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• 2014 sequenced WGS-Lung Cancer sample 30 pair

  This data is belong to WGS-Lung Cancer patients' genome data which is aligned to human reference(human_g1k_v37.fasta). There are 30 paired tumor/normal samples from Samsung Hospital. All samples has passed QC and recalibration steps while aligning to reference.

  Dataset EGAD00001003978

• 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

• Single nucleus RNA sequencing of squamous cell carcinoma arising from mature teratoma of the ovary

  Squamous cell carcinoma arising from mature teratoma is one of the rare ovarian cancers. Therefore, the detailed molecular background of this disease has not been elucidated. The purpose of this study is to investigate the single-cell transcriptional landscape of this disease.

  Study JGAS000521

• Emirati Haploid Single-Sample-Assemblies (30 Individuals, 60 Assemblies)

  This dataset provides 27 phased diploid genome assemblies for Emirati trios, delivered in FASTA format. Assemblies were built with hifiasm (trio mode) from PacBio HiFi reads at ≥25× coverage for each parent and offspring, then scaffolded with NTLink and reference-guided merging using RagTag against CHM13v2. As part of the same program, a complementary set of single-sample diploid assemblies for 30 individuals (yielding 60 haplotypes) is being generated from deep PacBio HiFi data to expand a population-matched pangenome reference. Together, these resources capture Emirati genomic diversity and support downstream variant discovery and annotation.

  Dataset EGAD50000001753

• Whole genome sequencing of patients with or at risk for HCC

  Liver cancer is a major cause of cancer mortality worldwide. Screening individuals at high risk, including those with cirrhosis and viral hepatitis, provides an avenue for improved survival, but current screening methods are inadequate. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome analyses to evaluate 724 individuals from the United States, the European Union, or Hong Kong with hepatocellular carcinoma (HCC) or who were at average or high-risk for HCC. Using a machine learning model that incorporated multifeature fragmentome data, the sensitivity for detecting cancer was 88% in an average-risk population at 98% specificity and 85% among high-risk individuals at 80% specificity. We validated these results in an independent population. cfDNA fragmentation changes reflected genomic and chromatin changes in liver cancer, including from transcription factor binding sites. These findings provide a biological basis for changes in cfDNA fragmentation in patients with liver cancer and provide an accessible approach for noninvasive cancer detection.

  Study EGAS00001007249

• Predicting Chemotherapy-Induced Mucositis with Genetic and Clinical Factors

  We hypothesized that genetic variability in the enzymes/proteins involved in drug metabolism, inflammation, and immune function is a major underlying contributor to mucositis incidence and progression and that, based on this variability we can identify variants that influence risk, and develop a mucositis progression prediction model that improves on existing models by incorporating genetic variability along with clinical factors. Using genome wide association study (GWAS) combined with a pathway candidate gene approach and a modified case-control study method, we investigated the hypothesis in a sample of 1092 patients who received a myeloablative dose of melphalan (MEL) followed by autologous hematopoietic stem cell (ASCT) transplantation as treatment for multiple myeloma and for whom banked blood stem cell samples and clinical data were available.

  Study phs000545

• SNP array analysis of spondylocostal dysostosis patient iPSCs and gene edited isogenic controls

  This study, "SNP Array Analysis of Gene Edited SDV Patient iPSCs" is part of a larger study where we applied our recently established experimental in vitro model system of the human segmentation clock, for the analysis of human segmentation defects of the vertebrae (SDV) including spondylocostal dysostosis (SCD). To this end we generated patient-derived iPSC lines, identified putative disease-causing mutations and corrected these mutations using CRISPR/Cas9-based genome editing technology. We identified in the patient-sample originally obtained from the NIGMS Human Genetic Cell Repository at the Coriell Institute for Medical Research (#: GM13539) heterozygous compound mutations in MESP2. These mutations were corrected accordingly and the resulting clones were genotyped by SNP array analysis.

  Study phs001975

• Clinical validity of post-surgery circulating tumor DNA (ctDNA) in stage III colon cancer patients treated with adjuvant chemotherapy: the PROVENC3 study

  The PROVENC3 study aimed to determine the clinical validity of post-surgery ctDNA testing in patients with stage III colon cancer treated with adjuvant chemotherapy (ACT). Blood was collected pre-surgery, post-surgery and post-adjuvant chemotherapy. Tumor-informed plasma ctDNA detection was performed through integrated whole genome sequencing (WGS) analyses of formalin-fixed paraffin-embedded tumor tissue DNA (80x), white blood cell germline DNA (40x) and plasma cell-free DNA (30x). These raw WGS data for 209 patients are shared in .cram format in this EGA submission. For 196/209 of these patients there is overlapping FFPE tumor RNA sequencing data available, shared in .fastq format in this EGA submission.

  Study EGAS50000000804

• Digitalis Investigation Group (DIG-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. Objectives To determine the effect of increasing age on mortality, hospitalizations, and digoxin side effects in patients with heart failure (HF), and to determine whether the effect of digoxin on clinical outcomes varies as a function of age. Background The incidence and prevalence of HF increase with advancing age, but there are limited data on the clinical course and response to specific interventions in elderly patients with HF. Participants A total of 302 centers in the United States and Canada enrolled 7,788 patients between February 1991 and September 1993. Design The Digitalis Investigation Group (DIG) study was a prospective, randomized clinical trial involving 7,788 patients with HF randomized to digoxin or placebo and followed for an average of 37 months. Interactions between age and the following clinical outcomes were examined: total mortality, all-cause hospitalizations, HF hospitalizations, the composite of HF death or HF hospitalizations, hospitalization for suspected digoxin toxicity and withdrawal from therapy because of side effects. Conclusions Increasing age is associated with progressively worse clinical outcomes in patients with HF. However, the beneficial effects of digoxin in reducing all-cause admissions, HF admissions, and HF death or hospitalization are independent of age. Thus, digoxin remains a useful agent to the adjunctive treatment of HF due to impaired left ventricular systolic function in patients of all ages.

  Study phs003872

• Somatic mutations of non-malignant T cells

  Somatic mutations in T cells can cause cancer but also have implications for immunological diseases and cell therapies. The mutation spectrum in non-malignant T cells is unclear. Here, we examined somatic mutations in CD4+ and CD8+ T cells from 90 patients with hematological and immunological disorders and used T cell receptor (TCR) and single-cell sequencing to link mutations with T cell expansions and phenotypes. CD8+ cells had higher mutation burden than CD4+ cells. Notably, the biggest variant allele frequency (VAF) of non-synonymous variants was higher than synonymous variants in CD8+ T cells, indicating non-random occurrence. The non-synonymous VAF in CD8+ T cells strongly correlated with the TCR frequency, but not age. We identified mutations in pathways essential for T cell function and often affected in lymphoid neoplasia. Single-cell sequencing revealed cytotoxic Temra phenotypes of mutated T cells. Our findings suggest that somatic mutations contribute to CD8+ T cell expansions without malignant transformation.

  Study EGAS50000000237

• Gut Microbiome and Types of Colorectal Polyps

  Colorectal cancer is a heterogeneous disease arising from at least two precursors-the conventional adenoma and the serrated polyp. This dataset was used to test the relationship of the gut microbiota to specific colorectal polyp types. We included samples from two independent study populations based at colonoscopy clinics: the Centers for Disease Control and Prevention (CDC) Study of In-home Tests for Colorectal Cancer (SIT), and the New York University (NYU) Human Microbiome and Colorectal Tumor study. Gut microbiota were assessed in 667 colonoscopy-screened adults by 16S rRNA gene sequencing of stool samples, of which 540 were included in our analysis. Participants were categorized as conventional adenoma cases, serrated polyp cases, or polyp-free controls. CA cases were further classified as proximal or distal and as non-advanced or advanced. Serrated polyp cases were further classified as hyperplastic polyp or sessile serrated adenoma. Our results show associations between gut microbiome composition and presence of conventional adenomas, including reduced diversity and alterations in taxon abundance.

  Study phs001381

• California Teachers Study (CTS): Whole Genome Sequences From Under-Represented Populations

  The California Teachers Study (CTS) is a prospective observational cohort of N=133,477 adult women who have been followed since 1995. Participants completed up to six surveys and have been linked with cancer, hospitalization, and mortality data. In 2013-2016, over 14,000 CTS participants donated blood samples for future research. For this project, DNA was extracted in 2023 from 1694 buffy coats and 56 blood clots from N=1750 CTS participants whose self-reported race/ethnicity was Asian (398), Asian or Pacific Islander (18), Black or African American (189), Native American (128), Native Hawaiian or Other Pacific Islander (66), White Hispanic (719), or more than one race (232). Whole genome sequencing (WGS) was performed at CIDR in 2023-2024. WGS data and accompanying phenotype data are available through dbGaP. In addition, all CTS data are available to the research community via the CTS Researcher Platform (www.calteachersstudy.org), a secure cloud-based environment that includes data, software, documentation, and collaboration workspaces.

  Study phs002918

• TONIC-Trial-cfDNA-Project

  Cell-free DNA (cfDNA) is an emerging technology to predict and monitor response to cancer treatment, including immune checkpoint blockade (ICB). However, data on cfDNA dynamics during ICB in metastatic triple negative breast cancer (mTNBC) are limited. While most applications of cfDNA involve assays that focus on mutation detection, mTNBC and multiple other cancer types are driven by copy number alterations (CNAs). We evaluate cfDNA-based copy number profile abnormality (CPA) score as a potential biomarker for monitoring ICB response in mTNBC, analyzing data from 87 patients enrolled in stage 1 and stage 2 of the TONIC-trial. We find significant concordance between cfDNA-based and tissue-based CNA profiles. Additionally, responders show a decrease in CPA scores upon ICB at week 6 (3 cycles of nivolumab). These findings underscore the potential of cfDNA-based CNA dynamics as a non-invasive biomarker for ICB early response assessment in patients with mTNBC.

  Study EGAS50000001308

• Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs drug target discovery in ankylosing spondylitis

  Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterised by enthesitis of the spine and sacroiliac joints. Genome-wide association studies have revealed >100 genetic associations but their functional effects remain largely unresolved. Here, we present a comprehensive transcriptomic and epigenomic map of disease-relevant blood immune cell subsets from AS patients and healthy controls. We report differential disease signatures for specific genomic regions from individual -omic modalities and multi-omic integration, showing enrichment at genetically associated loci and evidence for altered monocyte function in AS. We link putative functional SNPs with cognate genes using high-resolution Capture-C at 10 loci, including PTGER4 and ETS1. We also show how disease-specific functional genomic data can be integrated with GWAS evidence to enhance therapeutic target discovery. This study combines multiple epigenetic and transcriptional analysis with GWAS to identify cell types, candidate drug target genes and transcriptional regulation of likely pathogenic relevance.

  Study EGAS00001006233

• Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs drug target discovery in ankylosing spondylitis

  Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterised by enthesitis of the spine and sacroiliac joints. Genome-wide association studies have revealed >100 genetic associations but their functional effects remain largely unresolved. Here, we present a comprehensive transcriptomic and epigenomic map of disease-relevant blood immune cell subsets from AS patients and healthy controls. We report differential disease signatures for specific genomic regions from individual -omic modalities and multi-omic integration, showing enrichment at genetically associated loci and evidence for altered monocyte function in AS. We link putative functional SNPs with cognate genes using high-resolution Capture-C at 10 loci, including PTGER4 and ETS1. We also show how disease-specific functional genomic data can be integrated with GWAS evidence to enhance therapeutic target discovery. This study combines multiple epigenetic and transcriptional analysis with GWAS to identify cell types, candidate drug target genes and transcriptional regulation of likely pathogenic relevance.

  Study EGAS00001006945

• Genome-wide Rare Variant Score Associates With Morphological Subtypes of Autism Spectrum Disorder

  Defining different genetic subtypes of Autism Spectrum Disorder (ASD) can help predict developmental outcomes. Based on minor physical and major congenital anomalies, we categorized 325 Canadian children with ASD into dysmorphic and non-dysmorphic subgroupings. We developed a method to calculate a genome-wide rare variant score (GRVS) from whole-genome sequencing (WGS) data for each ASD proband. GRVS is a sum of the number of variants in morphology-associated coding and non-coding regions, weighted by their effect sizes. Probands with dysmorphic ASD had a significantly higher GRVS compared to those with non-dysmorphic ASD (P= 0.027). Using the polygenic transmission disequilibrium test, we observed an over-transmission of ASD-associated common variants in non-dysmorphic ASD probands (P= 2.9×10-3). We replicated our findings using 442 ASD probands that had accompanying morphology data in the Simons Simplex Collection. Our findings provide support for an alternative genomic classification of ASD subgroups using morphology data, which may inform intervention protocols.

  Study EGAS00001005753

• PRE-DETERMINE: Biologic Markers and MRI SCD Cohort Study

  The PRE-DETERMINE Study is a prospective, multi-center study of 5,764 patients with a history of coronary artery disease (CAD) and documentation of either a prior myocardial infarction (MI) or mild to moderate left ventricular dysfunction (LVD) with left ventricular ejection fraction (LVEF) 35-50%. Patients were enrolled at 136 sites where information on baseline demographics, clinical characteristics, pertinent past medical history, lifestyle habits, cardiac test results, and medications were collected via electronic data capture. Electrocardiograms (ECG) along with a blood sample was also collected at baseline, sent to central laboratories, and stored for future analyses. Contrast-enhanced magnetic resonance imaging (CE-MRI) scans were collected on a subset of patients and analyzed. Enrollment closed in November 2013 and patients are now being followed centrally by the Clinical Coordinating Center via mail/phone to document interim non-fatal arrhythmic events and cause-specific mortality. Questionnaires that inquire about intervening implantable cardiac defibrillator (ICD) implantations, ICD therapies, cardiac arrest, and other pertinent cardiovascular endpoints are mailed to participants every six months, and follow-up telephone calls are made to non-responders. Study endpoints are being confirmed through review of medical records, interviews with next-of-kin, and autopsy reports, if available.The primary objective of PRE-DETERMINE is to determine whether biologic markers and ECGs can be utilized to advance sudden cardiac death (SCD) risk prediction in patients with coronary heart disease (CHD) and LVEF >30-35%. The overarching goal of the study is to identify a series of markers that alone or in combination specifically predict risk of arrhythmic death as compared to other causes of mortality among this at risk population of CHD patients with preserved LVEF> 30-35%. If biologic or ECG markers are identified that can specifically predict risk of ventricular arrhythmias, then these markers may serve as relatively inexpensive methods to identify those at risk. The public health impact of identifying markers could be quite substantial, leading to more efficient utilization of ICDs and advances in our understanding of mechanisms underlying SCD.Among the 95% of participants that provided a blood sample at baseline, genome wide genotyping using the Illumina Global Screening Array (GSA) has been performed. A total of 4,335 participants with European ancestry gave consent that allows genetic research and deposition of data into dbGaP.

  Study phs002940

• Molecular profiling of blastic plasmacytoid dendritic cell neoplasm (BPDCN) as compared to acute myeloid leukemia (AML)

  Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, male-predominant myeloid malignancy that is characterized by the malignant proliferation of precursor plasmacytoid dendritic cells (pDCs) with morphologic and molecular similarities to acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in its presentation within the bone marrow and peripheral blood. To identify disease-specific molecular features of BPDCN, we profiled bone marrow, peripheral blood and serum samples from primary patient samples using an in-house hematologic malignancy panel (“T300” panel), transcriptome microarray, and serum multiplex immunoassays and compared results to a cohort of AML patients.

  Study EGAS00001003453

• Cancer Research UK Manchester Institute/ Cancer Research UK National Biomarker Centre Data Access Committee

  Cancer Research UK Manchester Institute/Cancer Research UK National Biomarker Centre Data Access Committee is created to • Review and approve data access requests. • Ensure data security and compliance with institutional and legal obligations. • Maintain accurate records of access decisions For questions or further information, please contact: Chair of the Data Access Committee: Caroline Wilkinson Email: dac@cruk.manchester.ac.uk

  Dac EGAC50000000795

• Predictor_ChemoNEAR_TNBC (2019-08-14)

  In this study a collection of core biopsies from breast cancer patients receiving neoadjuvant chemotherapy as part of the ChemoNEAR trial will be investigated. The study is intended to detect early acquired resistance in women with diagnosed breast carcinoma. Samples will undergo whole genome sequencing and analysis, including use of HR Predict. . This dataset contains all the data available for this study on 2019-08-14.

  Dataset EGAD00001005255

• The mutation burden of narrowband ultraviolet B phototherapy in human skin - Nanoseq

  Background: Ultraviolet radiation (UV) is used as a treatment for psoriasis, but UV can also induce mutations which may lead to development of skin cancer. Information on the mutagenicity of narrowband UVB (NBUVB) would help inform clinicians and patients who are concerned about the potential risks of this treatment.

  Dataset EGAD00001015249

• The mutation burden of narrowband ultraviolet B phototherapy in human skin - WGS

  Background: Ultraviolet radiation (UV) is used as a treatment for psoriasis, but UV can also induce mutations which may lead to development of skin cancer. Information on the mutagenicity of narrowband UVB (NBUVB) would help inform clinicians and patients who are concerned about the potential risks of this treatment.

  Dataset EGAD00001015250

• Early detection of ovarian cancer using cell-free DNA fragmentomes and protein biomarkers

  Ovarian cancer is the leading cause of death from gynecological cancers worldwide. No effective screening methods exist, and tumors are commonly detected at advanced stages where treatment is much less effective. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women from the European Union or the United States with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model that incorporated multi-analyte fragmentome data and protein measurements, we detected ovarian cancer with high specificity >99% and sensitivity of 72%, 69%, 87%, and 100% for stages I–IV, respectively (AUC=0.96, 95% CI: 0.94-0.99), including 90% of high grade serous ovarian cancers. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100% of ovarian cancers for stages I–IV (p=0.001, two-sided test of equal proportions). Additionally, our approach distinguished benign masses from ovarian cancers with high accuracy (AUC of 0.88, 95% CI=0.83-0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation.

  Study EGAS50000000484

• Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy

  Background: Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits including cardiovascular diseases.Results: Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 149 (97)* patients with dilated cardiomyopathy and 113 (108)* non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage and allele specific expression. Systematic annotation of genome wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome wide association signals in two independent cohorts.Conclusions: RNA transcription, splicing and allele specific expression are each important determinants of the DCM phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics. (*) numbers in parentheses represent samples that the publication is based on.

  Study EGAS00001002454

• University of Utah Pelvic Organ Prolapse Disorder Study

  The overall purpose of this University of Utah Pelvic Organ Prolapse Disorder Study was to identify and localize predisposition genes contributing to pelvic organ prolapse (POP). POP cases recruited for this study were identified by one of three methods: high-risk POP pedigree cases, POP sister pairs, and surgically-treated POP cases reporting a family history of POP. High-risk POP pedigree cases were identified using the Utah Population Database (UPDB), a genealogy database of residents in Utah that has been linked to diagnostic ICD9 and CPT codes in medical records at the University of Utah and Intermountain Healthcare. We identified families with a significant excess number of POP cases compared to matched population rates and targeted these individuals for recruitment as well as any other POP cases in the family. POP sister pair cases were identified at the University of Utah Urogyncology clinic for women who had undergone POP surgery and also self-reported one or more sisters who were also surgically treated for POP. POP affection status of all sisters was confirmed either by physical examination or by chart review. Surgically treated-POP cases reporting a family history of POP were identified at the University of Utah Urogyncology clinic by self-report of a family history of POP. Efforts were made to recruit other affected family members and confirm affection status. To obtain DNA, subjects provided either a blood specimen or saliva. Medical records were reviewed by a urogynecologist and diagnostic information for pelvic organ prolapse and stress and overactive bladder were obtained. Collected DNA was genotyped and analyzed. To maintain confidentiality of the familial data, genetic data from only one subject per family has been submitted to dbGaP. Use of the University of Utah Pelvic Organ Prolapse Disorder Study data is limited to investigators studying pelvic floor disorders. These pelvic floor disorders include pelvic organ prolapse, urinary and anal incontinence, and other conditions related to weakening or injury to the muscles and connective tissue in the pelvis as a result of pelvic surgery, pregnancy, or vaginal delivery of a child. These data will be used only for research purposes related to pelvic floor disorders. They will not be used to determine the individual identity of any person or their relationship to another person or for research on non-disease traits.

  Study phs001439

• ENU_HT_29_BRAF_Triple_Therapy_Clones

  KRAS mutant CRC is currently in clinical trial with a combination of a MEK and Akt inhibitor. These patients will likely develop resistance to this combination. We aim to identify the mechanisms of resistance via ENU mutagenesis, with a view to identifying additional therapeutics which have the ability to overcome this resistance.

  Study EGAS00001001778

• Small-molecule inhibitors in melanoma - Kenski / Kong - WES (2019-04-11)

  Small-molecule inhibitors targeting the most commonly activated pathway in melanoma, MAPK pathway (either alone or in combination) are already given to melanoma patients for few years, and initially reduce tumour burden dramatically, eventually melanomas become resistant and tumours progress while on treatment. Resistance to this treatment occurs by acquisition of additional mutations or other alterations that affect the mitogen-activated protein kinase (MAPK) pathway by either direct or indirect signalling. Many resistance mechanisms somehow lead to reactivation of extracellular signal-regulated kinase (ERK), thereby restoring signalling of the oncogenic BRAF/MEK/ERK pathway. In addition, PI3K pathway activation contributes to resistance to BRAF inhibition. Less frequent but equally important to the phenomenon of targeted drug resistance is the observation that B15-20% of BRAF mutant melanoma patients fail to respond to BRAF inhibition already early on treatment, owing to intrinsic resistance. These patients have little therapeutic options, unless immunotherapy can be given. To better understand the resistance mechanisms in MAPK inhibitor-treated melanoma patients and melanoma biology, our lab generated a big panel of MAPK inhibitor resistant melanoma cell lines by continuous drug exposure. The understanding of the genetic landscape and gene expression as well as cross resistance to other treatment regimens, and other aspects of melanoma biology such as phenotype switch, will allow us to better exploit new therapeutic strategies for melanoma patients. . This dataset contains all the data available for this study on 2019-04-11.

  Dataset EGAD00001004952

• The study on genomic profiling using clinical specimens (tissue, blood, etc.) form patients with lung and thymic tumors

  The objective is to generate a comprehensive immunogenomic profiling in thymoma using RNA sequencing and TCR repertoire analysis and to evaluate the potential of immunotherapy in thymoma from multiple perspectives.

  Study JGAS000552

• Genomic and Transcriptomic Profile of Paired Primary-Metastasis Colorectal Tumors

  The goal of this study is to identify mechanisms of metastization in a portuguese cohort of colorectal cancer. Namely, we want to identify patterns of genomic and transcriptomic diversification associated with metastasis.

  Study EGAS00001005276

• Dedifferentiated_Melanoma_RNAseq

  De- and transdifferentiation of melanoma is a rare histopathological phenomenon that has not be characterised genetically. In this project we plan to sequence the genomes of de and transdifferentiated cases so as to define their genetic make-up.

  Study EGAS00001003601

• Targeted Pulldown Validation of mutations found in whole genome sequencing

  This experiment is to inform us of the validity of using pre-made library material to perform a bespoke pulldown experiment to validate the mutations found between the whole genome sequencing of the DNA from the same individuals cancer and normal material. This is to identify the valid and informative mutations in cancer genomes.

  Dataset EGAD00001001061

• Asian Indian Diabetic Heart Study (AIDHS) /Sikh Diabetes Study (SDS)

  The Punjabi Sikh population is a well-defined, carefully collected homogeneous sample from northern India and the US. It has unique characteristics, which are ideal for genetic studies. Sikhs are strictly a non-smoking population and about 50% of participants are life-long vegetarians. All subjects included in the genome-wide association studies (GWAS) were recruited from one geographical location. Our population demonstrates a strong familial clustering of type 2 diabetes and related cardio-metabolic disorders that may be genetic and we believe that the contribution of alleles at specific loci are likely to be unique to Punjabi Asians compared to Europeans. Our group first showed that the association of a common variant at rs9939609 in the FTO (fat mass and obesity) gene in South Asians was independent of BMI (PMID:18598350) in contrast to Europeans where the association of same variant with T2D is mediated through obesity (PMID:17434869). These findings were later confirmed in an independent sample of South Indians (PMID:19005641), Pakistanis (PMID:21294771), and even East and South Asians in a large meta-analyses study comprising 96,551 individuals (PMID: 22109280). Earlier reported association of MTNR1B with fasting glucose concentrations and type 2 diabetes in European GWAS could not be confirmed in our Sikh cohort. On the other hand, our study revealed, for the first time, a significant protective association of another less common variant in MTNR1B with fasting glucose levels that was modulated by obesity. Ours was the first report that suggested that the low CETP activity was associated with higher CAD risk (PMID:22143414) in South Asians and that the genetic effects are significantly modulated by environmental factors (alcohol consumption). Our recent GWAS on type 2 diabetes has identified a novel locus at chromosome 13q12 in the SGCG gene (p=1.82x10-8) associated with type 2 diabetes (PMID:23300278) in Punjabi Sikhs. From these findings, we are optimistic that our resource will provide new insights to gene functions in the diabetic pathway and better help researchers to understand and translate these insights to novel therapeutic treatment and early prevention to T2D that may be important beyond Indians.

  Study phs000583

• Advancing Precision Oncology in a Humanized, Fully Autologous Mouse Model

  Progress in the early detection and treatment of cancer requires accurate model systems to further evaluate new, promising discoveries. Small animal and, in particular, mouse model systems are attractive to researchers for numerous reasons, including their ease of use and well-described platforms. The ability to grow human tumors in immune-deficient mice (so-called patient-derived xenografts, or PDXs) allows researchers to work directly with human cancer tissue in a controlled setting. However, PDX models are limited by their lack of an intact immune system. Immunotherapy has revolutionized clinical oncology, but lacks pre-clinical models of the human immune system and human cancer to investigate new modalities and limitations/toxicities of treatment regimens. The broad objective of this study is to validate an in vivo model to evaluate human tumors in the context of a complete and intact human immune system in a completely personalized and autologous fashion to study cancer immunotherapy. Herein, we will: (1) validate the ability of our humanized system to serve as a model for cancer immunotherapy treatment response and toxicity in patients with melanoma, including immunotherapy checkpoint blockade and vaccine strategies, and (2) extend our current work in melanoma by validating the ability to establish humanized mice and evaluate tumor growth and leukocyte development in autologous human pancreatic and colorectal tumors established in humanized mice. In each of these areas, we will leverage our multi-institutional team's individual expertise along with our institutional infrastructure to maximize the success of the experimental aims. The results from this project will be widely available to the general research community for future, hypothesis-driven research. Taken together, our study will meet multiple goals and address several unmet needs in cancer immunotherapy, thus significantly enhancing the applicability of a fully autologous and immunocompetent precision model system for use in translational oncology research.

  Study phs003090

• LLDeep DAG2+: scRNA-seq in PBMCs

  Single cell transcriptomics of PBMCs of 47 donors from the Lifelines Deep cohort (general population, Northern part of the Netherlands). Cells of five or six different donors were pooled together in one sample pool, resulting in eight different sample pools. In total, 28.855 cells were captured and their transcriptomes were sequenced to an average depth of 74k. Genotype data was available for each donor, which allowed us to use the Demuxlet method that uses variable SNPs between the pooled individuals to determine which cell belongs to which individual. Since genotype information is lacking of 2 individuals, the transcriptome of only 45 individuals could be retrieved.

  Dataset EGAD00001003459

• Mutational patterns and regulatory networks in epigenetic subgroups of meningioma (H033)

  DNA methylation patterns delineate clinically relevant subgroups of meningioma. We previously established the six meningioma methylation classes (MC) benign-1, 2, 3, intermediate-A, B and malignant. Here, we set out to identify subgroup-specific mutational patterns and pathway regulation. Whole-genome-sequencing was performed on 62 samples across all MCs and WHO grades from 62 patients with matched blood control, including 40 sporadic and 22 radiation-induced (Mrad) meningiomas. RNA sequencing was added for 18 cases and chromatin-immunoprecipitation for the enhancer mark H3K27ac followed by sequencing (ChIP-seq) for 16 samples. Besides the known mutations in meningioma, structural alterations were found to contribute to the spectrum of mechanisms inactivating NF2 in sporadic meningioma similar to previous reports for Mrad. Aberrations of DMD were found to be enriched in MCs with NF2 mutations and DMD was among the most differentially upregulated genes in NF2 mutant compared to NF2 wild-type cases. The mutational signature AC3 was detected in both sporadic meningioma and Mrad, but distributed across the genome in sporadic cases and enriched near genomic breakpoints in Mrad. In general, the malignant MC presented a significantly higher exposure to AC3 and higher genomic instability beyond the mutational load than the other MCs. Pathway analysis of the ChIP-seq clusters revealed that the FOXM1 is most differentially activated in high-grade cases, along with super enhancer recruitment near HOX genes and respective upregulation of expression. This data further elucidate the biological mechanisms differentiating meningiomas of different WHO grade and epigenetic subgroups and suggest leveraging the genomic instability as novel therapeutic targets.

  Study EGAS00001003481

• Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY)

  The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) has sponsored a consortium of investigators to conduct a clinical treatment trial, Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY). The primary objective of the TODAY trial is to compare the efficacy of three treatment arms on time to treatment failure based on glycemic control. The secondary aims are to:compare and evaluate the safety of the three treatment arms;compare the effects of the three treatments on the pathophysiology of type 2 diabetes (T2D) with regards to beta cell function and insulin resistance, body composition, nutrition, physical activity and aerobic fitness, cardiovascular risk factors, microvascular complications, quality of life, and psychological outcomes;evaluate the influence of individual and family behaviors on treatment response; andcompare the relative cost effectiveness of the three treatment arms.The three treatment regimens are: (1) metformin alone, (2) metformin plus rosiglitazone, and (3) metformin plus an intensive lifestyle intervention called the TODAY Lifestyle Program (TLP). The study recruits patients over a three-year period and follows patients for a minimum of two years. Patients are randomized within two years of the diagnosis of T2D.

  Study phs002447

• Brain tumor sequencing data

  This study contains tumor DNA (with matched normal) for 1 medulloblastoma and 1 ependymoma patient. Tumor RNA sequencing data is also present for the medulloblastoma patient

  Study EGAS00001006352

• Genetic analysis of short stature using whole exome sequencing

  The aim of the study is to find the genetic aetiologies of short stature, using whole-exome sequencing technology.

  Study EGAS50000000578

• Somatic_mutations_in_twin_breast_cancers

  The aim of this study is to investigate the somatic mutations in twins with BRCA1/2 negative breast cancer with no strong family history.

  Study EGAS00001002379

• Genomics of acral lentiginous melanoma

  Melanoma is the most aggressive type of skin cancer, causing about 75% of dermatological cancer deaths. Acral lentiginous melanoma (ALM) is the most common subtype of melanoma in admixed Latin American populations, but very few tumour genomes and exomes, all from European-descent individuals, have been analysed across several studies. Because of this, the genomic landscape of ALM is mostly unknown. Our aim in this project is to define this landscape and identify driver somatic alterations by whole-exome sequencing a collection of ALM germline/tumour paired FFPE samples from the National Cancer Institute of Mexico. . This dataset contains all the data available for this study on 2023-03-09.

  Dataset EGAD00001010126

• ICGC Oesophageal adenocarcinoma - tumour samples

  The oesophageal project will focus on adenocarcinoma which is increasing in incidence in the UK and other developed countries and has a very poor outcome. The primary aims of this project are to deeply sequence tumour and normal genomic DNA (including the precursor condition Barrett’s oesophagus when material is available) to provide a comprehensive catalogue of somatic mutations. This will be achieved through a UK-wide network of hospitals involved in a research collaboration called the OCCAMS consortium. The goal of this project is to use high quality clinical material with accurately annotated clinic-pathological, treatment and outcome data.

  Study EGAS00001000725

• The Placenta Harbors a Unique Microbiome

  This study is to investigate placental microbiome through 16S rDNA-based and whole genome shotgun metagenomic sequencing. Identified taxa and their gene carriage patterns were compared to other human body sites niches. The placental microbiome profiles were most akin to the human oral microbiome.

  Study phs000735

• Resistance_to_MAPK_inhibitor_induces_internal_duplication_in_BRAF

  2 BRAFV600E cell lines that have been made resistance to 1. the BRAF inhibitor PLX4720 and 2. the combination therapy of dabrafenib and trametinib seem to have a internal duplication in the kinase domain. We would like to know if this is caused by a translocation.

  Study EGAS00001001304

• Diabetic Retinopathy Genomics Study (DRGen) - Genetic Biomarkers of Diabetic Retinopathy

  Using a well-defined, clinically supported phenotypic strategy, we seek to better understand the role of common and rare genetic variants in the progression of diabetic retinopathy (DR). Whole exome/whole genome sequencing (WES/WGS) was used to systematically search the human genome to detect DR susceptibility genes or genes that protect people from developing advanced DR. Clinical data and bio specimens were obtained from clinically defined DR phenotypes such as, (i) No/Mild NPDR (non-proliferative DR) with a subset of extreme phenotype, ii) Diabetic macular edema (DME) alone and iii) Proliferative diabetic retinopathy (PDR) alone. In this ongoing comprehensive genomic study, we wish to i) Identify potential common and rare variants that may influence the phenotypic differentiation of DR into DME or PDR, ii) Define genetic variants stratified based on the "extreme phenotype," and iii) Characterize genetic factors that determine the differential response to anti-VEGF drugs in DME patients. Definition of Diabetic Retinopathy and classification of groups Study 1. Proliferative diabetic retinopathy (PDR). Anybody showing evidence of retinal neovascularization on the disc (NVD) or elsewhere (NVE) with or without pre-retinal and vitreous hemorrhage will be considered PDR. We will include only those "active" PDR patients. The total number of consented subjects in this study is 182. Study 2. Isolated Phenotype: Varied response with anti-VEGF treatment is a significant limiting factor for better clinical outcomes. We quantify the response to anti-VEGF treatment based on visual acuity changes and anatomic features of DME assessed by optical coherence tomography (OCT). Depending on the response at one month following three monthly intravitreal anti-VEGF injections, we have observed two phenotypes: 1) Good responders: Participants were considered "good responders" if the anatomical outcome to anti-VEGF treatment resulted in a significant reduction of baseline central retinal thickness (CRT) > 25% after three anti-VEGF injections. 2) Poor Responders: Participants were classified as "poor responders" if the outcome of anti-VEGF treatment resulted in a reduction of CRT < 20% or in any increase in CRT after three monthly injections. The total number of consented subjects in this study is 17.

  Study phs002501

• Ischemia Reperfusion Responses in Human Lung Transplants at the Single Cell Resolution

  Ischemia reperfusion is an unavoidable step of organ transplantation. Development of therapeutics for lung injury during transplantation has proved challenging; understanding lung injury from human data at the single cell resolution is required to accelerate the development of therapeutics. Donor lung biopsies from six human lung transplant cases were collected at the end of cold preservation and 2-hour reperfusion and underwent single cell RNA sequencing. Donor and recipient origin of cells from the reperfusion timepoint were deconvolved. Gene expression profiles were (1) compared between each donor cell type between timepoints and (2) compared between donor and recipient cells. Inflammatory responses from donor lung macrophages were found after reperfusion with upregulation of multiple cytokines and chemokines, especially IL-1 and IL-1. Significant inflammatory responses were found in alveolar epithelial cells (featured by CXCL8) and lung endothelial cells (featured by IL-6 upregulation). Different inflammatory responses were noted between donor and recipient monocytes and CD8+ T cells. The inflammatory signals and differences between donor and recipient cells observed provide insight into the cellular and molecular mechanisms of ischemia reperfusion induced lung injury. Further investigations may lead to the development of novel targeted therapeutics.

  Study EGAS50000000490

• Somatic Mutations in Individual Skin Cells

  Ultraviolet (UV) radiation is the primary cause of melanoma through the acquisition of driver mutations in melanocytes. It also plays a significant role in oncogenesis in other skin cells, such as keratinocytes. However, the mutational profiles vary widely among different skin cancers, and the early mutational processes in different cell types from the same skin, is not well understood. Additionally, our preliminary studies also suggest that the mutation burden in different skin cells vary significantly based on risk factors such as the anatomical site and the use of tanning beds. To explore this, we employed innovative Next Generation Sequencing (NGS) tools to perform a site-matched comparison of the genomic landscapes of melanocytes, keratinocytes, and fibroblasts. From 20 biopsies of physiologically normal skin, collected from various anatomical sites across 16 donors, we have performed DNA-sequencing on 106 melanocytes, 78 keratinocytes and 13 fibroblasts. Of these samples, we have also simultaneously performed RNA-sequencing on 78 melanocytes, 46 keratinocytes and 9 fibroblasts. For normal bulk DNA, we also performed targeted (UCSF500; n=9) or exome sequencing (n=8) of skin or saliva samples from the donors.

  Study phs003683

• Distinct immune cell infiltration patterns in PDAC exhibit divergent immune cell selection and immunosuppressive mechanisms

  Pancreatic ductal adenocarcinoma has a dismal prognosis. A comprehensive analysis of single-cell multi-omic data from matched tumour-infiltrated CD45+ cells and peripheral blood in 12 patients, and two published datasets, reveals a complex immune infiltrate. Patients have either a myeloid-enriched or adaptive-enriched tumour microenvironment. Lymphocyte enrichment is intrinsically linked with highly distinct B and T cell clonal selection, diversification, and differentiation. Using TCR data, we see the largest clonal expansions in CD8 effector memory, senescent cells, and highly activated regulatory T cells which are induced within the tumour from naïve cells. We identify pathways that potentially lead to a suppressive microenvironement, including targets of immunotherapy and checkpoints including TIGIT/PVR and SIRPA/CD47. PDAC patient tumors from the APACT clinical trial revealed that patients with myeloid enrichment had the shorter overall survival compared to those adaptive cell enrichment. We identify multiple therapeutic targets that should form the basis for rational design including boosting of B cell responses, targeting immunosuppressive macrophages, and specific Treg depletion approaches. The dataset is scRNA-seq data from PDAC patients.

  Study EGAS50000000726

• Transcriptome human nasal epithelium

  1. Odors are detected, firstly, by olfactory sensory neurons (OSNs) in the olfactory epithelium of the nose. This neurons then project directly to the olfactory bulb in the brain. Olfaction depends on cellular regeneration of the OE, olfactory bulb and hippocampus, and on their continual re-wiring. The olfactory neural pathway includes regions of the frontal, temporal and limbic brain, which in turn overlap with brain areas involved in brain disorders. OSNs are the only aspect of the human brain exposed to the external environment. This not only makes them vulnerable to environmental changes, but also accessible for biomedical studies. We have already sequenced and developed a protocol for analyzing the transcriptome of mouse main olfactory epithelium and single OSNs. We propose here to perform a similar study for samples from the human olfactory epithelium. We have developed a minimally invasive method for obtaining human OSNs, among other cells from the nasal epithelium. In this experiment, we have obtained cell samples from the olfactory epithelium, including OSN, from healthy volunteers. We would like to further characterize them by RNA sequencing. This will give us valuable insight into human olfaction. It will also provide a first step into a new avenue to study, and find biomarkers for, brain diseases though the analysis of these easily available neurons. 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 EGAD00001002226

• NHLBI TOPMed: Rare Variants for Hypertension in Taiwan Chinese (THRV)

  The THRV-TOPMed study consists of three cohorts: The SAPPHIRe Family cohort (N=1,271), TSGH (Tri-Service General Hospital, a hospital-based cohort, N=160), and TCVGH (Taichung Veterans General Hospital, another hospital-based cohort, N=922), all based in Taiwan. 1,271 subjects were previously recruited as part of the NHLBI-sponsored SAPPHIRe Network (which is part of the Family Blood Pressure Program, FBPP). The SAPPHIRe families were recruited to have two or more hypertensive sibs, some families also with one normotensive/hypotensive sib. The two Hospital-based cohorts (TSGH and TCVGH) both recruited unrelated subjects with different recruitment criteria (matched with SAPPHIRe subjects for age, sex, and BMI category).

  Study phs001387

• Loss of SDHB promotes dysregulated iron homeostasis, oxidative stress and sensitivity to ascorbate

  Succinate dehydrogenase is a key enzyme in the tricarboxylic acid cycle and the electron transport chain. All four subunits of succinate dehydrogenase are tumor suppressor genes predisposing to paraganglioma, but only mutations in the SDHB subunit are associated with increased risk of metastasis. Here we generated an Sdhd knockout chromaffin cell line and compared it to Sdhb-deficient cells. Both cell types exhibited similar SDH loss of function, metabolic adaptation, and succinate accumulation. In contrast, Sdhb-/- cells showed hallmarks of mesenchymal transition associated with increased DNA hypermethylation and a stronger pseudo-hypoxic phenotype compared to Sdhd-/- cells. Loss of SDHB specifically led to increased oxidative stress associated with dysregulated iron and copper homeostasis in the absence of NRF2 activation. High-dose ascorbate exacerbated the increase in mitochondrial reactive oxygen species, leading to cell death in Sdhb-/- cells. These data establish a mechanism linking oxidative stress to iron homeostasis that specifically occurs in SDHB deficient cells and may promote metastasis. They also highlight high-dose ascorbate as a promising therapeutic strategy for SDHB-related cancers.

  Study EGAS00001005279

• CRC Promoter capture Hi-C

  Genome organisation determines chromosome interactions between regulatory elements, such as promoters and enhancers, influencing gene expression. Despite the fact that it is possible to assess whether a gene is actively transcribed, it has been challenging to point out the genomic regions that are involved in the regulation of a particular gene. We are interested in better understanding the interactions between promoters and their regulatory elements in colorectal cancer in order to unveil novel non-coding regions which might have a role in tumour development. To do so, we utilise the HiC method complemented with promoter capture in combination with NGS to map promoter interactions in two CRC cell lines, representing two distinct CRC subtypes.

  Study EGAS00001001946

• Heterogeneous metabolic signatures are linked to cancer cell differentiation in colorectal cancer

  Colorectal cancer (CRC) is characterized by functional intratumor heterogeneity that shares many similarites with the hierarchical organization of the normal intestinal epithelium. In order to relate transcriptional subtypes to functional tumor cell heterogeneity we applied scRNA-seq to 12 patient-derived CRC spheroid cultures. We identified shared expression programs that relate to intestinal lineages and revealed metabolic signatures that are linked to cancer cell differentiation. In addition, we validated and complemented sequencing results by quantitative microscopy using live-dyes and multiplexed RNA fluorescence in situ hybridization, thereby revealing metabolic compartmentalization and potential cell-cell interactions. Finally, we demonstrate functional differences between metabolically distinct lineage subtypes that might have strong implications for future treatment strategies of CRC.

  Dataset EGAD00001005524

• Genetic analysis of Hirschsprung disease

  Hirschsprung disease (HSCR) is a birth defect resulting from the absence of nerve (ganglion) cells in the gastrointestinal tract. Hirschsprung disease has a population incidence of 1/5,000 live births and most often occurs as an isolated condition. However, approximately 30% of HSCR cases are associated with other birth defects such as Down syndrome, deafness, hypopigmentation, and Congenital Central Hypoventilation syndrome (CCHS). Hirschsprung disease is a genetic condition with autosomal dominant, autosomal recessive, and multigenic patterns of inheritance described. The goal of the research study is to identify genes harboring causative HSCR mutations and to better understand the complex inheritance of HSCR in families using whole genome mapping and sequencing studies with functional follow-up of candidate genes and variants. We intend to ascertain the frequency with which mutations in any human gene lead to familial and isolated forms of HSCR. Clinical information is collected to allow investigation of possible genotype - phenotype correlations. The subject population consists of individuals diagnosed with HSCR and their unaffected relatives. Individuals/families are ascertained through support groups, web-based listings of research studies and genetic testing services, an educational study website, and referrals from genetic counselors and physicians. Blood, or tissue, samples are requested from affected individuals and their unaffected relatives.

  Study phs000497

• Genetic Epidemiology Network of Arteriopathy (GENOA)

  The Genetic Epidemiology Network of Arteriopathy (GENOA): GENOA is one of four research networks that form the NHLBI Family Blood Pressure Program (FBPP). From its inception in 1995, GENOA's long-term objective was to elucidate the genetics of hypertension and its arteriosclerotic target-organ damage, including both atherosclerotic (macrovascular) and arteriolosclerotic (microvascular) complications involving the heart, brain, kidneys, and peripheral arteries. Two GENOA cohorts were originally ascertained (1995-2000) through sibships in which at least 2 siblings had essential hypertension diagnosed prior to age 60 years. All siblings in the sibship were invited to participate, both normotensive and hypertensive. These include non-Hispanic White Americans from Rochester, MN (n =1583 at the 1st exam) and African Americans from Jackson, MS (N=1854 at the 1st exam). During the second exam (2000-2005), approximately 80% of participants were re-recruited. The GENOA data consists of biological samples (DNA, serum, urine) as well as demographic, anthropometric, environmental, clinical, biochemical, physiological, and genetic data for understanding the genetic predictors of diseases of the heart, brain, kidney, and peripheral arteries. Family Blood Pressure Program (FBPP): GENOA's parent program, the FBPP, is an unprecedented collaboration to identify genes influencing blood pressure (BP) levels, hypertension, and its target-organ damage. This program has conducted over 21,000 physical examinations, assembled a shared database of several hundred BP and hypertension-related phenotypic measurements, completed genome-wide linkage analyses for BP, hypertension, and hypertension associated risk factors and complications, and published over 130 manuscripts on program findings. The FBPP emerged from what was initially funded as four independent networks of investigators (HyperGEN, GenNet, SAPPHIRe and GENOA) competing to identify genetic determinants of hypertension in multiple ethnic groups. Realizing the greater likelihood of success through collaboration, the investigators began working together during the first funding cycle (1995-2000) and formalized this arrangement in the second cycle (2000-2005), creating a single confederation with program-wide and network-specific goals.

  Study phs000379

• Anaplastic oligodendroglioma exome and RNA sequencing 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.

  Study EGAS00001001209

• Whole-genome sequencing in 14 cases and whole-exome sequencing in 90 cases of Chinese ESCC

  Esophageal cancer is one of the most aggressive cancers and the sixth leading cause of cancer death worldwide1. Approximately 70% of the global esophageal cancers occur in China and over 90% histopathological forms of this disease are esophageal squamous cell carcinoma (ESCC)2-3. Currently, there are limited clinical approaches for early diagnosis and treatment for ESCC, resulting in a 10% 5-year survival rate for the patients. Meanwhile, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we show a comprehensive genomic analysis in 158 ESCC cases, as part of the International Cancer Genome Consortium (ICGC) Research Projects (http://icgc.org/icgc/cgp/72/371/1001734). We conducted whole-genome sequencing in 14 ESCC cases and whole-exome sequencing in 90 cases.

  Study EGAS00001001487

• Heart Failure Network - Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (HFN RELAX-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 StudyEcho images are available through HFN RELAX-ImagingObjectivesThe RELAX trial tested the hypothesis that chronic phosphodiesterase type-5 inhibitor therapy with sildenafil would improve exercise capacity and clinical status in heart failure patients with normal ejection fraction, as compared to placebo. Background Heart failure (HF) with preserved ejection fraction (HFpEF) is a common and highly morbid condition that is characterized by chronic exercise intolerance, progressive functional decline and a high rate of readmission. At the time of the RELAX trial, clinical trials of renin-angiotensin system antagonists had not demonstrated improvement in outcomes or clinical status in HFpEF, and effective therapies were needed. Phosphodiesterase type-5 (PDE-5) metabolizes the nitric oxide (NO) and natriuretic peptide (NP) systems' second messenger cyclic guanosine monophosphate (cGMP), and thus may limit beneficial NO and NP actions in the heart, vasculature and kidney. Pre-clinical studies suggest that inhibition of PDE-5 reverses adverse cardiac structural and functional remodeling and enhances vascular, neuroendocrine and renal function. In clinical studies, PDE-5 inhibitor therapy improved exercise tolerance and clinical status in patients with idiopathic pulmonary arterial hypertension and in patients with HF and reduced ejection fraction (HFrEF). A small, single-center study in HFpEF observed improved hemodynamics, left ventricular (LV) diastolic function, right ventricular (RV) systolic function, LV hypertrophy and lung function with chronic PDE-5 inhibition as compared to placebo. In aggregate, these studies suggested the potential for PDE-5 inhibition to ameliorate several key pathophysiological perturbations in HFpEF, and thus improve exercise capacity and clinical status. ParticipantsA total of 216 participants were enrolled in the trial with 113 in the Sildenafil group and 103 in the placebo group. Design Participants who met screening criteria underwent baseline studies including a history and physical examination, cardiopulmonary exercise test (CPXT), six-minute walk distance, Minnesota Living with Heart Failure Questionnaire (MLWHFQ), echocardiography, cardiac magnetic resonance imaging, and phlebotomy for biomarkers. Subjects were then randomly assigned, in a 1:1 ratio, to either the sildenafil or placebo intervention group. The study drug was administered orally at 20 mg three times daily (TID) for 12 weeks. If the dose was well tolerated at 12 weeks, it was increased to 60 mg TID for another 12 weeks. If side effects developed, study staff could recommend discontinuation or return to a lower or previously tolerated dose of study drug. Sildenafil levels 2 hours after a scheduled dose of study drug were obtained at 12 and 24 weeks. The primary endpoint was exercise capacity determined by change in peak oxygen consumption during the CPXT after 24 weeks of therapy. Secondary endpoints included change in six-minute walk distance at 12 and 24 weeks, change in peak oxygen consumption at 12 weeks, and a three tier score reflective of clinical status where patients were ranked based on time to death (lowest tier), time to cardiovascular or cardiorenal hospitalization (middle tier), and change in the MLWHFQ for patients alive without cardiovascular or cardiorenal hospitalization after 24 weeks (highest tier). Conclusions Chronic phosphodiesterase type-5 inhibitor therapy with sildenafil for 24 weeks did not alter exercise capacity or clinical status compared to placebo in patients with heart failure and preserved ejection fraction.

  Study phs003565

• Etiological Investigation of Cancer Susceptibility in Inherited Bone Marrow Failure Syndromes: A Natural History Study

  Background: A prospective cohort of Inherited Bone Marrow Failure Syndrome (IBMFS) will provide new information regarding cancer rates and types in these disorders. Mutations in IBMFS genes are relevant to carcinogenesis in sporadic cancers. Patients with IBMFS who develop cancer differ in their genetic and/or environmental features from patients with IBMFS who do not develop cancer. These cancer-prone families are well suited for cancer screening and prevention trials targeting those at increased genetic risk of cancer. Carriers of IBMFS gene mutations are at increased risk of cancer. The prototype disorder is Fanconi Anemia (FA); other IBMFS will also be studied. Objectives: To determine the types and incidence of specific cancers in patients with an IBMFS. To investigate the relevance of IBMFS gene mutations in the carcinogenesis pathway of the sporadic counterparts of IBMFS-associated cancers. To identify risk factors for IBMFS-related cancers in addition to the primary germline mutations. To determine the risk of cancer in IBMFS carriers. Design: Natural history study, with questionnaires, clinical evaluations, clinical and research laboratory tests, review of medical records, cancer surveillance. Primary endpoints are all cancers, solid tumors, and cancers specific to each type of IBMFS. Secondary endpoints are markers of pre-malignant conditions, such as leukoplakia, serum or tissue evidence of carcinogenic viruses, and bone marrow morphologic myelodyplastic syndrome or cytogenetic clones.

  Study phs001481

• WES data for Early evolutionary branching across spatial domains predisposes to clonal replacement under chemotherapy in neuroblastoma

  Neuroblastoma (NB) is one of the most lethal childhood cancers due its propensity to treatment resistance. By spatial mapping of subclone geographies before and after chemotherapy across 89 tumor regions from 12 NBs, we find that densely packed territories of closely related subclones present at diagnosis are replaced under effective treatment by islands of distantly related survivor subclones, originating from a different most recent ancestor compared to lineages dominating before treatment. Conversely, in tumors that progressed under treatment, ancestors of subclones dominating later in disease are present already at diagnosis. Chemotherapy treated xenografts and cell culture models replicates these two contrasting scenarios and shows branching evolution to be a constant feature of proliferating NB cells. Phylogenies based on whole genome sequencing of 505 individual NB cells indicate that a rich repertoire of parallel subclones, emerges already with the first oncogenic mutations and lays the foundation for clonal replacement under treatment.

  Dataset EGAD00001015413

• scDNA-seq for 'Early evolutionary branching across spatial domains predisposes to clonal replacement under chemotherapy in neuroblastoma'

  Neuroblastoma (NB) is one of the most lethal childhood cancers due its propensity to treatment resistance. By spatial mapping of subclone geographies before and after chemotherapy across 89 tumor regions from 12 NBs, we find that densely packed territories of closely related subclones present at diagnosis are replaced under effective treatment by islands of distantly related survivor subclones, originating from a different most recent ancestor compared to lineages dominating before treatment. Conversely, in tumors that progressed under treatment, ancestors of subclones dominating later in disease are present already at diagnosis. Chemotherapy treated xenografts and cell culture models replicates these two contrasting scenarios and shows branching evolution to be a constant feature of proliferating NB cells. Phylogenies based on whole genome sequencing of 505 individual NB cells indicate that a rich repertoire of parallel subclones, emerges already with the first oncogenic mutations and lays the foundation for clonal replacement under treatment.

  Dataset EGAD00001015414

• Research on the identification of cancer stem cells for peidatric and adult malignancies.

  In recent years, "cancer stem cells" have been reported to exist in many cancers. Many reports have shown that they are the main cause of cancer recurrence. The aim of this study is to test whether cancer stem cells can be identified using patient samples. We will perform omics analysis of rare pediatric cancers by integrating genomics, transcriptomics, proteomics and metabolomics, including somatic and germline mutations, to deepen our understanding of the biological characteristics of the target disease. Based on the knowledge gained and clinical information from patients, we will conduct preclinical pharmacological studies using mouse models and in vitro models to investigate the therapeutic effects of novel therapeutic agents and novel therapeutic strategies such as cellular therapies.

  Study JGAS000623

• BGISEQ-500 Cancer Dataset - WGS tumour/normal pairs

  This study contains whole genome sequencing data for 3 matched tumour / normal pairs from Mesothelioma patients. The sequencing is 50bp paired-end generated using the BGISEQ-500 and is provided as 6 aligned and duplicate-marked BAM files.

  Study EGAS00001002298

• Transcriptome of Chronic Pain and Disease

  The Functional Genomics Section (FGS) is a part of the National Institute of Dental and Craniofacial Research (NIDCR) within the National Institutes of Health (NIH). Research at the FGS focuses on understanding the mechanics involved in nociception through both clinical samples from patients with chronic pain and mouse models of pain. Pain is relayed from the periphery to the central nervous system through specialized sensory neurons known as nociceptors. The cell body of nociceptors resides in neuronal structures that branch off of the spinal cord known as dorsal root ganglia (DRG). The DRG is a heterogenous tissue containing not only sensory neurons like nociceptors, but also glial cells, capillaries, fibroblasts, and resident macrophages. The interaction between the nociceptors and these DRG cell types can have a significant role in affecting neuronal hyperexcitability and downstream pain sensitivity. To better understand the cellular factors involved in producing conditions of chronic pain, DRGs from consenting organ donors were collected from individuals experiencing pain disorders such as painful diabetic neuropathy and rheumatoid arthritis. A multi-omics approach is being used to identify molecular mechanisms that lead to pain hypersensitivity in patients with chronic pain.  

  Study phs002548

• Whole Exome Sequencing in Alopecia Areata Identifies Rare Mutations in KRT82

  Alopecia areata (AA) is an autoimmune disorder, in which the body's own immune cells attack hair follicels resulting in hair loss. It is a complex genetic disease with 14 associated loci previously identified in our genome-wide association study (GWAS). In the study, we performed the whole-exome sequencing (WES) on 849 AA patients with the aim to identify the novel rare variants in genes contributing to AA susceptibility. We performed gene-collapsing analyses and identified keratin 82 (KRT82 Gene ID: 3888) as the highest associated AA gene in the three rare damaging collapsing models with p<6.7E-07 in one of the models. The KRT82 gene is a hair-specific type II keratin expressed in the hair shaft cuticle during the anagen phase of the hair cycle. We reported the lower expression of KRT82 in AA hair follicles, compared to controls, and the KRT82 expression is absent from the bulb region, the site of AA immune attack. This study emphasizes the significance of using WES and gene collapsing analyses to identify rare variation in a functionally relevant risk gene using a moderate sample size.  

  Study phs002632

• Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and is Associated with Worse Outcomes

  Small-cell lung cancer (SCLC) is a very aggressive neuroendocrine lung cancer often associated with oncogenic MYC amplifications, which are known to drive SCLC heterogeneity marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states. The genetic mechanisms of MYC amplification and phenotypic plasticity between cell states is not known. Using data from cell-lines and a few patient-derived samples along with integrated whole-genome sequencing, long-range optical mapping, single-cell DNA sequencing, and fluorescence in situ hybridization, we have attempted to successfully characterize extrachromosomal DNA (ecDNA) as the primary source of MYC amplifications and driver fusions in SCLC.

  Study phs003190

• Amplicon-based sequencing of drug resistant lung cancer cell lines (2017-07-05)

  A EGFR mutant NSCLC cell line which is sensitive to AZD9291 inhibition was mutagenised with the chemical mutagen ENU and then drug selected using a AZD9291. Single cell derived colonies were then manually picked and expanded in drug. Resistance was confirmed in a 14 day assay and DNA was collected. These then underwent targeted amplicon-based sequencing to confirm candidate resistance effectors hypothesised from currently available literature. This dataset contains all the data available for this study on 2017-07-05.

  Dataset EGAD00001003425

• Pseudotime ordering of cell cycle state (2020-01-29)

  We will be using G&T method to sequence single cell genome and transcriptome derived from FS13B iPSCs cell line. The cell cycle state of each of the single cells is known. Hence, we will be analysing the genome and transcriptome of single cells from each of the cell cycle state to generate a copy number profile and transcriptome profile per given cell cycle stage: G1, S, G2, S. . This dataset contains all the data available for this study on 2020-01-29.

  Dataset EGAD00001005919

• Orphan_Tumour_Study___familial_neuroblastoma

  The aim of this study is to study the genomes of ultra rare childhood tumours

  Study EGAS00001002171

• Count Me In (CMI): The Angiosarcoma (ASC) Project (CMI-ASCproject)

  Count Me In - The Angiosarcoma Project: A Patient-Partnered Research Initiative to Accelerate Research in a Rare Sarcoma The Angiosarcoma Project (ASCproject) is a research study that directly engages angiosarcoma patients online and empowers them to accelerate cancer research by sharing medical information and clinical samples. Angiosarcoma is an exceedingly rare soft tissue sarcoma with an incidence of ~300 newly diagnosed cases per year in the United States. This low incidence has impeded large-scale research efforts in this disease that are strongly needed to catalyze research and improve clinical outcomes. The Angiosarcoma Project, launched in March 2017, has demonstrated the feasibility of directly engaging geographically dispersed patients to democratize research and establish a large patient cohort to characterize the genomic and clinical landscape of a rare disease. Angiosarcoma patients living in the US or Canada can access the study and consent online through an online portal (ASCproject.org). Enrolled patients are mailed saliva and blood draw kits, which can be used to extract germline DNA and cell-free DNA (cfDNA), respectively. The study team contacts participants' healthcare institutions to obtain medical records and a portion of archived tumor samples. All received tumor samples are subjected to centralized histological re-review by an expert pathologist to confirm a diagnosis of angiosarcoma. Whole exome sequencing is performed on tumor DNA, germline DNA, and cfDNA; transcriptome sequencing is performed on tumor RNA. De-identified data, including linked genomic, clinical, and patient-reported data, are shared via public databases on a recurring pre-publication basis. Participants are regularly provided updates on the study.

  Study phs001931

• Polymorphisms in the mitochondrial genome are associated with bullous pemphigoid in Germans

  Bullous pemphigoid (BP) is the most prevalent autoimmune skin blistering disease and is characterized by the generation of autoantibodies against the hemidesmosomal proteins BP180 (type XVII collagen) and BP230. Most intriguingly, BP is distinct from other autoimmune diseases because it predominantly affects elderly individuals above the age of 75 years, raising the question why autoantibodies and the clinical lesions of BP emerges mostly in this later stage of life, even in individuals harboring known putative BP-associated germline gene variants. The mitochondrial genome (mtDNA) is a potential candidate to provide additional insights into the BP etiology; however, the mtDNA has not been extensively explored to date. Therefore, we sequenced the whole mtDNA of German BP patients (n=180) and age- and sex-matched healthy controls (n=188) using next generation sequencing (NGS) technology, followed by the replication study using Sanger sequencing of an additional independent BP (n=89) and control cohort (n=104). While the BP and control groups showed comparable mitochondrial haplogroup distributions, the haplogroup T exhibited a tendency of higher frequency in BP patients suffering from neurodegenerative diseases (ND) compared to BP patients without ND (p= 0.1448, Fisher’s exact test). A total of four single nucleotide polymorphisms (SNPs) in the mtDNA, namely, m.16263T>C, m.11914G>A, m.16051A>G, and m.16162A>G, were found to be significantly associated with BP based on the meta-analysis of our NGS data and the Sanger sequencing data (p=0.0017, p=0.0132, p=0.0129, and p=0.0076, respectively, Peto’s test). In summary, our study is the first to interrogate the whole mtDNA in BP patients and controls and to implicate multiple novel mtDNA variants in disease susceptibility. Studies using larger cohorts and more diverse populations are warranted to explore the functional consequences of the mtDNA variants identified in this study on immune and skin cells to understand their contributions to BP pathology.

  Study EGAS00001003932

• HG_Retroduplications_in_Neurodevelopmental_Disorders

  Mobile genetic Elements (MEs) are pieces of DNA which, through an RNA intermediate, can generate new copies of themselves elsewhere in the host genome. Additionally, MEs can facilitate the duplication of non-ME transcripts, typically genes, through the mechanism of retroduplication. In humans, several disorders have been directly attributed to ME-derived mutagenesis but not to retroduplication events. We propose to whole genome sequence the 7 individuals with putative de novo gene retroduplications in order to identify the site of insertion. This sequencing will serve two primary purposes: 1.) Identify the first documented case of a de novo retrogene insertion event causing a disease in humans 2.) provide additional whole genome sequencing of undiagnosed probands recruited into the DDD 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 EGAS00001002907

• Cell-Type Specific Effects of Genetic Variation on Chromatin Accessibility During Human Neuronal Differentiation

  Common genetic risk for neuropsychiatric disorders is enriched in regulatory elements active during cortical neurogenesis. However, the mechanisms mediating the effects of genetic variants on gene regulation are poorly understood. To determine the functional impact of common genetic variation on the non-coding genome longitudinally during human cortical development, we performed a chromatin accessibility quantitative trait loci (caQTL) analysis in neural progenitor cells and their differentiated neuronal progeny from 92 donors. We identified significant genetic effects on 988/1,839 neuron/progenitor regulatory elements, with highly cell-type and temporally specific effects. A subset (~30%) of caQTLs were also associated with changes in gene expression. Motif-disrupting alleles of transcriptional activators generally led to decreases in chromatin accessibility, whereas motif-disrupting alleles of repressors led to increases in chromatin accessibility. By integrating cell-type specific caQTLs and brain-relevant genome-wide association data, we were able to fine-map and identify regulatory mechanisms underlying non-coding neuropsychiatric disorder risk loci.

  Study phs001958

• Single-Cell Analysis of Human Adipogenesis

  The data in this study consists of RNA sequencing reads and read counts from single-cell and single-nuclei RNA sequencing experiments performed on two cell lines to investigate the transcriptional landscape of human adipogenesis in both the brown and white adipose tissue lineage. The two cell lines are human preadipocytes collected and isolated from a defined anatomical location in the neck of a single individual. This depot is known to harbor white adipose tissue (WAT) and brown adipose tissue (BAT). These white and brown preadipocytes were immortalized for the purposes of studying human adipogenesis in vitro. In this study we induced differentiation of these two preadipocyte lines and performed RNA sequencing on over 135,000 single cells spanning a 20-day time course from unperturbed preadipocytes to mature adipocytes from both brown and white lineages. Additionally, we performed both single-cell and single-nuclei RNA sequencing to comprehensively compare the advantages and disadvantages of either technique.

  Study phs002461

• Genomic Analysis of Paired Endometrial Cancer Primaries and Metastases

  Formation of metastases is the major cause of cancer related deaths. Recent studies have sequenced primary endometrial carcinomas yielding data for a single entity in the progression from the birth of a progenitor tumor cell to metastatic disease. However, the progression of these tumors to metastases has not been characterized. We performed whole-exome sequencing of 98 tumor biopsies including complex atypical hyperplasias, primary tumors and paired abdominopelvic metastases to survey the evolutionary landscape of endometrial cancer. We expanded and reanalyzed TCGA-data, identifying novel recurrent alterations in primary tumors, including mutations in the estrogen receptor cofactor NRIP1 in 12% of patients. We found that likely driver events tended to be shared by primary and metastatic tissue-samples, with notable exceptions such as ARID1A mutations. Phylogenetic analyses in cases with multiple metastases indicated these metastases typically arose from one lineage of the primary tumor. These data indicate extensive genetic heterogeneity within endometrial cancers and relative homogeneity across metastatic sites.

  Study phs001127

• Multi-Ethnic Study of Atherosclerosis (BioLINCC)

  The Multi-Ethnic Study of Atherosclerosis (MESA) is a study of the characteristics of subclinical cardiovascular disease (disease detected non-invasively before it has produced clinical signs and symptoms) and the risk factors that predict progression to clinically overt cardiovascular disease or progression of the subclinical disease. MESA researchers study a diverse, population-based sample of 6,814 asymptomatic men and women aged 45-84. Thirty-eight percent of the recruited participants are white, 28 percent African-American, 22 percent Hispanic, and 12 percent Asian, predominantly of Chinese descent. Data available for request include phenotypic data previously released on BioLINCC as well as raw images (E.g. Echocardiogram) and raw tracing data files (e.g. Electrocardiogram). These new data are intended to be made available to interested researchers via BioData Catalyst, will include participants irrespective of participation in genetics (i.e. the full MESA cohort), and may be merged with currently posted (to dbGaP) phenotype and molecular datasets (WGS, GWA, RNA Seq, Methylation, Metabolomics, and Proteomics).

  Study phs003288

• WGS analysis of Japanese liver cancer

  Liver cancer is prevalent worldwide, mainly associated with virus infection, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 Japanese liver cancers. Our comprehensive analysis elucidated point mutations in non-coding regions, structural variants (SVs), and virus integrations, in addition to coding mutations, and demonstrated new mutational signatures related with liver carcinogenesis, novel recurrently mutated coding and non-coding regions such as lincRNA NEAT1/MALAT1, promoters, CTCF binding sites, and regulatory regions. SV analysis found a significant association with replication timing, and revealed that known cancer genes (CDKN2A, CCND1, APC, and TERT) and new cancer genes (ASH1L, NCOR1, MACROD2) were recurrently affected by SVs, leading to altered expression of nearby genes. These results emphasize the value of whole genome sequencing analysis to discover cancer driver mutations and to understand comprehensive molecular profiles of liver cancer, especially for SVs and non-coding mutations.

  Study JGAS000151

• A tumor-associated photoreceptor signature unifies distinct central nervous system malignancies

  Pineoblastoma is a clinically aggressive childhood brain tumor composed of distinct molecular subgroups with divergent driver genes, demographics, and clinical outcomes. To identify developmental origins and mechanisms governing disease pathogenesis, we derive single-cell transcriptomes from pineal parenchymal tumors, aligning malignant cells with our atlas of pineal gland development to retrace cellular origins. Integrative computational analyses maps pineoblastoma origins to transient cycling pinealocyte progenitors during development. Lineage-specific perturbation of suspected drivers in the early pineal gland yields preclinical models representative of consensus molecular subgroups. Multi-omic characterization of patient tumors and these models uncovers a tumor-associated photoreceptor signature common to pineoblastoma, retinoblastoma, and Group 3 medulloblastoma. Transcriptional activity of this signature within respective cellular origins establishes a developmental basis for molecular similarities between entities. Photoreceptor signature constituents are selective dependencies across these anatomically distinct central nervous system malignancies, motivating future studies evaluating developmentally encoded programs of malignancy as potential therapeutic liabilities.

  Study EGAS50000001457

• Single Cell RNA Transcriptomics of Mantle Cell Lymphoma Reveals the Presence of Treatment-Resistant Subclones at the Time of Diagnosis

  Mantle cell lymphoma is a chronically relapsing B cell neoplasm characterized by clonal heterogeneity. We implemented single cell RNA sequencing of paired tumor samples from four patients with an aggressive nodal MCL at diagnosis and after failure of standard immunochemotherapy. Clustering the cells based on the inferred CNVs showed small subclones present at diagnosis with a CNV profile similar to the major subclone at relapse. Comparison of these subclones to major subclones present at diagnosis revealed 119 upregulated pathways common for the four patient with an aggressive MCL, including NF-kappaB and PTEN signaling pathways. Additionally, we sequenced a patient with an indolent to blastoid MCL transformation with intestinal tissue involvement. In contrast to other compartments at relapse, the cells in the intestine showed strikingly different CNV profile and presence of new driver mutations including NOTCH1. In conclusion, our study demonstrates that scRNAseq can potentially detect therapy resistant subclones at diagnosis.

  Study EGAS50000000825

• Exome_sequencing_of_blastic_plasmacytoid_dendritic_cell_neoplasms

  Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive haematological malignancy derived from precursors of plasmacytoid dendritic cells. Due to the rarity of BPDCNs our knowledge of their molecular pathogenesis was until recently confined to observations describing reccurent chromosomal deletions involving chromosomes 5q, 12p, 13q, 6q, 15q and 9. A recent publication went on to delineate the common deleted regions using aCGH and demonstrated that these centred around known tumour suppressor genes including CDKN2A/B (9p21.3), RB1 (12p13.2-14.3), CDKN1B (13q11-q12) and IKZF1 (7p12.2).These mutations are found recurrently in several different cancers and in most cases are thought to be involved in tumour progression rather than initiation. However, the well-defined nature and cellular ontogeny of these neoplasms suggests strongly that they share one or a few characteristic mutations as has been demonstrated for other uncommon but well-defined neoplasms such as Hairy Cell Leukemia (BRAF) and ovarian Granulosa Cell tumours (FOXL2).

  Study EGAS00001000171

• Single-cell RNA-seq of cervix and placenta

  Placental trophoblasts have been detected in cervical smears early in gestation, creating opportunities for non-invasive prenatal diagnosis. However, trophoblast isolation is limited by the lack of a cell catalogue and molecular profile of cervical smears. To establish an atlas and to explore the potential of single-cell RNA-sequencing to detect cervical trophoblasts, 10,539 single-cell transcriptomes from 12 non-invasive exocervical smears from pregnant women were profiled. In addition, we characterized 34,565 cells from six placental biopsies. We uncovered a novel extravillous trophoblast cell subtype characterized by epithelial marker genes and reduced HLA-G expression. Integration of both cell atlases demonstrated surprisingly similar expression profiles between maternal epithelial cells and placental extravillous trophoblasts, indicating that these trophoblasts retained epithelial properties without an invasive mesenchymal phenotype. Additionally, differential expression analysis identified novel markers discriminating cervical and placental cell types. Those analyses may contribute to trophoblast discovery and isolation from cervical smears.

  Study EGAS00001007044

• Human Autism Genetics

  The goal of this study is to bring together the power of 1) whole exome sequencing, 2) homozygosity mapping in consanguineous families, and 3) transcriptional analysis in brain tissue to identify genetic causes of autism spectrum disorders (ASD).

  Study phs000639

• SAPCS Blood RNA-seq of prostate cancer patients

  The study aims to quantify the gene expression in blood samples in 20 prostate cancer patients under the Southern African Prostate Cancer Study (SAPCS). The objective is to identify a list of differentially expressed genes.

  Study EGAS50000000702

• Tumor gene project

  The study focuses on human tumor susceptibility as well as somatic cancer genomics. We use high-throughput sequencing approaches to achieve a comprehensive molecular characterization of tumors. Our goal is to better understand their genesis and management opportunities.

  Study EGAS50000000984

• Comprehensive analyses of genetic aberrations in cholangiolocarcinoma

  The nature of CLC is still unclear and its pathological classification still remains controversial. To clarify the positioning of CLC among primary liver cancers, and to find characteristics that could distinguish CLC from other liver cancers.

  Study JGAS000597

• Dedifferentiated_Melanoma

  De- and transdifferentiation of melanoma is a rare histopathological phenomenon that has not be characterised genetically. In this project we plan to sequence the genomes of de and transdifferentiated cases so as to define their genetic make-up.

  Study EGAS00001003471

• Hydroxyurea to Prevent Organ Damage in Children with Sickle Cell Anemia (BABY HUG) Phase III Clinical Trial and Follow-Up Observational Studies I and II

  Sickle cell anemia is associated with substantial morbidity from acute complications and organ dysfunction beginning in the first year of life. In 1995, the Multicenter Study of Hydroxyurea (MSH) (dbGaP phs002348) demonstrated that, in adults, hydroxyurea is effective in decreasing the frequency of painful crises, hospitalizations for crises, acute chest syndrome, and blood transfusions by 50%. The phase I/II study of hydroxyurea in children (HUG KIDS) demonstrated that children have a response to hydroxyurea similar to that seen in adults in terms of increasing fetal hemoglobin levels and total hemoglobin, and decreasing complications associated with sickle cell anemia. In addition, this study demonstrated that the drug does not adversely affect growth and development between the ages of 5 and 15. A pilot study of hydroxyurea (HUSOFT) given to children between the ages of 6 months and 24 months demonstrated that the drug was well tolerated and that the fetal hemoglobin levels rose and remained elevated compared to baseline with continued hydroxyurea administration. A Special Emphasis Panel (SEP) met on April 12, 1996 to review the results of the MSH trial and the progress to date of the HUG KIDS study. The SEP recommended that NHLBI undertake the BABY HUG trial. The BABY HUG Randomized Controlled Trial concluded that hydroxyurea treatment in very young children seemed to have an acceptable safety profile and to reduce complications of sickle cell anemia. However, more data were needed on the long-term safety of hydroxyurea use in very young children. As a result, follow-up studies were initiated. The Follow-Up Study II provided longer follow-up than Follow-Up Study I, and included more assessment types than Follow-Up Study I.The BABY HUG program consisted of three related studies, each of which has associated datasets and bio-specimens. A randomized controlled trial comparing hydroxyurea to placebo in very young children with sickle cell anemia (BABY HUG Randomized Controlled Trial) The first observational follow-up study of children from the randomized controlled trial (BABY HUG Follow-Up Study I). All children in Follow-Up Study I were offered the option of taking open-label hydroxyurea, with treatment decisions made by the family and the clinical team caring for the child. The second observational follow-up study of children from BABY HUG Follow-Up Study I. All children in Follow-Up Study II were offered the option of taking open-label hydroxyurea, with treatment decisions made by the family and the clinical team caring for the child.The purpose of the Randomized Controlled Trial was to determine if hydroxyurea can safely prevent early end organ damage in very young children with sickle cell anemia. The purpose of the BABY HUG Follow-up Study I was to provide structured follow-up of the children enrolled in the BABY HUG Randomized Controlled Trial, in order to characterize the long-term toxicities and unexpected risks (if any) associated with treatment with hydroxyurea at an early age. The objective of Follow-Up Study II was to obtain additional data about the long-term safety and efficacy of hydroxyurea use in children with Sickle Cell Anemia through at least the first decade of life.Instructions for requesting individual-level data are available on BioData Catalyst at https://biodatacatalyst.nhlbi.nih.gov/resources/data/. Apply for data access in dbGaP. Upon approval, users may begin accessing requested data in BioData Catalyst. For questions about availability, you may contact the BioData Catalyst team at https://biodatacatalyst.nhlbi.nih.gov/contact.

  Study phs002415

• Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C)

  Reprinted from http://www.haltctrial.org/ Purpose The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial is a randomized controlled trial designed to evaluate the safety and efficacy of long-term use of pegylated interferon for the treatment of chronic hepatitis C in patients who failed to respond to previous interferon therapy. The HALT-C Trial was developed to determine whether prolonged interferon therapy altered histological and clinical outcomes in a group of patients who had failed to eradicate hepatitis C virus with previous interferon treatment. Study Hypotheses In patients with chronic hepatitis C and bridging fibrosis who failed to eradicate the virus with previous interferon therapy, long-term treatment with interferon is safe and can prevent progression to cirrhosis. In patients with cirrhosis secondary to chronic hepatitis C who failed to eradicate the virus with previous interferon therapy, long-term treatment with interferon is safe and can reduce the risks of hepatic decompensation or of hepatocellular carcinoma. Study Design 1145 patients with chronic HCV and advanced hepatic fibrosis (Ishak stage 3-6) who failed to respond to previous treatment with interferon were enrolled at 10 clinical centers and entered into a Lead-in phase. They were treated with a combination of pegylated interferon (Pegasys®, Hoffmann-La Roche) 180 µg/week and ribavirin (1000-1200 mg/day) for 24 weeks. Patients who had no detectable HCV-RNA at week 20 continued on combination therapy until week 48. 662 patients who did not clear virus were randomly assigned at week 24 to either continue treatment with pegylated interferon alone (90 µg/week) for an additional 42 months, or to have treatment discontinued. All patients were followed at 3-month intervals following randomization. Liver biopsy was performed at baseline and after 1.5 and 3.5 years of treatment. Because of slower than expected enrollment and the approval by the FDA of peginterferon alfa-2b after the start of the trial, we modified the study protocol in three ways. First, criteria for admission to the trial were liberalized to allow patients to enter the trial with lower platelet and white blood cell counts than had been initially considered safe or tolerable. Second, 151 Lead-in patients and those continuing on therapy after 24 weeks who demonstrated return of viremia during or after their 48-week treatment period (called "Breakthrough" or "Relapse" patients, respectively) were allowed to return to enter the randomized trial. Third, 237 patients treated with peginterferon alfa-2b (or with peginterferon alfa-2a in licensing trials) outside the HALT-C Trial who in other respects met all study criteria, having received the equivalent of Trial Lead-in period therapy, were allowed to enter the long-term trial as "Express" patients. A total 1050 patients were randomized. Those patients who completed Month 48 were offered an "extended follow-up (observation only)" until October 2009. These visits will primarily be to identify outcome events, and to provide information to patients concerning the current status of the trial. Some questionnaires, blood tests, and an ultrasonogram will be performed. Quarterly (every 3 months) Interval history of complications, adverse events Current medications Brief physical examination Laboratory tests: liver panel, CBC, INR, AFP Child-Pugh Score Stored serum Annual Complete physical examination Ultrasound of liver 1.5 years (M24 visit, middle of study) Liver biopsy: formalin fixed histology, frozen liver tissue (subset of patients) 3.5 years (M48, end of study) Liver biopsy: formalin fixed histology, frozen liver tissue (subset of patients) Endoscopy: evaluate esophageal varices and portal hypertension After Month 48 Observation only (no treatment) to determine clinical outcomes Clinic visit every 6 months with current medications, brief PE, liver panel, CBC, AFP, stored Serum Ultrasound of liver every 6 months Outcome Variables Primary outcome variables to be assessed in the two groups of patients include: Development of cirrhosis on liver biopsy (progression of Ishak fibrosis score by 2 points or more) Development of hepatic decompensation, as shown by: Sustained increase in the Child-Turcotte-Pugh score to 7 points or higher Variceal hemorrhage Ascites Spontaneous bacterial peritonitis Hepatic encephalopathy Development of hepatocellular carcinoma Death Secondary outcomes include quality of life, serious adverse events, events requiring dose reductions, and development of presumed hepatocellular carcinoma.

  Study phs000430

• Reasons for Geographic and Racial Differences in Stroke Cardiorenal GWAS

  REGARDS is a national, population-based, longitudinal study of incident stroke and associated risk factors including over 30,000 Black and White adults aged 45 years or older from all 48 contiguous U.S. states and the District of Columbia. The study was designed to investigate reasons underlying the higher rate of stroke mortality among Black participants compared to White participants and among residents of the Southeastern U.S. compared to other U.S. regions. By design, Black adults and residents of the deep south were oversampled. Between 2003 and 2007 (baseline visit) participants completed a computer-assisted telephone interview to collect demographic information and medication adherence, and an in-home visit for blood pressure measurements and collection of blood and urine samples. Following the baseline visit, participants have been contacted by phone at six-month intervals to obtain information on incident stroke or secondary outcomes. Additionally, samples and data were collected on about 50% of the original cohort during a second study visit an average of 10 years after the baseline visit. Genotyping was performed as part of an ancillary study on 10,788 (84% Black) participants using Illumina MEGA arrays.

  Study phs002719

• Genomic Profiling of Thyroid Cancer Reveals a Role for Thyroglobulin in Metastasis -Part II

  Papillary thyroid carcinoma (PTC) has a wide geographic variation in incidence, being highest in Saudi Arabia where it is only second to breast cancer as the most common cancer among females. Genomic profiling of PTC from Saudi Arabia has not been attempted previously. We performed whole-exome sequencing of 101 PTC samples and the corresponding genomic DNA to identify genes with recurrent somatic mutations, followed by sequencing of these genes using a next-generation gene panel approach in further 785 samples. In addition to BRAF, N-RAS and H-RAS, which have previously been shown to be recurrently mutated in PTC, our analysis highlights additional genes, including thyroglobulin (TG), which harbored somatic mutations in 3% of the entire cohort. Surprisingly, although TG mutations were not exclusive to mutations in the RAS-MAP kinase pathway, their presence was associated with a significantly worse clinical outcome, which suggests a pathogenic role beyond driving initial oncogenesis. Analysis of metastatic PTC tissue revealed significant enrichment for TG mutations (p<0.001), including events of apparent clonal expansion. Our results suggest a previously unknown role of TG somatic mutations in the pathogenesis of PTC and its malignant evolution.

  Study EGAS00001003357

• Genomic Profiling of Thyroid Cancer Reveals a Role for Thyroglobulin in Metastasis

  Papillary thyroid carcinoma (PTC) has a wide geographic variation in incidence, being highest in Saudi Arabia where it is only second to breast cancer as the most common cancer among females. Genomic profiling of PTC from Saudi Arabia has not been attempted previously. We performed whole-exome sequencing of 101 PTC samples and the corresponding genomic DNA to identify genes with recurrent somatic mutations, followed by sequencing of these genes using a next-generation gene panel approach in further 785 samples. In addition to BRAF, N-RAS and H-RAS, which have previously been shown to be recurrently mutated in PTC, our analysis highlights additional genes, including thyroglobulin (TG), which harbored somatic mutations in 3% of the entire cohort. Surprisingly, although TG mutations were not exclusive to mutations in the RAS-MAP kinase pathway, their presence was associated with a significantly worse clinical outcome, which suggests a pathogenic role beyond driving initial oncogenesis. Analysis of metastatic PTC tissue revealed significant enrichment for TG mutations (p<0.001), including events of apparent clonal expansion. Our results suggest a previously unknown role of TG somatic mutations in the pathogenesis of PTC and its malignant evolution.

  Study EGAS00001001788

• PTEN homozygous deletion is a negative prognostic factor in Tumor Treating Fields-treated glioblastoma, IDH wildtype patients

  This study investigates genomic determinants of outcome in glioblastoma, IDH-wildtype patients treated with Tumor Treating Fields (TTFields) in addition to standard radiochemotherapy. Tumor tissue from primary glioblastoma at initial diagnosis was profiled using the Illumina TruSight Oncology 500 (TSO500) targeted sequencing panel to characterise somatic alterations. The overarching goal is to provide exploration of genomic determinants of survival and treatment response in TTFields-treated glioblastoma, IDH-wildtype.

  Study EGAS50000001469

• UCSF Center for Reproductive Health (CRH) Research Bank

  The purpose of this study is to provide a reference profile of small extracellular RNAs in body fluids. These samples were originally obtained in a study that had a different purpose. The purpose of the original study was to add excess biological materials during the course of IVF treatment to a tissue bank. These biological materials included follicular fluid (the liquid that comes out of the ovary with the egg), granulosa cells (cells that surround the egg and help it grow), and other biological materials that help eggs, sperm, and embryos stay healthy and grow outside the body. These banked specimens would allow researchers to learn more about infertility and how to treat it, including studying how to identify the healthiest eggs, sperm, and embryos and how to help them stay healthy and grow.

  Study phs001695

• Prospective Analysis of Genotypes in Adults Undergoing Therapy for Lung Cancer (Paclitaxel Cohort)

  Lung cancer is frequently treated with paclitaxel in combination with several other agents; however, paclitaxel treatment is often ineffective or limited by treatment-related toxicities. Heritable variants in genes associated with absorption, distribution, metabolism, and elimination may predict paclitaxel clinical outcome and toxicity. We designed a prospective multi-institutional study that recruited 546 patients receiving therapy with a 5-year follow up. All patients were genotyped using the Drug Metabolizing Enzymes and Transporters (DMET) platform, which ascertains 1931 genotypes in 235 genes. Genotypes were compared to the progression-free survival of paclitaxel therapy and clinically-significant paclitaxel toxicities. Seven genetic variants were associated with paclitaxel PFS (in ABCB11, ABCC3, ABCG1, CYP8B1, NR3C1, FMO6P, and GSTM3), whereas four genetic variants (in VKORC1, SLC22A14, GSTA2, and DCK) were associated with paclitaxel toxicities. The present SNPs have limited clinical utility but suggest that certain genes are related to important paclitaxel pathways in lung cancer.

  Study phs001660

• Exome sequencing of familial high-grade serous ovarian carcinoma reveals heterogeneity for rare candidate susceptibility genes

  High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, approximately half of which cannot be explained by known genes. To discover genes, we analyse germline exome sequencing data from 516 BRCA1/2-negative women with HGSOC, focusing on genes enriched with rare, protein-coding loss-of-function (LoF) variants. Overall, there is a significant enrichment of rare protein-coding LoF variants in the cases (p < 0.0001, chi-squared test). Only thirty-four (6.6%) have a pathogenic variant in a known or proposed predisposition gene. Few genes have LoF mutations in more than four individuals and the majority are detected in one individual only. Forty-three highly-ranked genes are identified with three or more LoF variants that are enriched by three-fold or more compared to GnomAD. These genes represent diverse functional pathways with relatively few involved in DNA repair, suggesting that much of the remaining heritability is explained by previously under-explored genes and pathways.

  Study EGAS00001004235

• Indonesian Genome Diversity Project

  Indonesia, the world’s fourth largest country by population, comprises an archipelago of about 900 permanently inhabited islands in tropical Asia, and hosts an astonishing array of human diversity that remains largely underrepresented in modern biological surveys. The region is unique for its key role in both the early and recent evolution of Homo outside of Africa. It has one of the first traces of anatomically modern humans in Eurasia, and was the focus of extensive interaction between archaic hominins and humans – both in the likely co-existence of H. floresiensis with modern humans, and in the introgression of Denisovans into the ancestors of its present inhabitants. More recently, Indonesia was a center of the spread of Neolithic culture by Austronesian speakers. Advancing maritime technologies allowed farming populations to treat this region as a springboard to reach oceanic islands as remote as Madagascar, Hawaii, Easter Island and New Zealand. Here we present complete human genomes from healthy individuals from multiple key islands in Indonesia and Papua. The genomes were sequenced to high depth (30x). The purpose of this dataset is to address different questions of human evolution in Island Southeast Asia and beyond, including early settlement of the area by anatomically modern humans, population structure, genetic admixture and adaptation, and contacts with archaic hominins. We employed a sampling strategy to capture a broad range of diversity across the region incorporating an average of 12 samples from each of 14 islands spanning Indonesia and Papua, from Sumatra in the west to New Britain in the east. Genomes from this dataset form part of an ongoing project to describe and understand human evolutionary history in Island Southeast Asia and Eurasia in general.

  Study EGAS00001003054

• 1 Intratumoral genetic heterogeneity and clonal evolution following neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal tumors.

  Purpose: Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment forpatients with locally advanced rectal cancer. However, little is known about the effect of nCRT in the mutational landscape and intratumoral genetic heterogeneity (ITGH) of rectal tumors. Moreover, response to nCRT vary substantially among patients and the genetic determinants of treatment response are not fully understood. Here, we sought to determine the impact of nCRT in the mutational landscape and ITGH of rectal tumors and to identify putative drivers of therapeutic resistance. Patients and Methods: We analyzed whole-exome sequencing (WES) and clinical data from 79 primary non-treated rectal cancers obtained from The Cancer Genome Atlas (TCGA). We also compared the mutational landscape of a matched set of peripheral blood cells, irradiated tumor-adjacent colonic mucosa and pre and post-treatment tumor samples to determine the iatrogenic effects of nCRT and its impact in tissue genetic heterogeneity. Finally, we performed WES of 7 matched pre and post-treatment tumor samples to examine how nCRT affects the clonal architecture of rectal tumors. Results: We show that rectal tumors exhibit remarkable ITGH, which increases with disease progression. We also show that nCRT, per se, does not introduce novel somatic mutations, nor alters the clonal architecture of the irradiated colonic mucosa. Instead, we show that it acts as a potent selective pressure, favoring the expansion of tumor cell subpopulations more prone to resist therapy and increasing ITGH in the residual tumor. Conclusion: Our results reveal the highly heterogeneous and dynamic clonal architecture of rectal tumors undergoing nCRT. Our results also uncover putative genetic determinants of response to nCRT and a possible role for ITGH in predicting treatment outcome.

  Study EGAS00001003250

• Alzheimer's Disease Sequencing Project (ADSP)

  NOTICE OF CHANGE IN LOCATION FOR ALZHEIMER'S DISEASE SEQUENCING PROJECT (ADSP) GENETIC AND PHENOTYPIC DATA: ADSP whole exome and whole genome sequence data that are shared through dbGaP were mapped to the Genome Reference Consortium human genome GRCh37 (build 37). These data are from the Discovery Phase of the project (described below) and will continue to be available at this site. Please see the ADSP Design page for the complete study description. All data that are mapped to GRCh38 (hg38) are being shared through the NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) Data Sharing Service (DSS). For instructions on how access the ADSP Build 38 data that are shared through NIAGADS DSS, visit the Application Instructions page. STUDY DESCRIPTION FOR dbGaP BUILD 37 ADSP DATA: The overarching goals of the Alzheimer's Disease Sequencing Project (ADSP) are to: (1) identify new genomic variants contributing to increased risk of developing Alzheimer's Disease (AD), (2) identify new genomic variants contributing to protection against developing AD, and (3) provide insight as to why individuals with known risk factor variants escape from developing AD. These factors will be studied in multi-ethnic populations in order to identify new pathways for disease prevention. Such a study of human genomic variation and its relationship to health and disease requires examination of a large number of study participants and needs to capture information about common and rare variants (both single nucleotide and copy number) in well phenotyped individuals. Using existing samples from NIH funded and other studies, three NHGRI funded Large Scale Sequencing and Analysis Centers (LSAC) - Broad, Baylor, and Washington University - produced the DNA sequence data. Variant call data are being made available to the scientific community through NIH-approved data repositories. Statistical analysis of the sequence data is anticipated to identify new genetic risk and protective factors. The ADSP will conduct and facilitate analysis of sequence data to extend previous discoveries that may ultimately result in new directions for AD therapeutics. Analysis of ADSP data will be done in two phases. The Discovery Phase analysis (2014-2018) is funded under PAR-12-183. The entire Discovery dataset contains whole-genome sequencing data on 584 subjects from 113 families, and pedigree data for > 4000 subjects; whole exome sequencing data on 5096 cases 4965 controls; and whole exome sequence data on an additional 853 (682 Cases [510 Non-Hispanic, 172 Hispanic]), and 171 Hispanic Control subjects from families that are multiply affected with AD. The Replication Phase (2016-2021) analysis will be funded under RFA-AG-16-001 and RFA-AG-16-002 and is expected to include a combination of genotyping and sequencing approaches on at least 30,000 subjects. Targeted sequencing will be done by the LSACs. GRCh37 Data Releases The first ADSP data release occurred on November 25, 2013. It included the whole-genome sequencing data in BAM file format on 410 individuals. The second ADSP data release occurred on March 31, 2014, and included the whole-genome sequencing data in BAM file format for an additional 168 individuals. The third ADSP data release occurred on November 03, 2014 and included whole-exome sequencing data in BAM file format for 10,939 individuals. The fourth ADSP data release occurred on February 13, 2015 and included revised ethnic data for subjects with whole-exome sequencing data. The fifth ADSP data release occurred on July 13, 2015 and included whole-genome genotypes and updated phenotypes as well as changes to pedigree structures and sample IDs. The sixth ADSP data release occurred on December 8, 2015, and included whole-exome genotypes and updated phenotypes as well as changes to subject IDs. This seventh ADSP data release on April 12, 2016 includes: (1) WES and WGS SNV VCF files (2) WES and WGS Indel PLINK files ADSP Data Available through dbGaP: ADSP - Whole Genome Sequencing ADSP - Whole Exome Sequencing Comments DNA-Seq (BAM) n=578 n=10913 Sequence data available (plus n=38 replications w/out genotype data) Concordant SNV Genotypes (PLINK format) N/A n=10913 QC'ed genotypes that are concordant between the Atlas (Baylor's) and GATK (Broad's) calling pipelines (a subset of the consensus genotype set) Consensus Genotypes (PLINK and VCF format) n=578 n=10913 QC'ed genotypes that are concordant between Atlas and GATK pipelines as well as those that that were called uniquely by Atlas or GATK Concordant Indel Genotypes (PLINK format) n=578 n=10913 QC'ed genotypes that are concordant between the Atlas and GATK calling pipelines Phenotype Data n=4735 n=10913 Data of n=53 phenotype variables available (plus administrative data), including APOE genotype. WGS phenotypes include data of connecting family members. Please use the release notes provided by dbGaP to obtain detailed information about study release updates. The ADSP data portal provides a customized interface for users to quickly identify and retrieve files by covariates, phenotypes, and data properties such as sequencing facility or coverage. For more information about the ADSP study and the data portal, please visit https://www.niagads.org/adsp/.

  Study phs000572

• Ongoing Replication Stress Tolerance and Clonal T Cell Responses Distinguish Liver and Lung Recurrence and Patient Outcomes in Pancreatic Ductal Adenocarcinoma

  Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) survive longer when disease spreads to the lung but not to the liver. We generated overlapping, multi-omic datasets to identify molecular and cellular features that distinguish patients whose disease develops liver metastasis (liver cohort) from those whose disease progression results in lung metastasis without liver metastases (lung cohort). Lung cohort patients generally survived longer than liver cohort patients, independent of tumor subtype. We developed a pORG gene signature that distinguishes primary tumors in the liver and lung cohorts. We identified ongoing replication stress (RS) response pathways in high pORG/liver cohort tumors, while low pORG/lung cohort tumors had greater densities of lymphocytes and shared T cell clonal responses. Our study demonstrates that liver-avid PDAC is associated with tolerance to ongoing RS, limited tumor immunity, and less favorable outcomes; whereas low RS, lung-avid/liver-averse tumors are associated with active tumor immunity that may account for favorable outcomes. As expected, we found high frequencies of KRAS, TP53, CDKN2A, and SMAD4 gene alterations in our tumor samples. High pORG activity (GSVA scores) in our primary tumors appear to be positively correlated with alteration frequencies in both TP53 and CDKN2A. We did not see a correlation with alterations in KRAS as almost all the tumor samples have KRAS alterations. From a de-identified dataset of 1,873 patients diagnosed with and/or treated for PDAC at our institution between 2004 and 2020, we identified 422 patients for which we had specimens with sequencing data (N=374) and/or specific evidence of disease metastasis site(s) from the OHSU cancer registry or disease-relevant computed tomography (CT) scans to allow cohort classification. Note that our study includes RNA-Seq, DNA-Seq panel, and TCR-Seq (T-cell Receptor Sequencing) data, but that this dbGaP submission just includes the patients/samples with RNA-Seq and/or DNA-Seq panel data. Therefore, this submission includes 290 samples from 278 patients. TCR sequence data is available on the Adaptive Biotechnologies platform. Clinical course timepoints, patient demographics, stage, grade, nodal involvement, resection margins, and angiolymphatic invasion were provided as deidentified data by the OHSU cancer registry with quality control data verification in a subset by pathologists (BB and TM). We reviewed all available computed tomography (CT) scans for all patients with primary tumor resection dates recorded by the cancer registrar, with tumor samples analyzed by RNA-seq, DNA-seq, or TCR-seq, and/or with additional information indicating metastatic spread (e.g., metastatic samples received for related studies). We abstracted the site of all lesions proven to be metastatic by biopsy and/or that clearly increased in size during progression or decreased in size during treatment as long as a radiologist described the lesion as “likely”, “suspicious for”, “concerning for”, or “favor” metastasis. Clinical imaging was reviewed by a radiologist (AG) to validate patient assignments to the liver, lung, and neither liver nor lung (other recurrence site) cohorts. Time to recurrence was calculated from the earliest of either the recurrence date provided by the OHSU cancer registry, or the date of earliest lesion abstracted from CT reports. The subject attributes reported in this submission were up to date at the time of our data freeze, which occurred July 2021.

  Study phs003597

• ARRA - NHLBI Lung Cohorts Sequencing Project: Genetic modifiers of

  The major goal of this project is to apply second generation resequencing technology to identify disease causing variants influencing pediatric and adult lung diseases in a collection of two longitudinal population cohorts of cystic fibrosis patients that have been well characterized for a comprehensive set of clinical traits. In Phase I, exome sequencing was performed on 43 cystic fibrosis patients with early Pa infection and 48 cystic fibrosis patients with late Pa infection to identify variants influencing the time to onset of Pa infection. In Phase II, additional exomes were added to the study, to reach a total of 91 individuals with early Pa infection and 96 with late Pa infection. The majority of the 340 subjects of Phase II do not have a Pa infection phenotype, but instead have a pulmonary function phenotype (121 severe vs. 124 mild impairment) as determined by the survival corrected Kulich FEV percentile of Corey et al. A small minority have intermediate phenotypes and/or show severe decline in lung function during childhood.

  Study phs000254

• Targeted sequencing of Burkitt lymphoma tumour samples from the UK's Haematological Malignancy Research Network

  The UK’s Haematological Malignancy Research Network (www.HMRN.org) was established in 2004 to provide robust generalizable data to inform clinical practice and research. HMRN is a collaboration between researchers in the Epidemiology & Statistics Group (ECSG) at the University of York, a unified Clinical Network operating across 14 hospitals, and an integrated Haematological Malignancy Diagnostic Service (HMDS) in Leeds. Covering a population of around 4 million, HMRN collects detailed information about all patients diagnosed with a haematological malignancy within the HMRN region, accruing around 2,400 new diagnoses each year. The population has a similar socio-demographic profile to the country as a whole, and HMRN’s maturing data present an increasingly valuable resource to address real questions of concern to haematologists, commissioners and health service researchers – locally, nationally and internationally. This study forms part of a larger project employing targeted exome sequencing on tumour samples from patients diagnosed with a variety of both lymphoid and myeloid malignancies. The results for samples collected from 39 Burkitt lymphoma patients, diagnosed within HMRN from 2005 to 2012, are provided.

  Study EGAS00001004649