatment trial with participants randomized to a systolic blood-pressure target of either less than 140 mm Hg (the standard-treatment group) or less than 120 mm Hg (the intensive-treatment group). Following randomization, baseline hypertensive regimens were adjusted in accordance with study treatment algorithms established for each group. The study formulary included all major classes of antihypertensive agents. Investigators could prescribe other antihypertensive medications, but the use of drug classes with the strongest evidence for reduction in cardiovascular outcomes was encouraged. This included thiazide-type diuretics as the first-line agent, loop diuretics for participants with advanced chronic kidney disease, and beta-adrenergic blockers for participants with coronary artery disease. Medications for participants in the intensive-treatment group were adjusted on a monthly basis to target a systolic blood pressure of less than 120 mm Hg. Medications for participants in the standard-treatment group were adjusted to target a systolic blood pressure of 135 to 139 mm Hg, and the dose was reduced if systolic blood pressure was less than 130 mm Hg on a single visit or less than 135 mm Hg on two consecutive visits. Lifestyle modification was encouraged as part of the management strategy.Participants were seen monthly for the first 3 months and every 3 months thereafter. Demographic data were collected at baseline. Clinical and laboratory data were obtained at baseline and every 3 months thereafter. A structured interview was used in both groups every 3 months to obtain self-reported cardiovascular disease outcomes. Medical records and electrocardiograms were obtained for documentation of events. Incidences of hypotension, syncope, injurious falls, electrolyte abnormalities, and bradycardia that were evaluated in an emergency department were included in adverse event reporting. Occurrences of acute kidney injury or acute renal failure requiring hospitalization were also monitored. The primary outcome was a composite outcome of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes.ConclusionsThe blood pressure intervention was stopped in August of 2015 (median follow-up of 3.26 years) after the cardiovascular outcome results exceeded the boundary for efficacy at two consecutive time points. Compared with a systolic blood pressure target of less than 140 mm Hg, an intensive systolic blood pressure target of 120 mm Hg resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause. Significantly higher rates of some adverse events were observed in the intensive-treatment group.

Study phs003483

Systolic Blood Pressure Intervention Trial (SPRINT-Imaging)

Available DataSystolic Blood Pressure Intervention Trial, SPRINT-Imaging, provides access to ECG signals data from the SPRINT clinical trial. The clinical phenotyping and outcomes data from the trial are associated with SPRINT-BioLINCC, phs003483.ObjectiveThe Systolic Blood Pressure Trial (SPRINT) was conducted to test the hypothesis that treating systolic blood pressure to a target of less than 120 mm Hg, as compared to a target of less than 140 mm Hg, would reduce the incidence of cardiovascular disease. BackgroundHypertension is a highly prevalent condition among adults and is a leading risk factor for myocardial infarction and stroke. Further, isolated systolic hypertension is the most common form of hypertension in adults over 50 years of age. Observational studies have shown a monotonic increase in cardiovascular risk with systolic blood pressures above 115 mm Hg; however, general population clinical trials have only documented the benefits of lowering systolic blood pressure to a target of 150 mm Hg. A 2007 expert panel sponsored by the National Heart, Lung, and Blood Institute designated the hypothesis that lowering the systolic blood pressure goal to a level SubjectsA total of 9361 participants were enrolled, with 4,678 randomized to the intensive-treatment group and 4,683 randomized to the standard-treatment group. DesignSPRINT was a randomized, single blinded (outcome adjudicators were blinded to treatment assignment) treatment trial with participants randomized to a systolic blood-pressure target of either less than 140 mm Hg (the standard-treatment group) or less than 120 mm Hg (the intensive-treatment group). Following randomization, baseline hypertensive regimens were adjusted in accordance with study treatment algorithms established for each group. The study formulary included all major classes of antihypertensive agents. Investigators could prescribe other antihypertensive medications, but the use of drug classes with the strongest evidence for reduction in cardiovascular outcomes was encouraged. This included thiazide-type diuretics as the first-line agent, loop diuretics for participants with advanced chronic kidney disease, and beta-adrenergic blockers for participants with coronary artery disease. Medications for participants in the intensive-treatment group were adjusted on a monthly basis to target a systolic blood pressure of less than 120 mm Hg. Medications for participants in the standard-treatment group were adjusted to target a systolic blood pressure of 135 to 139 mm Hg, and the dose was reduced if systolic blood pressure was less than 130 mm Hg on a single visit or less than 135 mm Hg on two consecutive visits. Lifestyle modification was encouraged as part of the management strategy. Participants were seen monthly for the first 3 months and every 3 months thereafter. Demographic data were collected at baseline. Clinical and laboratory data were obtained at baseline and every 3 months thereafter. A structured interview was used in both groups every 3 months to obtain self-reported cardiovascular disease outcomes. Medical records and electrocardiograms were obtained for documentation of events. Incidences of hypotension, syncope, injurious falls, electrolyte abnormalities, and bradycardia that were evaluated in an emergency department were included in adverse event reporting. Occurrences of acute kidney injury or acute renal failure requiring hospitalization were also monitored. The primary outcome was a composite outcome of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. ConclusionsThe blood pressure intervention was stopped in August of 2015 (median follow-up of 3.26 years) after the cardiovascular outcome results exceeded the boundary for efficacy at two consecutive time points. Compared with a systolic blood pressure target of less than 140 mm Hg, an intensive systolic blood pressure target of 120 mm Hg resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause. Significantly higher rates of some adverse events were observed in the intensive-treatment group.

Study phs003566

Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION-BioLINCC)

Accessing Data Please refer to “Authorized Access” below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP.ObjectivesThe HF-ACTION study examined whether exercise training reduces a composite endpoint of all-cause mortality or all-cause hospitalization for patients with left ventricular systolic dysfunction and heart failure symptoms. Background Heart failure (HF) is a major and growing cardiovascular syndrome that is the end result of many cardiovascular disorders. Although evidence-based drug and device therapies decrease mortality, hospitalizations, and HF symptoms and improve quality of life, many patients treated with these regimens often remain burdened by dyspnea and fatigue, diminished exercise tolerance, reduced quality of life, recurrent hospitalizations, and early mortality. Whereas rest was traditionally recommended for HF patients, there has been evidence that physical deconditioning may play a key role in the progression of symptoms and poor outcomes. Previous studies have shown positive effects of exercise training on exercise capacity, quality of life, and biomarkers and suggest that exercise training might improve survival and decrease HF hospitalizations. Nonetheless, there remains a safety concern regarding exercise training in HF and a large scale, multicenter, controlled clinical trial was needed to provide definitive clinical outcome data. Participants A total of 2,331 participants were randomized. 2,130 consented to share data with non-commercial entities, and 1,753 consented to share for commercial purposes. Design All participants underwent baseline cardiopulmonary exercise testing. Test results were reviewed by investigators to identify significant arrhythmias or ischemia that would prevent safe exercise training, to determine appropriate levels of exercise training, and to establish training heart rate ranges. Demographics, socioeconomic status, past medical history, current medications, physical exam, and the most recent laboratory tests were obtained prior to randomization. All participants received detailed self-management educational materials which included information on medications, fluid management, symptom exacerbation, sodium intake, and physical activity. Participants randomized to the exercise training arm first participated in a structured, group-based, supervised exercise program, with a goal of 3 sessions per week for a total of 36 sessions in 3 months. The primary exercises were walking, treadmill, or stationary cycling. Exercise was initiated at 15 to 30 minutes per session at a heart rate corresponding to 60% of heart rate reserve, and was increased after 6 sessions to 30 to 35 minutes duration and 70% of heart rate reserve. Participants began home-based exercise after completing 18 supervised sessions and were to fully transition to home exercise after 36 supervised sessions. The target training regimen for home exercise was 5 times per week for 40 minutes at a heart rate of 60% to 70% of heart rate reserve. Participants randomized to the usual care group were not provided with a formal exercise prescription. To provide comparable levels of attention from study personnel, all participants were called every 2 weeks for the first 9 months, monthly until 24 months of follow-up, and quarterly thereafter. Participants returned for clinic visits every 3 months for the first 2 years of participation and yearly thereafter for up to 4 years. Follow-up assessments included cardiopulmonary exercise testing, a 6-minute walk test, and a physical activity questionnaire. The primary end point was a composite of all-cause mortality or all-cause hospitalization. Secondary end points included all-cause mortality, the composite of cardiovascular mortality or cardiovascular hospitalization, and the composite of cardiovascular mortality or HF hospitalization. Conclusions After adjustment for highly prognostic predictors of the primary end point, exercise training was associated with modestly significant reductions for both all-cause mortality or hospitalization and cardiovascular mortality or heart failure hospitalization.

Study phs003599

Genome-Wide associations of Lung Health Study (LHS)

The 'Genome-Wide Associations Environmental Interactions in the Lung Health Study' at Johns Hopkins University aims to test for association between lung function decline as a primary outcome associated with chronic obstructive pulmonary disease (COPD) using banked DNA and phenotype data on 4,287 European Americans from the longitudinal, multicenter Lung Health Study (LHS). The broad goals of the LungGO/ESP-GO falls into two general categories: (i) discovery of all variants (i.e., common and rare) in all protein-coding regions of the human genome (i.e., the exome) conferring risk to complex pulmonary diseases including COPD, in a subset of the LHS cohort. The Johns Hopkins University LHS cohort offers a unique opportunity to elucidate genetic variants that cause COPD. The Lung Health Study I was a randomized multicenter clinical trial with 5887 participants carried out from October 1986 to April 1994, designed to test the effectiveness of smoking cessation and bronchodilator administration in smokers aged 35 to 60 with mild lung function impairment. Participants were randomly assigned to one of three groups: usual care, who received no intervention smoking intervention with the inhaled bronchodilator ipratroprium bromide smoking intervention with an inhaled placebo. The effect of intervention was evaluated by the rate of decline of forced expiratory volume in one second (FEV1). For the GWAS, only the subset of European American LHS participants for whom lung function data from three time points or more are available. Thus, the GWAS represents 73% of the 5,887 volunteers who participated in the LHS study. Importantly, LHS subjects included had similar demographics (including age, gender and BMI) and rates of lung function decline (mean annual change in FEV1% predicted: -0.96 %/yr vs. -0.99 %/yr, p=0.57) compared with those not included in the GWAS, reflecting little selection bias for our primary outcome. They were, however, more likely to have quit smoking after 5 years. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to lung function through large-scale genome-wide association studies of smokers enrolled in a multicenter clinical trial. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

Study phs000335

National Sleep Research Resource (NSRR): Cleveland Family Study (CFS)

The Cleveland Family Study (CFS) is a family-based study of sleep apnea, consisting of 2,284 individuals (46% African American) from 361 families studied on up to 4 occasions over a period of 16 years. The study began in 1990 with the initial aims of quantifying the familial aggregation of sleep apnea. National Institutes of Health (NIH) renewals provided expansion of the original cohort, including increased minority recruitment, and longitudinal follow-up, with the last exam occurring in February 2006. The CFS was designed to provide fundamental epidemiological data on risk factors for sleep disordered breathing (SDB). The sample was selected by identifying affected probands who had laboratory diagnosed obstructive sleep apnea. All first-degree relatives, spouses and available second-degree relatives of affected probands were studied. In addition, during the first 5 study years, neighborhood control families were identified through a neighborhood proband, and his/her spouses and first-degree relatives. Each exam, occurring at approximately 4-year intervals, included new enrollment as well as follow up exams for previously enrolled subjects. For the first three visits, data, including an overnight sleep study, were collected in participants' homes while the last visit occurred in a general clinical research center (GCRC). Phenotypic characterization of the entire cohort included overnight sleep apnea studies, blood pressure, spirometry, anthropometry and questionnaires. Currently, data of 710 individuals are available for use through BioData Catalyst (with genotype data available through dbGaP).The National Sleep Research Resource (NSRR) is a NIH-supported sleep data repository that offers free access to large collections of de-identified physiological signals and related clinical data from a large range of cohort studies, clinical trials and other data sources from children and adults, including healthy individuals from the community and individuals with known sleep or other health disorders. The goals of NSRR are to facilitate rigorous research that requires access to large or more diverse data sets, including raw physiological signals, to promote a better understanding of risk factors for sleep and circadian disorders and/or the impact of sleep disturbances on health-related outcomes. Data from over 15 data sources and more than 40,000 individual sleep studies, many linked to dozens if not hundreds of clinical data elements, are available (as of Feb. 2022). Query tools are available to identify variables of interest, and their meta-data and provenance.

Study phs002715

Genes for Non-Syndromic Congenital Heart Disease

Congenital heart defects (CHDs) are the most common serious birth defect and a leading cause of infant mortality. Affected individuals who survive infancy require substantial medical care and experience lifelong morbidity and early mortality. Despite their prevalence and impact upon public health, the etiology of CHDs is poorly understood. Our long-term goal is to better define the genetic basis of CHDs and using this information, develop preventive measures and provide precise medical management based on genotype. As CHDs are a heterogeneous group of conditions, we have focused our studies on cases with conotruncal heart defects (CTDs) that comprise at least 36% of all CHDs and are a prominent feature of the 22q11.2 deletion syndrome (22q11DS). We have conducted both SNP- and CNV-based genome-wide association studies as part of our previous and current P01 (HD070454). Our current analyses of genes and gene-sets provide new insights regarding the contribution of common and rare inherited genetic variants to CTDs. Specifically, based on the results from our studies as well as recently published findings, we hypothesize that: (1) CTDs are influenced by the full range of genetic variability (rare to common; de novo and inherited) in relevant gene-sets; (2) the number of disease-related variants within these gene-sets varies directly with CTD severity; and (3) gene-sets associated with CTDs in nonsyndromic individuals are also associated with CTDs in individuals with the 22q11DS. To augment our existing cohorts and thus substantially improve the statistical power of our proposed analyses, application was made to complete array genotyping of a set of patients with CTDs and in particular, those with mild disease represented by isolated aortic arch anomalies. The new cases with CTD and some with an isolated aortic arch anomaly were ascertained at the Children's Hospital of Philadelphia (CHOP) while some of the cases with isolated aortic arch anomalies were ascertained by the Pediatric Cardiac Genomics Consortium (PCGC). A small group of cases with left-sided obstructive lesions from CHOP were included to combine with our existing datasets to serve as a comparison to those with CTD. The additional genotype data will augment the statistical power of the proposed common variant analyses. We anticipate that this work will reduce the gaps in our understanding of CTDs by identifying an explicit set of genes associated with CTD-risk by way of common variants. This work will also help define the genetic architecture for the full clinical spectrum of these common birth defects.

Study phs002059

The Genomics and Randomized Trials Network (GARNET) Vitamin Intervention Stroke Prevention (VISP) Trial

The VISP trial (PI Jim Toole, M.D., Wake Forest University School of Medicine) was a multi-center, double-blind, randomized, controlled clinical trial that enrolled patients aged 35 or older with homocysteine (Hcy) levels above the 25th percentile at screening and a non-disabling cerebral infarction (NDCI) within 120 days of randomization (Toole, 2002, PMID: 12417369). The trial was designed to determine if daily intake of a multivitamin tablet with high dose folic acid, vitamin B6 and vitamin B12 reduced recurrent cerebral infarction (primary endpoint), and nonfatal myocardial infarction (MI) or mortality (secondary endpoints). Subjects were randomly assigned to receive daily doses of the high-dose formulation (n=1,827), containing 25mg pyridoxine (B6), 0.4mg cobalamin (B12), and 2.5mg folic acid; or the low-dose formulation (n=1,853), containing 200mcg pyridoxine, 6mcg cobalamin and 20mcg folic acid. Enrollment in VISP began in August 1997, and was completed in December 2001, with 3,680 participants enrolled. Within the trial, 2,164 participants from 46 clinic sites provided DNA and agreed for it to be shared for use in a genetic subset study of VISP. This study is part of Genomics and Randomized Trials Network (GARNET), funded by the National Human Genome Research Institute (NHGRI). The overarching goal is to identify novel genetic factors that contribute to stroke through large-scale genome-wide association studies of treatment response in randomized clinical trials. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were performed at the GARNET Coordinating Center at the University of Washington. The data of the VISP trial have been released to dbGaP users in several segments: Version 1 (phs000343.v1.p1), consisted of n=4 phenotype datasets, and all raw, cleaned and imputed genotype data. Version 2 (phs000343.v2.p1) included n=14 additional phenotype datasets (plus pedigree, consent, and sample-mapping data), and increased the available data to a total of n=970 phenotype variables. Version 3 (phs000343.v3.p1) included all n=36 phenotype datasets (plus pedigree, consent, and sample-mapping data), and increased the available data to a total of n=1918 phenotype variables.Version 4 (phs000343.v4.p1), the current release, includes all previous phenotypic datasets, includes one new phenotypic dataset for the untargeted metabolomics data of 50 individuals, includes DNA methylation profiles for n=180 individuals, and sequencing data for n=179 individuals.

Study phs000343

Genome-Wide Association of Native and Post Aspirin Platelet Function Phenotypes

The goal of this study was to identify genetic variants in a genome-wide association study (GWAS) that are associated with previously obtained platelet function phenotypes measured in each individual under baseline conditions and following 2 weeks of low dose aspirin (ASA). During this study we performed a high density 1 million-SNP genome scan on subjects from GeneSTAR (representing 800 2-generational families with a family history of premature coronary artery disease, 60% white and 40% African American, N=3232). We identified genomic loci associated with quantitative platelet phenotypes prioritized for their biological interest, determined associations between genomic loci and baseline platelet phenotypes (primary phenotypes are platelet aggregation in platelet rich plasma induced by collagen, adenosine diphosphate (ADP), arachidonic acid (AA), and epinephrine (Epi), determined associations between genomic loci and post-ASA platelet phenotypes, ie, measures of ASA "resistance" (primary phenotypes are as above, plus urinary levels of the prostaglandin metabolite, 11-dehydro-thromboxane B2 ), and compared peaks of association between genomic loci and three common baseline platelet phenotypes (collagen-, epinephrine-, and ADP-induced aggregation in platelet rich plasma) with associations found for these same phenotypes in the Framingham Heart Study. We also determined whether any significant genotype-phenotype associations in the 1 million SNP genome scan could be localized to any specific genes or potential genes of interest using publicly available databases and further examined whether candidate genes previously associated with a specific platelet phenotype are located in a genomic region of interest as determined from the SNP genome scan. We conducted replications of our findings, and are presently involved in larger scale meta-analysis of findings for pre-aspirin and post-aspirin associations. The study population is constituted of full siblings (SIBS) (ages 35-78 years) identified from The Johns Hopkins Sibling Study, now called GeneSTAR, the spouses of the SIBS, and their adult offspring (>21 years of age). They include 3200 individuals from approximately 300 African American and 500 white extended families. "Spouse" refers to the other parent of any SIB offspring, independent of marital status. Sibship sizes among families range from 1 to 16 (excluding index cases). On average, each SIB has 2 potentially eligible offspring. A family for this study is defined by all of the full sibships and the total numbers of offspring that come from all SIBS, rather than just the nuclear family.

Study phs000375

Mucociliary Clearance Consortium (MCC) Rare Genetic Disorders of the Airways: Cross-section Comparison of Clinical Features, and Development of Novel Screening and Genetic Test

We have established a consortium of 7 geographically-dispersed clinical research sites that are designed to study rare diseases of the airways, which involve defects in clearance of mucus secretions from the airways (defective "mucociliary clearance"). These sites will collaborate in diagnostic, genetic, and other studies in patients with impairments of mucociliary clearance, including primary ciliary dyskinesia (PCD), variant cystic fibrosis (CF), and pseudohypoaldosteronism (PHA). These disorders reflect genetic defects in airway host-defense, and typically result in chronic infection of the airways. Patients with these disorders of the conducting airways and sinuses have delayed (or incorrect) diagnoses, because diagnostic tests are not readily available. These patients may also have sub-optimal management of their clinical disease, because the cause of these disorders is not well-defined, and treatment regimens are usually not driven by evidence-based medicine. This current protocol is designed to employ a systematic approach to the diagnostic evaluation of these patients with chronic airways disease, which will yield precise diagnoses in individual patients, and will be associated with development of better diagnostic techniques, including genetic testing. In addition, we will compare/contrast clinical features (phenotype) across these disorders. A rigorous cross-sectional comparison of the clinical features will provide better understanding of the clinical disease of these disorders; in turn, this will lead not only to a better standard of clinical care, but will also assist in the identification of novel therapeutic approaches. The patient population for these studies includes individuals carrying a tentative diagnosis of the three disorders (PCD, variant CF or PHA), plus individuals suspected to have one of these disorders, but with inadequate or inconclusive diagnostic tests. Individuals in this latter category must have a preliminary clinical evaluation to evaluate for other more common disorders that may have similar manifestations including classical CF, immunodeficiency, asthma, and severe gastroesophageal reflux. We have an informal agreement with a network of pulmonologists across the United States to perform clinically-indicated (not research) preliminary clinical testing, if not directly available to patients who inquire about these studies. Blood will be collected for DNA to test for genetic mutations. The blood samples will be processed to establish a cell line (lymphocyte transformation) for a source of DNA for future genetic studies, in participants with disease. For participants unable to provide a blood sample, a buccal sample will be obtained for DNA.

Study phs000595

NHLBI TOPMed: The Cleveland Family Study (CFS)

The Cleveland Family Study (CFS) is one cohort involved in the WGS project. The CFS was designed to provide fundamental epidemiological data on genetic and non-genetic risk factors for sleep disordered breathing (SDB). In brief, the CFS is a family-based study that enrolled a total of 2284 individuals from 361 families between 1990 and 2006. The sample was selected by identifying affected probands who had laboratory diagnosed obstructive sleep apnea. All first degree relatives, spouses and available second degree relatives of affected probands were studied. In addition, during the first 5 study years, neighborhood control families were identified through a neighborhood proband, and his/her spouses and first degree relatives. Each exam, occurring at approximately 4 year intervals, included new enrollment as well as follow up exams for previously enrolled subjects. For the first three visits, data, including an overnight sleep study, were collected in the participants' homes while the last visit occurred in a general clinical research center (GCRC). Phenotypic characterization of the entire cohort included overnight sleep apnea studies, blood pressure, spirometry, anthropometry and questionnaires. The GCRC exam (n=735 selected individuals) included more comprehensive phenotype data on a focused subsample of the larger cohort, to permit linking SDB phenotypes with cardio-metabolic phenotypes, with an interest in identifying genetic loci that are associated with these related phenotypes. In this last round of data collection, a subset of 735 individuals was selected based on expected genetic informativity by choosing pedigrees where siblings had extremes of the apnea hypopnea index (AHI). Participants underwent detailed phenotyping including laboratory polysomnography (PSG), ECG, spirometry, nasal and oral acoustic reflectometry, vigilance testing, and blood and urine collection before and after sleep and after an oral glucose tolerance test. A wide range of biochemical measures of inflammation and metabolism were assayed by a Core Laboratory at the University of Vermont. 994 individuals were sequenced as part of TOPMed Phase 1, including 507 African-Americans and 487 European-Americans. Among the sequenced individuals, 156 were probands with diagnosed sleep apnea, an additional 706 were members of families with probands, and 132 were from neighborhood control families. 298 individuals were sequenced as part of TOPMed Phase 3.5, including 169 African-Americans and 129 European-Americans. Among the newly sequenced individuals, 33 were probands with diagnosed sleep apnea, an additional 214 were members of families with probands, and 51 were from neighborhood control families. Please note: Phenotype and pedigree data are available through "NHLBI Cleveland Family Study (CFS) Candidate Gene Association Resource (CARe)", phs000284.

Study phs000954

Assessing Neural Mechanisms of Injury in Inborn Errors of Urea Metabolism Using Structural MRI, Functional MRI, and Magnetic Resonance Spectroscopy

Urea cycle disorders represent a group of rare inborn errors of metabolism that lead to accumulation of ammonia, a toxic product of protein metabolism. Individuals with urea cycle disorders cannot metabolize the ammonia that accumulates due to enzyme deficiency. The symptoms of these disorders may present at birth, childhood or adulthood (milder deficiencies). There are currently eight enzyme deficiencies that constitute the range of inborn errors of ureagenesis. This project will focus on the most common enzyme disorder of the urea cycle, ornithine transcarbamylase deficiency, inherited as an X-linked trait. This project will study cognitive and motor dysfunction in patients who are female carriers of ornithine transcarbamylase deficiency (OTCD) or are males with late onset presentation of OTCD, utilizing state of the art MRI (magnetic resonance imaging), a non -invasive technique. This project seeks to improve our understanding of the underlying neural mechanisms that contribute to metabolic, cognitive, sensory and motor abnormalities in urea cycle disorders, which although individually rare, collectively constitute a major cause of neonatal encephalopathy, leading to significant morbidity and mortality. As a result of this study, a greater understanding of the anatomic, cognitive, motor, and biochemical underpinnings of neurologic damage attributable to this metabolic disorder will be gained. Experimental approaches will combine sensory, cognitive and motor testing with structural, functional and molecular magnetic resonance imaging to study symptomatic and asymptomatic heterozygous female carriers of X-linked ornithine transcarbamylase deficiency (OTCD), and late onset hemizygous males. Participants to be included in the studies will range from ages 18-60 years and will be compared to an age-matched typically developed (TD) comparison group. For our research, we use anatomic MRI, functional Magnetic Resonance Imaging (fMRI), and magnetic resonance spectroscopy (MRS) to monitor brain activity. The technique of fMRI provides detailed maps of the brain areas underlying human mental activities. By using fMRI, we are able to observe how the brain is functioning while a person is performing a specific task, such as reading. We can not only observe differences in the structure of the brain, but can also measure differences in brain function and activity as well. This information will ultimately be used to provide a basis for designing more effective interventions and methods for early identification of learning disabilities in patients with OTCD and related disorders. We will also use MRS to study various brain chemicals such as glutamine using the non-invasive MRI imaging techniques.

Study phs001108

Genomics of Kidney Transplantation

We have an established consortium consisting of 5 clinical centers which do a total of >800 kidney transplants/year. We have developed a quality-controlled multicenter database with high quality data, and obtained DNA samples and clinical data on 962 recipients and 442 donors. Using our developed infrastructure, we propose to study whether genetic variants are, in part, responsible for the differing outcomes of transplant recipients treated with contemporary immunosuppressive protocols. Our central hypotheses are that the genetic variation is associated with a) kidney transplant outcome, and b) immunosuppressive drug disposition and toxicity. Our long-term goals are to determine whether it is possible to individualize immunosuppressive therapy, based on genetics. At the same time, our studies may elicit new information on pathways important in the immune response or in immunosuppressive drug efficacy, disposition, and toxicity.Our application consists of 3 cores (Genetics Core, Clinical Core, and Administrative Core). We will do a genome wide association study (GWAS). Significant single nucleotide polymorphisms (SNPs) will be identified using the GWAS.Project 1 has 2 specific aims.Aim 1: To identify recipient SNPs that are associated with kidney allograft outcomes, including acute rejection, chronic graft dysfunction, and graft failure. Aim 2: To identify living donor SNPs that are associated with kidney allograft outcomes. Project 2 has 4 specific aims. Aim 1: To identify SNPs that are associated with tacrolimus blood levels.Aim 2: To identify SNPs that are associated with early tacrolimus-related nephrotoxicity and immune suppressant-related new onset diabetes.Aim 3: To identify SNPs that are associated with mycophenolate-related toxicity. Aim 4: To establish the relationships between candidate recipient SNPs, enzyme activity and mRNA expression of the pharmacologic targets of mycophenolate and calcineurin inhibitors. The projects use the genotyping data, which were provided by the Genetics Core, and clinical information, which were collected and entered into the multicenter database by the Clinical Core. Further, biostatistical support (Clinical Core) and administrative oversight and support (Administrative Core) will facilitate data collection, data entry, and data analyses for both projects. The Administrative Core will also facilitate interaction between Sites, Cores, and Projects.Technical note: Regarding to the study design, all transplant recipients should be unrelated. Given the nature of transplantation, some donors may be related to recipients. The donor-recipient relationships are reported in the demographic file under the "related" column. As we did not collect full pedigree information for the related donor-recipient pairs, we have included a IBD file (calculated using PLINK) with the genotype data.

Study phs001667

Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT-BioLINCC)

Accessing Data: Please refer to “Authorized Access” below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP.Objective: To determine whether an amino-terminal pro-B-type natriuretic peptide (NT-pro-BNP)-guided treatment strategy improves clinical outcomes vs usual care in high-risk patients with heart failure (HF) and reduced ejection fraction (HFrEF).Background: Heart failure is a common disorder. Standard treatment for HF includes diuretics to control fluid, and drugs called "neurohormonal antagonists" (such as beta-blockers and ACE-inhibitors) to help the heart work more efficiently. The natriuretic peptides, specifically NT-pro-BNP, are biomarkers that reflect HF severity and are significantly associated with adverse outcomes in HF. Smaller studies have evaluated adjusting HF therapy based on natriuretic peptide levels (“guided therapy”) with inconsistent results.Participants: A total of 894 participants were enrolled at 45 sites in the United States and Canada, with 446 randomized to the NT-pro-BNP-guided strategy treatment group and 448 randomized to the usual care treatment group.Design: GUIDE-IT was a multicenter randomized clinical trial with participants randomized to either the NT-pro-BNP-guided therapy strategy or usual care. Given the nature of the study intervention, treatment assignment was not blinded. For participants randomized to the NT-pro-BNP-guided strategy, clinicians were instructed to titrate HF therapy to target an NT-pro-BNP level After an initial visit at 2 and 6 weeks, visits occurred every 3 months throughout the remainder of the study. After therapy adjustment for HF (whether driven by NT-pro-BNP levels or clinical reasons), participants had a 2-week follow-up visit for reassessment. All participants in either group also had blinded NT-pro-BNP concentrations measured in a core laboratory at each study visit. The primary end point was the composite of time-to-first HF hospitalization or cardiovascular mortality. Secondary end points included all-cause mortality, total hospitalizations for HF, days alive and not hospitalized for cardiovascular reasons, the individual components on the primary end point, and adverse events. Conclusions: The guided strategy intervention was stopped in July of 2016 (median follow-up of 15 months) after the study met prespecified inefficacy criteria. Compared to usual care, a strategy of NT-pro-BNP-guided therapy was not more effective in improving time-to-first HF hospitalization or cardiovascular mortality in high-risk participants with HFrEF.

Study phs003621

Honolulu Heart Program (HHP-BioLINCC)

Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from HHP include DNA, plasma, serum, and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: The initial objectives of the Honolulu Heart Program were to: 1) estimate morbidity and mortality from coronary heart disease and stroke among Japanese men in Honolulu; 2) compare morbidity and mortality from coronary heart disease and stroke among Japanese men in Japan, Honolulu, and San Francisco; 3) investigate relationships among risk factors, coronary heart disease, and stroke in Japanese men in Honolulu; 4) compare distributions of risk factors among men in Japan, Honolulu, and San Francisco, and relate similarities and differences in risk factors to the occurrence of disease in these areas and in other populations, including Framingham and Puerto Rico; 5) conduct an autopsy study, and to relate pathological findings to morbidity and mortality data; and 6) investigate relationships between risk factors and pathological evidence of atherosclerosis and its complications.Background: The Honolulu Heart Program was initiated in 1965 by the NHLBI as a prospective study of environmental and biological causes of cardiovascular disease among Japanese Americans living in Hawaii. This population was known to have low incidence of coronary heart disease and higher incidence of stroke. The study provided opportunities to investigate relationships among disease frequencies, pathologic findings, and disease predictors in the cohort and to compare the findings in this population with those in other populations, especially cohorts of Japanese men resident in Japan or the U.S.Participants: There were 8006 participants.Design: The study began in 1965 with the first examination of a cohort of 8,006 Japanese-American men residing on the island of Oahu, Hawaii who were born during the period 1900-1919. The first examination was completed in 1968 and was followed by the initiation of a second examination that same year. Three subsequent sub-examinations (Lipoprotein Exams I, II and III) were conducted between 1970 and 1982 to collect lipid measurements on a subset of those who participated in Exam II. The fourth examination of surviving members of the original cohort was conducted during 1991-93 and collected data on 3,741 men. Morbidity and mortality follow-up continues through grant and contract-supported efforts, and the current HHP dataset includes events through 1998.

Study phs003907

Temptation Resistance Failures: Transdiagnostic Features and Influences

Multiple forms of psychopathology involve problems with resisting temptations and urges. This study utilizes experience sampling (ES) methodology to assess temptation resistance across different classes of temptations and urges including both common everyday temptations and more disorder-specific temptation classes. The study tests the hypothesis that the broad ability to successfully resist temptations and urges across temptation classes is a common features of the externalizing superspectrum (factor) of psychopathology, particularly the disinhibition spectra as defined by the Hierarchical Taxonomy of Psychopathology (HiTOP). Additional associations are expected to arise between reduced temptation resistance success for specific temptation classes and narrower symptom domains associated with the externalizing and internalizing spectra (e.g., binge eating, and nonsuicidal self-harm among internalizing symptoms). The study further tests genetic and environmental influences on temptation strength and resistance ability with a focus on polygenic scores, adverse childhood experiences and childhood neighborhood deprivation variables that have previously been related to externalizing. To address these issues, we will study up to 1200 subjects (minimum 1000) selected with enrichment for psychopathology. Subjects will be recruited from a combination of ResearchMatch, and targeted contact with Reddit groups, and targeted social media/online advertisements, with targeted recruitment of at least 150 subjects who indicate problems with SUD, alcohol use disorder (AUD) or nicotine dependence, 70 who indicate problems with gambling or other impulse control problems, 70 subjects with criminal/legal problems, and 70 subjects based on binge eating episodes 70 with self-injurious behavior, and 70 with obsessive-compulsive disorder. Subjects will complete the (Externalizing Spectrum Inventory-BF and HiTOP-SR) to measure externalizing and internalizing spectra. Diagnoses in key categories will be confirmed with structured diagnostic interviews. Subjects also complete information on childhood adversity and geocoding is used to assess environment during development. The two-week ES regimen collects data on the strongest types of temptations and urges experienced by the subject, their subjective strength, the goal of the urge (pleasure/relief from negative feelings), the level of conflict with other goals, whether the person attempted to resist the temptation, the resistance strategy, and resistance success, to allow assessment of the extent to which differences in each of these facets (and calculated temptation resistance efficacy) are related to narrow or broad dimensions of psychopathology. Whole genome sequencing with .5x coverage and imputation will be performed to allow generation of polygenic scores for externalizing and addiction in order to test the hypothesis that externalizing polygenic scores are related to poor temptation resistance efficacy across temptation classes.

Study phs004064

Multiomic Landscape of Multiple Myeloma Precursor and Relapsed Disease

Multiple myeloma (MM) is a treatable, though incurable, plasma cell malignancy. The molecular mechanisms driving disease onset and the emergence of drug resistance remain elusive. To better characterize the mutational, transcriptional, and epigenetic alterations that accompany MM disease evolution, we accessed molecular data from MM patients treated at Moffitt Cancer Center, with bone marrow biopsies collected between 2011 and 2023.We performed scMultiome (single-cell, paired RNA/ATAC-Seq, 10x Genomics) on 18 CD138+-selected bone marrow aspirate samples, including: 2 healthy donors, 3 patients with monoclonal gammopathy of undetermined significance (MGUS), 4 with smoldering myeloma (SMM), 3 with newly diagnosed MM (NDMM), 1 with early relapse MM (ERMM, 1 to 3 lines of therapy), and 5 with late relapse MM (LRMM, 4 or more lines of therapy). Our dataset includes a sequential sample: a patient with a premalignant condition ("scMultiome_SMM_4") that progressed to active myeloma ("scMultiome_NDMM_3"). These data allow for the assessment of transcriptional and epigenetic dysregulation at the cellular level. Our findings illustrate the dynamic epigenetic and transcriptional landscapes that accompany MM disease progression.We also conducted CUT&Tag analysis on 4 NDMM and 4 LRMM samples to map histone modifications, specifically H3K27ac, to investigate their role in transcriptional reprogramming observed in advanced stages of MM. This analysis revealed sample heterogeneity in terms of super-enhancer-regulated genes associated with active transcription.This cohort also includes samples from the clinical trial NCT04151667, “Daratumumab-Based Response-Adaptive Therapy for Older Adults With Newly Diagnosed Multiple Myeloma.” We performed scRNAseq (single-cell RNA sequencing, 10x Genomics) on 30 CD138+-selected bone marrow aspirate samples and 31 pre-sort samples featuring bone marrow mononuclear cells of various cell types from 5 healthy donors and 11 patients with newly diagnosed MM (NDMM). Our dataset includes sequential samples for all 11 NDMM patients, both prior to induction therapy (denoted by ‘a') with Daratumumab and Dexamethasone, and at cycle 2 day 22 (C2D22, i.e., 60 days after induction therapy start, denoted by ‘b'). For three NDMM patients, we also have samples at relapse (denoted by ‘c'). These data allow for the assessment of transcriptional dysregulation at the single-cell level in both the tumor and immune-tumor microenvironment, associated with Daratumumab treatment in NDMM patients.In addition to the molecular data, demographic, and phenotypic information for all samples is provided.

Study phs003892

Stability of gut microbiome after COVID-19 vaccination in healthy and immuno-compromised individuals

Bidirectional interactions between the immune system and the gut microbiota are key contributors to various physiological functions. Immune-associated diseases such as cancer and auto- immunity, and efficacy of immunomodulatory therapies, have been linked to microbiome variation. Although COVID-19 infection has been shown to cause microbial dysbiosis, it remains understudied whether the inflammatory response associated with vaccination also impacts the microbiota. Here, we investigate the temporal impact of COVID-19 vaccination on the gut microbiome in healthy and immuno-compromised individuals; the latter included patients with primary immunodeficiency and cancer patients on immuno- modulating therapies. We find that the gut microbiome remained remarkably stable postvaccination irrespective of diverse immune status, vaccine response, and microbial composition spanned by the cohort. The stability is evident at all evaluated levels including diversity, phylum, species, and functional capacity. Our results in- dicate the resilience of the gut microbiome to host immune changes triggered by COVID-19 vaccination and suggest minimal, if any, impact on microbiome-mediated processes. These findings en- courage vaccine acceptance, particularly when contrasted with the significant microbiome shifts observed during COVID-19 infection.

Study EGAS50000000179

Mechanisms of Therapy Driven Clonal Evolution in Oncogenic RAS Mutant Relapsed Acute Lymphoblastic Leukemia

Although multi-agent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die due to chemo-refractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape and pattern of clonal evolution at relapse in pediatric ALL cases. These analyses showed that ALL relapses originate from a common ancestral precursor clone of the diagnosis and relapsed populations and frequently harbor mutations implicated in chemotherapy resistance. RAS-MAPK pathway activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series. Notably, while some cases showed emergence of RAS mutant clones at relapse, in others, RAS mutant clones present at diagnosis were replaced by RAS wild type populations. Mechanistically, functional dissection of mouse and human wild type Kras and mutant Kras (Kras G12D) isogenic leukemia cells demonstrated induction of methotrexate resistance, but also improved response to vincristine, in mutant Kras- expressing lymphoblasts. These results identify chemotherapy driven selection as a central mechanism of leukemia clonal evolution and pave the road for the development of tailored personalized therapies for the treatment of relapsed ALL.

Study phs001072

Studies in the Natural History and Pathogenesis of Childhood-Onset and Adult-Onset Idiopathic Inflammatory Myopathies

The present study compares transcript and protein regulation in peripheral blood of adult and juvenile dermatomyositis (DM) patients vs. healthy control subjects to identify novel pathways in active patients under treatment. Whole blood data is submitted representing transcript and protein expression, including 14 adult DM and 11 juvenile DM (JDM) patients, and 11 healthy pediatric controls. Whole blood RNA was examined using Affymetrix Human U133 Plus 2.0, and whole blood protein measurements were obtained using SOMAscan Assay v3.2 aptamer-based DNA probes.Expression of 1,124 gene loci were significantly altered at the transcript or protein levels across DM or JDM, with 70 genes shared. A subset of interferon-stimulated genes was elevated. Innate immune markers specific to neutrophil granules and neutrophil extracellular traps were up-regulated in both DM and JDM. Pathway analysis revealed up-regulation of PI3K/AKT, ERK, and p38 MAPK signaling. Up-regulated components shared by DM and JDM included: cytokine:receptor pairs LGALS9:HAVCR2, LTF/NAMPT/S100A8/HSPA1A:TLR4, CSF2:CSF2RA, EPO:EPOR, FGF2/FGF8:FGFR; several Bcl-2 components; and numerous glycolytic enzymes. Pathways unique to DM included sirtuin signaling, aryl hydrocarbon receptor signaling, protein ubiquitination, and granzyme B signaling.

Study phs003270

A Study of the Genetic Causes of Complex Pediatric Disorders

The Center for Applied Genomics (CAG) at the Children's Hospital of Philadelphia (CHOP) is a high-throughput, highly automated genotyping and sequencing facility equipped with state-of-the-art genotyping and sequencing platforms. Children who are treated at the Children's Hospital Healthcare Network and their parents may be eligible to take part in a major initiative to collect more than 100,000 blood samples, covering a wide range of pediatric diseases. A large majority of participants consenting to prospective genomic analyses also consent to analysis of their de-identified electronic medical records (EMRs). EMRs are longitudinal, with a mean duration of 6.5 years. CAG has committed to releasing genotype and phenotype data for 4000 individuals diagnosed with asthma, ADHD, atopic dermatitis, GERD (1000 for each), and 1000 individuals on the upper and lower ranges of Low-Density Lipoprotein (LDL) levels to dbGaP. We will also release genotype/phenotype of 3000 controls. Relevant phenotype data includes primary diagnoses (ICD9 codes), secondary diagnoses (ICD9 codes), medical procedures/tests conducted in relation to the phenotype, and a listing of relevant medications. Further details of CAG's research programs and capacity are available at: http://www.caglab.org

Study phs000490

Detection of Genes Predisposing to Hematologic Malignancies

We have been conducting genetic studies on families at high risk of different hematologic malignancies, in order to define the related tumors in the families, define precursor and other related conditions, and map and identify susceptibility genes. We have focused mainly on four types of lymphoid malignancies: chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and Waldenström macroglobulinemia (WM). A few families with a rare lymphoma subtype, hairy cell leukemia (HCL) are included. In addition, single large pedigrees with acute myeloid leukemia (AML), and juvenile myelomocytic leukemia (JMML) are included. Families are ascertained for having at least two patients with the same hematologic malignancy and are classified by the type of malignancy that predominates in the family. Multiple types of lymphoid malignancies are often found in the same family. Other data has shown that these conditions aggregate together in families. Verification of cancer diagnoses is obtained through medical records, pathology reports, and flow cytometry. Family members with precursor traits are also included, monoclonal B-cell lymphocytosis (MBL) in CLL families and IgM monoclonal gammopathy of undetermined significance (MGUS) in WM families.

Study phs001219

Genome-Wide Association Studies in Upper Gastrointestinal Cancers (Asian)

This project aims to conduct genome-wide association studies (GWAS) in two anatomically different upper gastrointestinal (UGI) cancer sites in two populations with distinctly different disease rates and genetic profiles. One population has very high rates for both esophageal squamous cell carcinomas (ESCCs) and gastric cancers (GCs) and is comprised of Asians (the "Asian UGI GWAS"), while the other population has low rates of ESCC and GC and includes non-Asians from the Americas, Europe, and Australia (the "Non-Asian UGI GWAS"). Study participants for the Asian UGI GWAS reported here (Illumina 660W Quad chip) were drawn from 2 studies, the Shanxi Upper Gastrointestinal Cancer Genetics Project (Shanxi) and the Linxian Nutrition Intervention Trial (NIT), a prospective cohort, and included a total of 1898 ESCCs, 1625 GCs, and 2100 controls. For the 2nd phase (8 TaqMan SNPs), additional subjects from Shanxi and NIT as well as subjects from the Shanghai Men's Health Study (SMHS), the Shanghai Women's Health Study (SWHS), and the Singapore Chinese Health Study (SCHS) were also included (217 ESCCs, 615 GCs, 1202 controls). Altogether 2115 ESCCs, 2240 GCs, and 3302 controls were genotyped in this study.

Study phs000361

Whole Exome and Transcriptome Sequencing in Sporadic ALS

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a fatal and devastating neurodegenerative disorder that causes the progressive death of upper and lower motor neurons. Although many efforts have been done to elucidate molecular factors involved in the onset and progression of the disorder, the causes of ALS are yet unknown and undefined. Transcriptome studies, based mostly on microarrays, have revealed multiple perturbations of the motor neuron function, supporting the current idea that several cellular events contribute to the pathobiology of the disease, including mitochondrial dysfunction, enhanced apoptosis, glutamate-mediated excitotoxicity, free radical injury, protein misfolding, abnormal calcium metabolism and altered axonal transport. In the present study, we have deeply sequenced the whole transcriptome of ventral horns of the human lumbar spinal cord from matched control and ALS post-mortem donors. Whole exome sequencing from the same donors has also been performed to exclude known genetic variants associated to the familiar form of ALS. In addition, to characterize the ALS transcriptome we have sequenced the RNA fraction at low molecular weight in the same tissues and individuals. Genomic and transcriptomic reads have been generated using the Illumina HiSeq2000 sequencer.

Study phs000747

Evaluation of Nuclear DNA from Rootless Hairs for Forensic Purposes

The study aims to overcome current limitations in the recovery of DNA from small, difficult forensic samples. Particularly, our goal is to produce a robust laboratory protocol and the accompanying software to accelerate adoption, as well as to evaluate the reliability and robustness of both the laboratory and computational aspects of generating genotype files from minute and/or degraded DNA samples, such as single, rootless hairs.The data accompanying this study includes raw, paired-end reads from high-throughput sequencing of two panels of saliva, head hair, and pubic hair samples collected from anonymous volunteers at the University of California, Santa Cruz. The smaller set (Hair1.0) comprises 8 individuals, while the larger (Hair2.0) comprises 50 individuals, with 3 overlapping individuals between the two panels identified in post-collection analysis. We did not collect phenotype data or personally identifying information from the participants. For the Hair2.0 panel, only a subset of volunteers provided pubic hairs for DNA extraction and sequencing. Also included are saliva-derived genotype array data for all 8 individuals in the Hair1.0 panel and 44 of 50 individuals in the Hair2.0 panel.

Study phs002979

SNPs and Extent of Atherosclerosis (SEA) Study

The SEA study is a genome-wide association study to identify genetic variants associated with premature atherosclerosis in subjects included in the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) repository - a unique NHLBI resource including data, DNA and arterial specimens from over 3000 multi-ethnic subjects 15-34 years of age who died of non-atherosclerotic causes (mostly trauma). All PDAY subjects had post-mortem quantitative assessment of raised atherosclerotic lesions in their aorta and coronary arteries - making this the largest and most carefully phenotyped cohort for premature atherosclerosis in the world. The goal of the current project was to use the quantitative measure of raised atherosclerotic lesions in the PDAY cohort as the target phenotype for a genome-wide association study and to use quantitative measures of subclinical atherosclerosis (coronary calcium and carotid IMT) in the Multi-Ethnic Study of Atherosclerosis (MESA) to confirm or refute candidate loci identified from the PDAY analysis. Identifying genetic factors that predispose individuals to premature atherosclerosis could lead to more effective screening and early treatment of high risk individuals and suggest novel molecular targets for treatment and prevention interventions.

Study phs000349

Pharmacogenomics of HIV Therapy - Atazanavir Bilirubin-related Side Effects

This is an evaluation of genetic associations with atazanavir (ATV) discontinuation for bilirubin-related causes within 12 months of treatment. Patients were treated at an HIV primary care clinic in Nashville TN from 1998 to 2012. A previously known SNP in UGT1A1 (rs887829) was used to define metabolizer genotypes (extensive, intermediate, slow metabolizer). Over 500,000 SNPs from genome-wide genotyping were used to define MDS (Multidimensional Scaling) coordinates to account for population stratification. Patients were defined as cases if they discontinued ATV for bilirubin-related causes within 12 months of treatment, otherwise they were defined as controls if they did not stop treatment. Among 321 evaluable patients, 15 (4.6%) had bilirubin-related atazanavir discontinuation within 12 months. Homozygosity for rs887829 T/T was present in 28.1% of black, 21.4% of Hispanic, and 8.6% of white patients. Among all patients the hazard ratio (HR) for bilirubin-related discontinuation with T/T versus C/C genotype was 7.3 (95% C.I.: 1.7 to 31.5; p = 0.007). Among 152 white patients the HR was 14.4 (95% CI: 2.6 to 78.7; p = 0.002), but among 153 black patients the HR was 0.8 (95% C.I. 0.05 to 12.7; p = 0.87).

Study phs001484

Transcriptomic Characterization of Human Innate T Cells

We performed low input RNA-seq and single-cell RNA-seq on 7 lymphocyte populations with the objective of finding the common transcriptional programs shared among innate T cells. In brief, we drew blood from healthy donors and isolated CD4+ T cells, CD8+ T cells, Natural Killer cells, invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, and two γδ T cell populations: Vδ1 and Vδ2. We performed low input RNA-seq on samples with 1000 cells each, for 6 healthy individuals, in duplicate. We performed single-cell RNA-seq with DNA-barcoded hashing antibodies to identify the cell type of origin for each cell. We found a common transcriptional program across lymphocytes that is gradually turned on as lymphocytes have a more "innateness" state, promoting effector functions and sacrificing proliferative capacity. Additionally, we performed low input RNA-seq for Vδ3-expressing γδ T cells and δ/αβ T cells for one healthy individual in duplicate (1000 cells per sample). This revealed δ/αβ T cells are transcriptionally more adaptive-like and Vδ3 more innate-like.

Study phs002007

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