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• "Distinct immunometabolic signatures in circulating immune cells define disease outcome in acute-on-chronic liver failure"

  We performed single-cell transcriptomics of PBMC’s from healthy (n= 3), acute decompensated (AD) (n= 3) and Acute-on-chronic liver failure (ACLF) patients. Lay Summary: Acute-on-chronic liver failure (ACLF) develops in cirrhotic patients and is characterized by an hyper-inflammatory immune state driving multiple organ failure(s). As a paradox, circulating immune cells also show transcription and metabolic evidence of exhaustion, explaining why these patients are often susceptible to secondary infections. We characterized at a transcriptional level all circulating immune cells of ACLF patiens, and specifically unraveled a distinct recovery and non-recovery ACLF signature within the monocyte population. Moreover, these changes were closely linked to metabolic differences within these cells. The described alterations allowed for a robust prediction of recovery and non-recovery of patients at admission to the hospital.

  Study EGAS50000000391

• SUDC Registry and Research Collaborative

  The Sudden Unexplained Death in Childhood Registry and Research Collaborative (SUDCRRC), created at NYU Langone Health in 2014, connects academic investigators, forensic pathologists, and medical examiner and coroner partner offices to study sudden unexpected pediatric deaths, aged 1 month to 18 years, whose death is unexplained or unclear at the end of the public mandated investigation, including autopsy. Each case includes collection and analysis of all records (medical history from prenatal records throughout life, death scene investigation, autopsy/toxicology/ancillary death investigation reports including photographs and histology slides), biospecimens, and in-depth family interviews. Whole exome sequencing is performed on each deceased child and both biological parents. Additional studies are pursued when indicated by pathology review. Each case receives a multidisciplinary masked review process and parental written consent is obtained. The NYU institutional review board approved this study.

  Study phs003383

• Genome-wide mutation analysis of germinal-center B-cell derived lymphomas within the ICGC MMML-Seq Consortium

  Germinal-center B-cell derived lymphomas (GCB-lymphomas) are the most common B-cell lymphomas in children and adults, with Burkitt Lymphomas (BL) predominating in childhood and follicular lymphoma (FL) and diffuse large B-cell lymphomas (DLBCL) predominating in older age groups. The cell-of-origin in all these lymphomas is supposed to be a germinal center B-cell and transformation of FL in DLBCL or intermediate DLBCL/BL (intL) can occur. In the framework of the German ICGC MMML-Seq we are currently exploring sequencing data of GCB-lymphomas and paired normal controls as well as normal B-cell subsets separated by FACS. This includes whole genome, transcriptome, miRNAome and whole methylome datasets.

  Study EGAS00001000394

• Dynamics of genomic clones in breast cancer patient xenografts at single cell resolution

  Human cancers, including breast cancers, are comprised of clones differing in mutation content that evolve dynamically in space and time following principles of Darwinian evolution, underpinning important emergent features such as drug resistance and metastasis. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours. However the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours has not been systematically examined at single cell resolution. Here we show by both deep genome and single cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (<5% of starting population) clones to moderate, polyclonal engraftment. Furthermore, ongoing clonal dynamics during serial passaging is a feature of tumours experiencing modest initial selection. Through single cell sequencing, we show that major mutation clusters estimated from tumour population sequencing relate predictably to the most abundant clonal genotypes, even in clonally complex and rapidly evolving cases. Finally, we show that similar clonal expansion patterns can emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. Our results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies utilizing patient-derived breast cancer xenoengraftment.

  Study EGAS00001000952

• Quick Guide for data submission

  Quick Guide This is a quick guide to submit data to the EGA. Please select data type to display the right detailed instructions. Sequence data Array-based data Get your submission account You first need to create your EGA user. Then, once your account has been verified by the Help Desk team, request your submission account and provide details of the data type and platform(s) in your submission. Register Study/DAC Use Submitter Portal to register your study, samples, Data Access Committee (DAC) and Policy. Upload data Encrypt your data files using the and upload it to your inbox using SFTP. Register experiments and runs Associate each data file to a registered sample and study by Linking files to samples. Details of the experimental procedure you followed must be provided. Finalise your submission Group your runs/analysis into datasets and link them to your new or existing DAC and policy using DAC Portal. Data request are done at a dataset level, thus files within a datasets must share release conditions. Release and admin When finalising the submission, set a released date to instruct our Helpdesk to release your study. All registered studies are automatically placed on hold until the named submission or DAC contact instructs our Helpdesk for the study to be released. Get your submission account Fill the submission form and provide details of the data type and platform(s) in your submission. Register Study/DAC Use EGA Programmatic submission to register your study, samples, Data Access Committee (DAC) and Policy. Upload data Encrypt your data files using the EgaCryptor and upload it using default FTP clients or Aspera. Complete the Array-Format (AF) spreadsheet Download the AF spreadsheet and complete all four sections. Return the spreadsheet to the EGA helpdesk. Release and admin Instruct our Helpdesk to release your study. All registered studies are automatically placed on hold until the named submission or DAC contact instructs our Helpdesk for the study to be released.

  Documentation submission/quickguide

• 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

• Spatial predictors of response to immunotherapy in microsatellite stable metastatic colorectal cancer

  Microsatellite stable (MSS) colorectal cancers (CRC) are largely unresponsive to immune checkpoint inhibition (ICI), prompting investigation into strategies to enhance sensitivity. The MAYA trial, which utilized temozolomide (TMZ) in MGMT-silenced MSS mCRC, hypothesized that TMZ-induced hypermutation could sensitize tumors to ICI. This phase II trial met its primary endpoint, demonstrating durable clinical responses with TMZ combined with ipilimumab and nivolumab. To elucidate factors influencing response heterogeneity, we conducted multi-omic spatial profiling of samples from patients who participated in the MAYA trial, including baseline and on-treatment tissue and blood specimens. While increased neoantigen load following TMZ exposure did not consistently predict for deep responses, spatial profiling revealed key determinants. Lymphocyte proportions, particularly CD8+KI67+ cells, within stromal and tumor compartments, along with macrophage composition (CD68+CD163+ cells) at the tumor-stromal interface, were predictive of response. Treatment pressures dynamically altered the tumor microenvironment composition and activated peripheral immune cells. This study is the first to identify spatial predictors of response to this promising novel treatment approach for MSS CRC.

  Study EGAS50000001567

• Somatic_mutation_profiling_of_intestinal_crypts_from_IBD

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

  Study EGAS00001002896

• AC-ICAM: An Atlas and Compass of Immune-CAncer-Microbiome Interactions in Colon Cancer

  Fresh frozen tumor samples and matched normal colon specimens from chemotherapy naïve, consecutive patients with a histological diagnosis of colon adenocarcinoma at Leiden University Medical Center (LUMC) were subjected to multi-omics profiling at Sidra Integrated Genomics Services, part of Sidra Medicine, Doha, Qatar. This resulted in a high-quality dataset of samples collected between 2001 and 2015. Multi-step QC was performed, including assessment of the quality of the nucleic acid extraction, sequencing, and genetic concordance between DNA/RNA sequences from the same patient. After QC, this resulted in RNA sequencing on 348 tumor samples, whole exome sequencing (WES) on 281 tumor-normal sample pairs (n=562 samples), TCR sequencing of the TCR β locus (TRB) for 114 tumor and 10 matched normal samples, and 16S rDNA sequencing on 246 tumor-normal sample pairs (n=492 samples) and 42 tumor only samples, and 167 WGS non human-aligned reads of the tumor samples. Extensive clinicopathological and survival data of the cohort are available. The median follow-up time for this cohort is 4.6 years, and the distribution of gender and pathological stage are within expected ranges for this patient population with a mean age of 68. We refer to this resource as the Sidra-LUMC (SILU) colon adenocarcinoma (COAD) Atlas and Compass of Immune-Colon cancer-Microbiome interactions (AC-ICAM)."Reprinted from Nature Medicine,Roelands, J., Kuppen, P.J.K., Ahmed, E.I. et al. An integrated tumor, immune and microbiome atlas of colon cancer. Nat Med (2023). https://doi.org/10.1038/s41591-023-02324-5, with permission from Nature."

  Study phs002978

• Dana-Farber Cancer Institute (DFCI) Wu Lab/Avicenne CLL RNA-Seq Study

  Chronic Lymphocytic Leukemia (CLL) is a hematological malignancy characterized by accumulation of CD5+ B cells in peripheral lymphoid organs, bone marrow and blood. Recently, the advent of large-scale whole-exome sequencing of hundreds of CLL samples has led to gain a comprehensive understanding of the mutational landscape of this clonal B cell malignancy, but the functional effects of the putative driver mutations thus discovered are largely unknown. In this study, we analyze RNA-seq data from CLL patients to characterize dysregulated biological pathways regarding the presence of recurrent mutations. Source of tumor is patients' PBMC isolated from peripheral blood using the Ficoll method. Purity was confirmed using flow cytometry flow (>80% in all cases).

  Study phs002335

• Cell-free DNA sequencing data of healthy control, atrophic gastritis, and gastric cancer patients’ blood

  Sample cohort (n=48) is consisted of healthy, atrophic gastritis and gastric cancer patients. Some of the gastric cancer patients samples are collected at the separate time points: -1 before the operation; -2 after the operation; -3 during the control visit. For the hybridisation capture of the genes unique 15 gastric cancer-related gene panel was developed and very deep sequencing using TruSight Oncology Unique Molecular Identifier (UMI) Reagents (Illumina) was used.

  Dataset EGAD00001011153

• Samples from the Greek island of Crete, MANOLIS cohort

  Genome-wide association studies of complex traits have been successful in identifying common variant associations, but a substantial heritability gap remains. The field of complex trait genetics is shifting towards the study of low frequency and rare variants, which are hypothesised to have larger effects. The study of these variants can be empowered by focusing on isolated populations, in which rare variants may have increased in frequency and linkage disequilibrium tends to be extended. This work focuses on isolated populations from Greece. Sequencing is very efficient in isolated populations, because variants found in a few samples will be shared by others in extended haplotype contexts, supporting accurate imputation.

  Study EGAS00001000067

• Resuscitation Outcomes Consortium (ROC) Controlled Study of the Clinical Effectiveness of Automated Real-Time Feedback on CPR Process Conducted at a Subset of ROC Sites (CPR) (ROC-CPR-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: A substudy of the ROC PRIMED trial, the ROC CPR trial sought to investigate whether real-time audio and visual feedback during cardiopulmonary resuscitation (CPR) outside a hospital increases the proportion of participants who achieved prehospital return of spontaneous circulation.Background: Cardiopulmonary resuscitation is an essential link in the chain of survival for treating cardiac arrest. However, performance of CPR is highly variable both outside hospital and in hospital. Interruptions in chest compression, inadequate depth of chest compression, and high rates of ventilation adversely affect blood flow during chest compressions and can hinder resuscitation. Suboptimal CPR, particularly time spent without chest compressions (low chest compression fraction), can reduce survival of cardiac arrest patients.Current technology incorporated into a monitor-defibrillator can assess core components of CPR through the use of an accelerometer and impedance changes across the defibrillation electrodes. This technology can also provide real-time audiovisual feedback so that the rescuer is prompted to perform according to guideline specifications. Use of such feedback increases the likelihood of performing CPR in accordance with guidelines during training and simulation. Participants: There were 1586 participants: 771 treated without feedback and 815 with feedback.Design: CPR feedback was provided through proprietary Q-CPR software operating in the Philips MRx monitor-defibrillator. The feedback feature of the defibrillator includes audible voice prompts and visual messages on the monitor screen that are triggered when measured chest compressions or ventilation deviate from guidelines or are interrupted.The study was conducted in 21 emergency medical service (EMS) agencies at three ROC regions in the U.S. and Canada. Randomized treatment clusters, which ranged from individual emergency medical vehicles to groups of emergency agencies, were assigned to feedback-on or feedback-off treatments. Each cluster remained in its assigned mode for two to seven months, after which it switched to the opposite treatment arm. At the end of those two treatment periods, each cluster was again randomly assigned to feedback-on or feedback-off. This cycle continued for the duration of the study. Each cluster switched treatment arms at least once, and up to four times, during the study. Conclusions: Real-time visual and audible feedback during CPR altered performance to more closely conform with CPR guidelines. Clusters assigned to feedback were associated with increased proportion of time in which chest compressions were provided, increased compression depth, and decreased proportion of compressions with incomplete release. However, frequency of prehospital return of spontaneous circulation did not differ according to feedback status, nor did the presence of a pulse at hospital arrival, survival to discharge, or awake at hospital discharge (Hostler, et al., 2011, PMID: 21296838).

  Study phs003818

• scRNA-seq of total bone marrow and T cells from multiple myeloma long-term survivors

  scRNA This dataset contains 50 scRNA-seq samples from bone marrow aspirates of 11 multiple myeloma patients experiencing long-term survival and 3 healthy donors. For each donor, total bone marrow and CD3+ T cells were sequenced. For multiple myeloma patients, paired samples were collected at initial diagnosis and between 7-17 years after first-line therapy. Bone marrow mononuclear cells were isolated by Ficoll density gradient centrifugation. For sorting of total bone marrow cells singlet, live cells were gated and sorted, for sorting of T cells CD45+, CD3+ cells were gated and sorted on either FACSAria Fusion or FACSAria II. Single-cell RNA sequencing were generated using 10x Genomics single-cell RNAseq technology (Chromium Single Cell 3’ Solution v2) according to the manufacturer’s protocol and sequenced on an Illumina HiSeq4000 (paired end, 26 and 74 bp). Bulk RNA Singlet, live CD3+CD4- CXCR3+CD8+ and CD3+CD4- CXCR3-CD8+ cells were sorted from 7 bone marrow and 3 peripheral blood samples of 7 multiple myeloma patients using a FACSAria Fusion machine. Bulk-RNA sequencing libraries were generated using the SMART Seq Stranded Total RNA-Seq kit (Takara) and sequenced using the Illumina NovaSeq 6000 platform (2 x 100 bp).

  Dataset EGAD00001010025

• Arcagen - NET / NEC G3

  Arcagen is an EORTC/SPECTA pan-European project that aims to recruit 1000 rare cancer patients from different tumour domains of EURACAN. This study collected samples from advanced or metastatic rare cancer from patients older than 12, and analysed them using Foundation Medicine next-generation sequencing (NGS) panels (FoundationOne CDx for FFPE samples or FoundationOne Liquid CDx for blood samples). Here were are submitting the dataset that contains NGS files in .BAM format from 85 patients with extra-pulmonary neuroendocrine tumour or cancer grade 3 (NET / NEC G3).

  Dataset EGAD50000000913

• Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma - 30 whole exomes

  Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF/MAPK pathway activation. Here, we identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC. Functional analysis reveals these mutations ablate canonical TGFβ Smad signaling which is localised to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through BrafV600E or KrasG12D knockin) and TGFβ signaling ablation (through Tgfbr1 deletion) in LGR5+ve stem cells enables rapid cSCC development in the mouse. Mutation of Tp53 (which is commonly mutated in sporadic cSCC) coupled with Tgfbr1 deletion in LGR5+ve cells also results in cSCC development. These findings indicate that LGR5+ve stem cells can act as cells of origin for cSCC and that RAS/RAF/MAPK pathway hyperactivation or Tp53 mutation, coupled with loss of TGFβ signaling, are driving events of skin tumorigenesis.

  Study EGAS00001001892

• NHLBI TOPMed: African American Sarcoidosis Genetics Resource

  This study aims to comprehensively interrogate the genomes of African American sarcoidosis families. Sarcoidosis is characterized by a hyperimmune response resulting in granuloma formation in multiple organs. It affects African Americans (AAs) more frequently and more severely than whites. While previous linkage, admixture, candidate gene and genome-wide association (GWA) studies show statistically compelling effects, causal variants are still unknown and much of sarcoidosis heritability is yet to be explained. This "missing" heritability likely includes effects of both common (minor allele frequency (MAF)>5%) and rare variants (MAF

  Study phs001207

• IMPRESS: Improved methylation profiling using restriction enzymes and smMIP sequencing, combined with a new biomarker panel, creating a multi-cancer detection assay

  Background Despite the worldwide progress in cancer diagnostics, more sensitive diagnostic biomarkers are needed. The methylome has been extensively investigated in the last decades, but a low-cost, bisulfite-free detection method for multiplex analysis is still lacking. Methods We developed a methylation detection technique called IMPRESS, which combines methylation-sensitive restriction enzymes and single-molecule Molecular Inversion Probes. We used this technique for the development of a multi-cancer detection assay for eight of the most lethal cancer types worldwide. We selected 1791 CpG sites that can distinguish tumor from normal tissue based on DNA methylation. These sites were analysed with IMPRESS in 35 blood, 111 tumor and 114 normal samples. Finally, a classifier model was built. Results We present the successful development of IMPRESS and validated it with ddPCR. The final classifier model discriminating tumor from normal samples was built with 358 CpG target sites and reached a sensitivity of 0.95 and a specificity of 0.91. Moreover, we provide data that highlight IMPRESS’s potential for liquid biopsies. Conclusions We successfully created an innovative DNA methylation detection technique. By combining this method with a new multi-cancer biomarker panel, we developed a sensitive and specific multi-cancer assay, with potential use in liquid biopsies.

  Study EGAS50000000624

• Circumventing intratumoral heterogeneity to identify potential therapeutic targets in hepatocellular carcinoma. Details please contact lifuqiang@genomics and zhaoxin@genomics.cn.

  Background and aims: Intratumoral heterogeneity (ITH) challenges identifying mutations with target therapy potential whereas circulating cell-free DNAs (cfDNAs) could reflect nearly the entire mutation spectrum in given tumors. We investigated how to minimize the limit of ITH for profiling hepatocellular carcinoma (HCC).Methods: Thirty-two multi-regional HCC samples from five patients were subjected to whole exome sequencing (WES) and targeted deep sequencing (TDS). ITH extent was measured by the average percentage of non-ubiquitous mutations (present in parts of tumor regions). Matched cfDNAs were also analyzed by WES and TDS. Profiling efficiencies of single tumor specimen and cfDNA were compared and the one better depicted mutational landscape was selected to screen therapeutic targets.Results: We found variable extents of ITH in HCCs and observed branched and parallel evolution patterns. ITH level decreased at higher sequencing depth of TDS than that measured by WES (28.1% vs 34.9%, P < 0.01) but it remained unchanged upon additional samples analyzed. TDS of single tumor specimen detected an average of 70% the total mutations in HCC. Although more mutations were detected in cfDNA under TDS than WES, an average of 47.2% total HCC mutations uncovered by cfDNA suggested tissue outperform cfDNA and the latter may serve as alternative in profiling HCC genome. Consequently, TDS of single tumor tissue in 66 patients and cfDNAs in four unresectable HCCs identified 38.6% (26/66 and 1/4) patients bearing therapeutic targets.Conclusions: TDS of single tumor specimen could largely circumvent ITH to uncover mutations indicative of target therapy in HCC.

  Study EGAS00001002207

• The Institute for Genomic Medicine at Nationwide Children's Hospital Pediatric Cancer and Blood Disorder Project

  The aim of this study is to enable the unification of the clinical and research arms of comprehensive genomic profiling in the setting of cancer and hematologic disease. Increasingly, studies of the genomic etiology of cancer and hematologic diseases are being utilized for patient management, including prognostication, informing diagnosis, and evaluating eligibility for targeted therapeutics and clinical trials. Clinically available testing can be limited in scope and follow-up, and thus assessment of the impact on patient outcomes is difficult to ascertain. N-of-1 studies have the ability to more broadly impact our understanding of the mechanisms of cancer and hematologic disease, and can have benefit for the individual as well as the larger population of patients with these diseases. Thus, we seek to study and characterize the genomic underpinnings of cancer and hematologic disease through genomic profiling studies bridging both clinical and research components. We will rigorously perform and vet research sequencing and genomic studies protocols for the purpose of transitioning these assays to clinically valid testing for use in clinical patient care. We have been enrolling patients onto this comprehensive genomic profiling study since January 2018. As part of the genomic workup for these patients, we have been performing tumor and normal whole genome sequencing, whole exome sequencing and RNA-Seq. The project is largely supported by the Nationwide Children's Foundation, and we anticipate adding another 50-70 cases per year. This protocol is significant in that it expands our understanding of the etiology of cancer and hematologic disease through a comprehensive analysis aimed at detecting a broad scope of genomic aberrations. Additionally, it improves our understanding of the clinical utility of genomic profiling and has the potential to ultimately improve patient management and surveillance at both level of an individual and general populations of patients affected by these diseases. Primary Objectives: Aim 1: Use diagnostic, relapse, and/or germline samples for augmented whole exome sequencing to characterize the spectrum of germline and somatic genomic alterations in pediatric malignancies and hematologic disease. Aim 2: Examine gene expression and fusion events using whole RNA-seq "transcriptome" analysis or targeted RNA-seq analysis such as the Archer FusionPlex technology. Aim 3: Compare the results of our enhanced molecular profiling vs. that which is detectable by traditional methods as related to cytogenetic, molecular, and minimal residual disease analyses performed as part of standard of care. Aim 4: Examine the utility of comprehensive genomic profiling by collection and evaluation of outcomes data as related to enhancement/alteration in diagnosis, prognosis, treatment management, and clinical benefit. Secondary Objective: Aim 1: Use and clinically validate expanded laboratory methodologies and bioinformatic approaches to more broadly assess genomic complexity (e.g. whole genome sequencing, transcriptome sequencing, in vitro analyses, minimal residual disease testing, clonality assays, proteomics) in the setting of hematologic and oncologic disease. In so doing, we aspire to make novel discoveries and associations, as related to disease phenotypes and subtypes, variant causality, therapeutic targeting, and cancer biology.

  Study phs001820

• Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling (hipo_021)

  Parathyroid carcinoma (PC) is an orphan malignancy with a high risk of recurrence after surgery. Tumor-directed systemic treatments for PC are not established. We used whole-genome and RNA sequencing in four patients with advanced PC to identify molecular alterations that could guide clinical management. In two cases, the genomic and transcriptomic profiles provided targets for experimental therapies that resulted in biochemical response and prolonged disease stabilization: (i) immune checkpoint inhibition with pembrolizumab based on high tumor mutational burden and a single-base substitution signature associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) overactivation; (ii) multi-receptor tyrosine kinase inhibition with lenvatinib due to overexpression of FGFR1 and RET and, later in the course of disease, PARP inhibition with olaparib prompted by signs of defective homologous recombination DNA repair. In addition, our data provided new insights into the molecular landscape of PC with respect to the genome-wide footprints of specific mutational processes and pathogenic germline alterations. These data underscore the potential of comprehensive molecular analyses to improve care for patients with ultra-rare cancers based on insight into disease biology.

  Study EGAS00001006747

• Next Generation Mendelian Genetics: Kabuki Syndrome

  The ultimate purpose of this research is to identify genes causing hereditary disorders. We are scaling a new approach to identify the candidate genes and gene mutations that underlie rare human Mendelian (a set of primary tenets relating to the transmission of hereditary characteristics from parent to child) diseases by using exome (protein coding segments of DNA) resequencing. The exome sequences of ten unrelated individuals with a diagnosis of Kabuki Syndrome (OMIM: 147920) were obtained by massively parallel DNA sequencing.

  Study phs000295

• IMMUcan SCCHN1 cohort

  The goal of IMMUcan is to understand how the immune system interacts with tumors and how therapeutic interventions influence this interaction. This cohort includes patients with confirmed locally recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) who receive first-line treatment with immune checkpoint inhibitors (ICI) or ICI combined with chemotherapy. Comprehensive profiling data are integrated with longitudinally collected clinical information. Cellular profiling of the same tumor samples was performed using multiplex immunofluorescence imaging, imaging mass cytometry, and H&E staining.

  Study EGAS50000001533

• Whole genome sequencing of multiple myeloma identifies novel structural and non-coding mutations.

  The coding region of the myeloma genome is well understood with key mutations having been identified. However, the non-coding regions of the myeloma genome are yet to be analyzed. Here we have performed whole genome sequencing of myeloma patient samples to identify structural abnormalities including chromothripsis and chromoplexy, as well as gene dysregulation through super-enhancer juxtaposition with key oncogenes. We have also identified non-coding region hotspots of mutation, especially in promoter regions, that affect gene expression.

  Study EGAS00001003164

• Predicting resistance to chemotherapy using chromosomal instability signatures

  The aim of this study is to assess whether three chromosomal instability signature biomarkers are capable of predicting resistance to standard chemotherapies, namely platins, taxanes and anthracyclines. As part of this study we compiled a proof of principle cohort of ovarian cancers treated with these therapies, profiled using the Illumina TSO500 panel. Analysis of these data demonstrated that accurate biomarker calling can be computed from these gene panel data.

  Study EGAS50000000992

• CIRdb: Array genotype data

  The current inhabitants of the Canary Islands have a unique genetic makeup in the European diversity landscape due to the existence of African footprints from recent admixture events, especially of North African components (>20%). The underrepresentation of non-Europeans in genetic studies and the sizable North African ancestry, which is nearly absent from all existing catalogs of worldwide genetic diversity, justify the need to develop CIRdb, a population-specific reference catalog of natural genetic variation in the Canary Islanders. Based on array genotyping of the selected unrelated donors and comparisons against available datasets from European, sub-Saharan, and North African populations, we illustrate the intermediate genetic differentiation of Canary Islanders between Europeans and North Africans and the existence of within-population differences that are likely driven by genetic isolation. In addition, here we describe the overall design and the methods that are being implemented to develop CIRdb.

  Study EGAS00001006050

• The Role of CTCF in the Organization of the Centromeric 11p15 Imprinted Domain Interactome

  Beckwith-Wiedemann Syndrome (BWS) is the most common human imprinting disorder and comprises a spectrum of overgrowth phenotypes. While approximately 35% of BWS cases are caused by isolated loss of methylation (LOM) at the human imprinting center 2 (IC2) on chromosome 11p15, only around 5% of patients develop BWS due to structural alterations to the IC2 domain. In this study, we identify a BWS-causing 7.6 kB familial deletion within the IC2 domain by performing Whole Genome Sequencing (WGS) on patient-derived human fibroblasts. Using a chromatin conformation capture technique, Capture C, on 3 control fibroblast samples, 3 BWS LOM fibroblast samples, and the single familial deletion sample, we investigate how the domain interactome changes in BWS patients. We find that high-strength interactions occur within the IC2 domain between the 5’ end of KCNQ1, KCNQ1 intron 2, and the 5’ end of CDKN1C in the control profile that are largely abrogated in the BWS samples, but some lower frequency contacts between the imprinting control region (ICR), KCNQ1 intron 2, and the 5’ end of CDKN1C are unaffected. We conclude that the strong KCNQ1-CDKN1C interactions are important in maintaining the domain imprint.

  Study phs002408

• The Human Virome in Children and its Relationship to Febrile Illness

  Definition of the human microbiome is an important scientific priority. This study will expand the scope of the investigation to include viruses, which account for a substantial proportion of infectious disease morbidity and mortality, especially in children. The long-term goal of this project is to describe the human virome in children and to investigate its relevance to febrile illnesses in children. The project will also seek to understand the relationship of the immune system to the composition of the virome. Thus, the project's specific aims are 1) To elucidate the spectrum of viruses that can be detected using non-biased, high throughput sequencing on samples of blood, respiratory, and gastrointestinal secretions from healthy children and to use this information as a basis for understanding the role of viruses in acute febrile illnesses without an obvious source, and 2) to investigate the effect of various forms of immunosuppression on the spectrum of viruses detected in children, and to use this information as a basis for understanding the role of viruses in acute febrile illnesses occurring in these children. Our preliminary studies show that diverse viruses can be detected in children having undiagnosed fever. To carry out the specific aims, well children will be enrolled prior to having elective surgery, and febrile otherwise well children will be enrolled from the Emergency Department at St. Louis Children's Hospital. Immunocompromised children will be recruited from hematopoietic stem cell and solid organ transplant clinics, the HIV/AIDS clinic, and the rheumatology/immunology clinic from the same hospital. Children with fever will have samples obtained at the time of the febrile illness and at 1 and 6-month follow-up visits. Selected samples from each study group will be analyzed at the Genome Center at Washington University (GCWU) using next generation 454 high throughput sequencing to detect and sequence all viral sequences present. We anticipate detecting and sequencing a broad range of viruses, including previously unrecognized agents. A variety of techniques will be used to investigate the significance of viruses detected. Virus-specific PCR assays will be used to determine the frequency and extent of viruses detected by sequencing, using the full range of samples collected. Host response to the detected viruses will be investigated using serologic analysis, cytokine profiling, and microarrays to characterize host gene expression. These studies will take advantage of follow-up samples to compare the acute response with the response in the convalescent period. This study will draw upon the expertise and technological assets of one of the world's most powerful sequencing centers to provide the research community with a comprehensive sequence data base of the viruses that are present in children, which can be used to improve our understanding of the causes of febrile illnesses in young children, many of which are currently undiagnosed.

  Study phs000264

• Finnish_population_cohort_genotyping_B

  The FINRISK cohorts comprise the respondents of representative, cross-sectional populationsurveys that are carried out every 5 years since 1972, to assess the risk factors of chronicdiseases (e.g. CVD, diabetes, obesity, cancer) and health behavior in the working agepopulation, in 3-5 large study areas of Finland. DNA samples were collected in the followingsurvey years: 1987, 1992, 1997, 2002, 2007, and 2012. The MONICA and EHES (EU)procedures were applied in phenotype collection (cf. MORGAM) and a wide spectrum oflaboratory tests was carried out from serum and plasma samples. Background information onsocioeconomic status, medical history, diet, exercise, measured anthropometric measures,etc. was collected by questionnaires and during a clinical visit. Plasma/serum samples arestill available for the 2002-2012 cohorts. The cohort sizes are 6000-8800 per survey. Thecohorts have been followed up by linking them to the national hospital discharge register,causes-of-death register and cancer register.This project is an extension to previous efforts to build a catalogue of Finnish genome widedata on population-based Finsrisk samples with rich phenotypic characterisations and healthregistry link-up. These samples will extend the current Sequencing Initiative Suomi (SISu)samples with a combination of genotyping using Illumina HumanCoreExome array and SISu-based imputation. This will lead to high confidence common and low frequency variantcatalogue. The project will be funded by Aarno Palotie’s remaining faculty fundscomplemented by Finnish funding from FIMM.

  Study EGAS00001001047

• Next Generation Mendelian Genetics: Malignant Hyperthermia

  Malignant hyperthermia (MH) is a genetic disorder that causes a profound metabolic derangement following exposure to certain anesthetics. While approximately half of all cases are associated with ryanodine receptor-1 gene (RYR1) mutations, many cases have an unknown genetic cause. We sought to identify rare variants in novel MH candidate genes by sequencing the protein-coding regions of the genomes of individuals whose disease was either ruled in or out by the gold-standard diagnostic test. We also carefully selected individuals from well-characterized families to use gene-sharing information and maximize efficiency in the study design. Exome sequencing has helped identify the causes of over a dozen Mendelian disorders, has high power at low sample sizes, and is cost-efficient compared to whole-genome sequencing.

  Study phs000405

• 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

• Kids First: The Genomic Basis of Structural Birth Defects Associated with Chromosome 18 Copy Number Changes

  Chromosome abnormalities are a common cause of structural birth defects. Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions.However, because these genomic copy number changes involve multiple genes and because most of these conditions are individually rare, defining the specific causative genes behind specific phenotypes has been a challenge. We met that challenge by spending the last 28 years enrolling and evaluating anyone with a chromosome 18 abnormality. The cohort now includes over 700 individuals with a wide variety of chromosome 18 copy number changes (CNV), as well as their parents. Because the vast majority of these participants have individually unique CNVs, we have been able to perform extensive genotype-phenotype correlations resulting in 58 publications. Of the 263 genes on chromosome 18, 28 are linked to specific hemizygous phenotypes. However, most have low penetrance. Genomic sequence data could identify variants in the extant allele that are hypermorphic and compensate for hemizygosity, or are hypomorphic and exacerbate hemizygosity. Additionally, there are phenotypes within this cohort that are rare, or an extreme version of one of the more common phenotypes. Genomic sequence data could help discover new biallelic conditions by revealing functional sequence variants of the extant allele. In both of these cases, there could also be variants in other genes on other chromosomes that may be associated with the phenotype that confer susceptibility or resilience. Inclusion of this unique cohort in the Gabriella Miller Kids First Pediatric Research Program can advance the goals of the program in several ways. First, by adding known susceptibility loci to the existing Kids First cohorts for the structural birth defects that are also found in our cohort. Second, for those structural birth defects known to be polygenetic, this cohort has a single defined risk factor which can simplify the search for secondary factors. Third, these studies can also bring clarity to people with chromosome 18 conditions and help to make the genotype more accurately predict phenotype. This approach could be a model for understanding the many other rare chromosome abnormalities which collectively are a common cause of structural birth defects.

  Study phs002627

• GATA2 Deficiency and the MonoMAC Syndrome

  The aim of this study was to identify the germline mutation(s) in an extended family with individuals having MonoMAC Syndrome/GATA2 deficiency but lacking a canonical GATA2 mutation. GATA2 deficiency patients develop bone marrow failure, severe immunodeficiency and may progress to myeloid malignancies, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML). The definitive treatment for GATA2 deficiency is a bone marrow transplant. Approximately 90% of GATA2 deficiency patients have a known de novo or inherited germline mutation in the GATA2 gene, but ~10% have no identified mutation. The study was initiated with the first patient and her second cousin, both of whom were treated for MonoMAC Syndrome and received bone marrow transplants at the NIH. Pedigree analysis and clinical evaluation identified the individuals in several generations of these patients' near and distant relatives who are/were presenting or carrying the disease manifestations of GATA2 deficiency. Whole Genome Sequencing (WGS) was employed on these patients' two related nuclear families to identify variants that segregated with the disease trait and carrier status of their families. Genotyping was confirmed with direct DNA sequencing of these and other family members within the extended family across generations. A single base adenine-to-thymidine change was identified in a highly conserved enhancer element ~117,000 bp upstream of the GATA2 gene. It creates a new Composite Element, a DNA motif known to be critical in the regulation of hematopoiesis. This variant is unique to this family and is not present in dbSNP or other variant databases. It segregates with the disease trait and obligate carriers throughout a large pedigree. In vitro studies show that this variant drives allele-specific overexpression of the GATA2 gene in cultured cells and luciferase assays. The WGS sequence from the nuclear families will be shared on dbGaP.

  Study phs003269

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

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

  Dataset EGAD00001005316

• Genomic analysis Nasopharyngeal cancer through whole exome sequencing and whole genomic sequencing.

  Nasopharyngeal carcinoma (NPC) is a squamous-cell carcinoma and has remarkable ethnic and geographic distribution, with a high prevalence in southern China, southeast Asia, northern Africa and Alaska. Although there are previous studies implicated NF-κB pathway play an important role in NPC. Newer research also found several important cellular processes and pathways in NPC, including chromatin modification, ERBB-PI3K signaling and autophagy machinery. Put these studies together, although, NPC is still poorly understood at the genetic level. Here we determined the mutational landscape of 553 cases with NPC using whole-genomic and whole-exome sequencing. These approaches revealed a distinct mutational signature and significantly mutated genes.

  Study EGAS00001002788

• Genomic Heterogeneity and the Small Renal Mass

  Tumor heterogeneity is believed to represent a barrier to pre-operative genomic characterization in kidney cancer. Previous studies of heterogeneity in clear cell renal cell carcinoma (ccRCC) evaluated only large and metastatic tumors. In small renal tumors in which multiple biopsies are not feasible, the extent of heterogeneity remains unknown. In this study, we evaluated how the extent of genomic heterogeneity in small and large ccRCC. A total of 23 small (<4cm ) and 24 large (>7cm ) ccRCC had 3 regions sampled for evaluation of copy number, clear-cell A/clear-cell B (ccA/ccB) classification, and cell cycle progression (CCP) score. Small tumors have less genomic complexity and significantly fewer subclonal events. Pre-treatment genomic characterization based on a single biopsy in small ccRCC can provide insight into biologic potential to make clinical decisions.

  Study EGAS00001002919

• A Whole Genome Association Search for Type 2 Diabetes Genes in African Americans

  Over 2.8 million African Americans have type 2 diabetes mellitus (T2DM). This represents approximately 13% of the African American population and a significant proportion of the 21 million Americans living with diabetes. On average, an African American individual is twice as likely to have T2DM as a European American peer. Our research group has been actively involved in the study of African American diabetes genetics for over 15 years. We hypothesize that genes contributing to the development of T2DM in African Americans exist and can be located using modern molecular genetic methods. With the exception of TCF7L2(Transcription factor 7-like 2) evidence to date suggests variants that contribute T2DM risk in European-derived populations are not significant contributors to African American T2DM risk. We have performed a SNP-based Whole Genome Association (WGA) analysis on the Affymetrix 6.0 in a case control population of over 1000 African American T2DM cases and over 1000 non-diabetic controls. The DNAs have been collected from participants using uniform criteria from North Carolina and neighboring states. Genotype data will be subjected to extensive genetic analysis with the goal of defining a priority list of SNPs for genotyping in independent populations for confirmation and further detailed analysis.

  Study phs000140

• RNAseq from 6 organotypic co-cultures (OC cells bulk/OCSC with or without TME)

  The dataset contains samples of 6 organotypic co-cultures, assembled with patient-derived material from ovarian cancer (OC) patients. Tumor cells, both as bulk and as cancer stem cells-enriched (OCSC) populations, are cultured or not with in vitro peritoneal TME (for details see Battistini C et al, Tumor microenvironment-induced FOXM1 regulates ovarian cancer stemness, CDDis 2024). Dataset is composed by fastq file (paired end) type from bulk RNA-Seq.

  Dataset EGAD50000000523

• Capmatinib shows superior efficacy for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy

  Pediatric high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGGs, and are associated with devastating morbidity and mortality. To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion iHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy (RT).

  Study EGAS50000000137

• Heritable pulmonary arterial hypertension in a large Iberian family

  Data from a study of a large Iberian family (n=65 subjects, 5 generations) affected by pulmonary arterial hypertension (PAH) and segregating with the BMPR2 missense mutation p.Arg491Gln (rs137852749, c.1472G>A). PAH is a rare disease characterized by an abnormal rise in mean pulmonary arterial pressure (> or equal to 25 mmHg at rest), which, in turn, leads to a progressive increase in pulmonary vascular resistance and ultimately to death, due to right ventricular failure. Heritable PAH has an overall prevalence below 1 case per million adults and is defined by either the presence of a known genetic defect linked to the disease or a positive family history. Heritable PAH is inherited as an autosomal dominant disease. However, not all BMPR2 mutation carriers develop the disease, highlighting the presence of reduced penetrance. In this family, there are 22 mutation carriers from which 8 were diagnosed with heritable PAH and the other 14 were healthy at the time of examination.

  Study EGAS00001003123

• Regulatory T cell transcriptomic reprogramming characterizes adverse events by checkpoint inhibitors in solid tumors

  Immune checkpoint inhibitors (ICI), which target immune regulatory pathways to unleash antitumor responses, have revolutionized cancer immunotherapy. Despite the remarkable success of ICI immunotherapy, a significant proportion of patients whose tumors respond to these treatments develop immune-related adverse events (irAEs) resembling autoimmune diseases. Although the clinical spectrum of irAEs is well characterized, their successful management remains empiric. This is in part because the pathogenic mechanisms involved in the break-down of peripheral tolerance and induction of irAEs remain elusive. Herein, we focused on regulatory T cells (Tregs) in individuals with irAEs because these cells are vital for maintenance of peripheral tolerance, appear expanded in the peripheral blood of individuals with cancer and abundantly express checkpoint molecules, hence representing direct targets of ICI immunotherapy. Our data demonstrate an intense transcriptomic reprogramming of CD4+CD25+CD127– Tregs in the blood of individuals with advanced metastatic melanoma who develop irAEs following ICI immunotherapy, with a characteristic inflammatory, apoptotic and metabolic signature. This inflammatory signature was shared by Tregs from individuals with different types of cancer developing irAEs and individuals with autoimmune diseases. Our findings propose an inflammatory Treg reprogramming as a feature of immunotherapy-induced irAEs, that may facilitate translational approaches aiming to induce robust antitumor immunity without disturbing peripheral tolerance.

  Study EGAS00001004694

• Recapitulation of genetic predisposition to medulloblastoma in human neuroepithelial stem cells

  Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome, patients predisposed to medulloblastoma due to germline mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.

  Study EGAS00001003620

• Dissecting the Spatial Heterogeneity of Single Circulating Tumor Cells in Hepatocellular Carcinoma

  The dismal outcome of hepatocellular carcinoma (HCC) is closely associated with intra- and extrahepatic metastases, which have been proposed to be initiated by circulating tumor cells (CTCs). However, the plasticity of gene expression and immune evasion mechanisms of CTCs during systemic circulation are not well defined. Here, we determined intra- and inter-vascular transcriptional heterogeneity within the circulatory system using single-cell RNA-sequencing of 113 CTCs isolated from four key vascular sites along their dissemination route in ten HCC patients.

  Study EGAS00001005204

• Megabase scale methylation phasing using Nanopore long reads and NanoMethPhase

  This paper describes the work by Akbari V,. et al. on detection of allele specific methylation using oxford nanopore sequencing data. They have developed set of tools, SNVoter and NanoMethPhase, and workflow which enable the detection of allele specific methylation even in samples with sparse coverage of nanopore sequencing data.

  Dataset EGAD00001007920

• Comprehensive characterization of pre- and post-treatment samples of breast cancer reveal potential mechanisms of chemotherapy resistance

  When locally advanced breast cancer is treated with neoadjuvant chemotherapy, the recurrence risk is significantly higher if no complete pathologic response is achieved. Identification of the underlying resistance mechanisms is essential to select treatments with maximal efficacy and minimal toxicity. Here we employed gene expression profiles derived from 317 HER2-negative treatment-naïve breast cancer biopsies of patients who underwent neoadjuvant chemotherapy, deep whole exome and RNA-sequencing profiles of 22 matched pre- and post-treatment tumors, and treatment outcome data to identify biomarkers of response and resistance mechanisms. Molecular profiling of treatment-naïve breast cancer samples revealed that expression levels of proliferation, immune response and extracellular matrix (ECM) organization combined predict response to chemotherapy. Triple negative patients with high proliferation, high immune response and low ECM expression had a significantly better treatment response and survival benefit (HR 0.29, 95% CI 0.10-0.85; p=0.02), while in ER+ patients the opposite was seen (HR 4.73, 95% CI 1.51-14.8; 0=0.008). The characterization of paired pre-and post-treatment samples revealed that aberrations of known cancer genes were either only present in the pre-treatment sample (CDKN1B) or in the post-treatment sample(TP53, APC, CTNNB1). Proliferation-associated genes were frequently down-regulated in post-treatment ER+ tumors, but not in triple negative tumors. Genes involved in ECM were upregulated in the majority of post-chemotherapy samples. Genomic and transcriptomic differences between pre- and post-chemotherapy samples are common and may reveal potential mechanisms of therapy resistance. Our results show a wide range of distinct, but related mechanisms, with a prominent role for proliferation- and ECM-related genes.

  Study EGAS00001005876

• Gabriella Miller Kids First Pediatric Research Project in Cornelia de Lange Syndrome, Related Diagnosis and Structural Birth Defects

  This study involves a cohort of 400 individuals and family members with Cornelia de Lange Syndrome (CdLS) and CdLS-like phenotypes for which a molecular etiology has not yet been established. CdLS is a developmental disorder characterized by development delays, cognitive impairment, short stature, hearing loss, specific facial features, and structural birth defects such as differences of the limbs, heart, kidneys, and GI tract. Our approach to tease out genetic contributions to birth defects has been to identify the underlying causes of syndromic birth defects which are often Mendelian in nature and therefore lend themselves more readily to genetic causal identification. Once identified, these genetic causes of syndromic forms of birth defects can be leveraged to understand the genetic contributions to isolated birth defects seen in constellation in syndromes such as CdLS. This work will lead to the identification of genes critical in human embryonic development, provide novel insights into transcriptional regulation and help to identify genetic causes and candidate genes for isolated birth defects seen in constellation in similar diagnoses.

  Study phs002174

• HCA_Thymus_Disease_DiGeorge_Transplant_RNA

  Single cell transcriptomics study of thymic transplant biopsies Allogeneic thymus transplantation is the only curative therapy for complete DiGeorge Syndrome (cDGS), a rare severe primary immunodeficiency characterised by athymia. GOSH is one of only two centres worldwide to offer this treatment. Despite a lack of major histocompatibility complex (MHC)-matching between donor and host, transplanted thymus becomes repopulated by recipient bone marrow derived precursor cells and supports development of functional T-cells. The mechanisms underlying thymopoiesis in this context are poorly understood, but over time we observe reconstitution of T-cell immunity, with the ability to produce host naïve T-cells showing a broad T-cell receptor (TCR) repertoire and to generate MHC-restricted T-cell proliferative responses. Although lifesaving, the achieved immunological reconstitution is typically not complete with circulating T-cell numbers usually remaining below the age related normal ranges. Additionally, we observe persistence of donor-derived T-cells of unknown clinical significance. To gain more insight into the mechanisms by which MHC-mismatched transplanted thymus supports T-cell development with self-tolerance, as well as into the basis of suboptimal T-cell immunity, we now aim to investigate immune reconstitution after thymus transplantation in further detail by using single-cell transcriptomics, applied to thymic transplant biopsies and peripheral blood samples collected during standard post-transplant patient care. By identifying which lineages of host- derived cells repopulate the thymic tissue after transplantation, we will be able to address the role of MHC in positive and negative T-cell selection during T-cell differentiation. We will also be able to clarify the exact ontogeny of the persistent donor T-cells, as well as their possible role. Understanding the mechanisms of action of HLA-mismatched transplanted thymus will contribute to treatment optimisation. Additionally, our research provides a unique opportunity to further investigate key immunological concepts, such as tolerance and autoimmunity, challenging existing paradigms in thymus immunology. 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 EGAS00001004025

• NHLBI GO-ESP: Early-Onset Myocardial Infarction (Broad EOMI)

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. In the Grand Opportunities Exome Sequencing Program Early MI Project (GO ESP - EOMI), we are sequencing cases with extremely early-onset MI drawn from 8 cohorts. These cohorts include five hospital or community-based studies that ascertained individuals based on MI status. These include PennCATH, Cleveland Clinic Genebank, Massachusetts General Hospital Premature Coronary Artery Disease Study (MGH-PCAD), Heart Attack Risk in Puget Sound (HARPS), and Translational Research Investigating Underlying Disparities in Myocardial Infarction Patients' Health Status (TRIUMPH). Cases were selected based on MI occurring in men aged ≤50 years and women aged ≤60 years. In addition, early-MI cases are being drawn from three population-cohort studies including the Framingham Heart Study, the Women's Health Initiative, and the Atherosclerosis Risk in Communities Study. MI-free controls are being drawn from five population-based cohort studies including the Framingham Heart Study, the Women's Health Initiative, Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and the Jackson Heart Study. Controls were selected based on two factors: (1) highest predicted risk for MI based on Framingham risk score; and (2) absence of prevalent or incident MI despite a high predicted risk.

  Study phs000279

• Human Lung Tissue eQTL Study

  Genetic risks underlying respiratory diseases (e.g. COPD and asthma) are carefully studied by large genome-wide association studies (GWAS), where many loci were identified. In the post-GWAS era, the main challenge is to find the causal genes and pathways in GWAS-nominated chromosomal regions and to characterize etiology mechanism. The Lung eQTL Consortium is an international effort to systematically capture the genetic architecture of gene expression regulation in human lung. By studying lung specimens from 1,103 individuals of mostly European ancestry, we report a large number of genetic variants affecting gene expression in the lung, or lung expression quantitative trait loci (eQTL). These lung eQTLs will serve as an important resource to aid in the understanding of the molecular underpinnings of lung biology and its disruption in disease.

  Study phs001745

• DNA repair in BLM deficient hiPSCs

  We are aiming to investigate repair of a double strand break (DSB) within the genome in the presence and absence of the BLOOM protein. Zinc Finger Nucleases introduce DSBs at specified loci within the genome. Using sequencing we will assess the size of the deletion following repair. Protocol 1. Transfect normal and BLOOM deficient human iPS cells with ZFNs, using AMXA 2. Harvest cells after 5 days 3. Perform column extraction of DNA 4. PCR-amplify the ZFN region 5. Sequence and analyse repair of the DSB 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 EGAD00001000819

• Transdisciplinary Studies of Genetic Variation in Colorectal Cancer(CORECT): Axiom GWAS

  This study is part 1 of 2 for Schumacher et al, Nat Commun. 2015 Jul 7;6:7138. Part 1 is the original GWAS data for 9,259 participants on the Affymetrix Axiom platform of the studies listed below in the Inclusion Criteria.

  Study phs001856

• Single-Cell Mitochondrial Mutation Lineage Tracing of Non-Dysplastic and Dysplastic Barrett's Esophagus

  This study addresses a critical knowledge gap in understanding Barrett's esophagus (BE), a common metaplastic condition and precursor to esophageal adenocarcinoma, by identifying lineage connections and cell states underlying its development and malignant transformation. We collected biopsies from 13 Barrett's esophagus patients undergoing routine surveillance endoscopy, sampling metaplastic tissue alongside normal squamous esophagus and gastric cardia tissues when clinically appropriate. Our novel approach integrated single-cell RNA sequencing of nearly 180,000 cells with mitochondrial DNA mutation analysis for lineage tracing, coupled with spatial transcriptomics and comprehensive whole-exome sequencing. For one patient with high-grade dysplasia, we performed detailed whole-exome sequencing analysis at 100x coverage on dissociated Barrett's esophagus cells alongside matched normal esophagus and gastric cardia tissues. This genomic profiling revealed critical genetic drivers of malignant transformation, including a truncating mutation in the mutation cluster region of APC (a negative WNT regulator), mutations in the tumor suppressor genes CDKN2A and TP53, and significant copy number alterations including loss of CDKN2A on chromosome 9. These genetic alterations corresponded with the transcriptional changes observed in our single-cell data, particularly WNT pathway dysregulation and the expansion of LGR5-expressing stem cells, providing molecular evidence for how single clones can initiate the dysplastic transformation. Data deposited in dbGaP consist specifically of the whole-exome sequencing raw files, processed variant calls, and copy number analyses from the single patient with high-grade dysplasia and matched normal esophagus and stomach control tissue. Whole exome sequencing was performed on an Illumina NovaSeq 6000. Sequencing data was preprocessed following the Genome Analysis Toolkit's (GATK) Best Practices. Sequencing data was analyzed with Mutect2 (GATK, v4.2.5.0) to identify short somatic mutations including single-nucleotide polymorphisms and insertions and deletions. The Barrett's esophagus sample was run with the two matched normals, as well as the publicly available germline resource somatic-hg38_af-only-gnomad.hg38.vcf.gz (GATK). Somatic variant calls were filtered using FilterMutectCalls (GATK) and loaded into the Integrative Genomics Viewer (v2.12.3) for identification of high-quality variants in known esophageal adenocarcinoma regulators. Copy number alterations in the Barrett's esophagus sample were estimated using CNVkit (v0.9.9). CNV, Mutect2, and SVC analyses will be made available through dbGAP. Copy number alterations in the Barrett's esophagus sample were estimated using CNVkit (v0.9.9) with the default run settings; a pooled reference was generated from the normal esophagus and stomach samples. Copy number results were plotted directly within CNVkit using the function scatter.

  Study phs003949

• UK10K_NEURO_ASD_FI

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches.These samples are a subset of a nationwide collection of Finnish autism spectrum disorder (ASD) samples. The samples have been collected from Central Hospitals across Finland in collaboration with the University of Helsinki. The samples consist of 93 individuals with a diagnosis of autistic disorder or Asperger syndrome from 36 families with at least two affected individuals. Of these individuals, 16 can be genealogically connected to form two large pedigrees originating from Central Finland, suggesting possible genetic risk factors shared identical by descent within the pedigrees. All diagnoses are based on ICD-10 and DSM-IV diagnostic criteria for ASDs. Additional phenotypic data is available for a subset of the individuals.For further information with regard to this cohort please contact Aarno Palotie (Aarno.palotie@helsinki.fi).

  Study EGAS00001000110

• POPRES: Population Reference Sample

  POPRES version 1 and 2 Technological and scientific advances, stemming in large part from the Human Genome and HapMap projects, have made large-scale, genome-wide investigations feasible and cost-effective. These advances have the potential to dramatically impact drug discovery and development by identifying genetic factors that contribute to variation in disease risk as well as drug pharmacokinetics, treatment efficacy, and adverse drug reactions. In spite of the technological advancements, successful application in biomedical research would be limited without access to suitable sample collections. To facilitate exploratory genetic research, we have assembled a DNA resource from a large number of subjects participating in multiple studies throughout the world. This resource was initially genotyped using the Affymetrix 500K SNP panel. This project includes nearly 6,000 subjects of African American, East Asian, South Asian, Mexican, and European origin. POPRES version 3 The discovery and development of novel drugs is challenging and with high attrition rates. Selection of the right target and optimal indications for novel therapeutics represent key decision points in this process, and are often hampered by our limited understanding of the biology of the target in humans. Building a robust body of knowledge of variation within drug target genes has in several cases increased the probability of success for novel therapeutics. Our knowledge of variation within drug target genes and their influence on traits of medical interest is still very limited. In an effort to fill this gap, we resequenced the exons of 202 known or suspected drug target genes in over 16,000 well-phenotyped individuals. A total of 863,883 bases were targeted, including 351 kb of coding and 323 kb of untranslated exon regions. The sequenced subjects included 3,381 from two studies that were part of the Population Reference Sample (POPRES) project: CoLaus (N = 2,059) and LOLIPOP (N = 1,322). Genotyping data generated through the targeted next generation sequencing is available through the dbGaP.

  Study phs000145

• FFPE CRC WGS Data

  The data consists of 3 BAM files. Two of three BAMs are tumour FFPE samples (1 repaired-FFPE; 1 unrepaired-FFPE); The other BAM file is sequenced from normal colon tissue

  Dataset EGAD00001007716

• Transcriptomic Characterization of Human Innate T Cells

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

  Study phs002007

• Novel immunodeficiency caused by homozygous mutations of SLC19A1

  The male proband suffered from infancy oral lesions, recurrent fever, diarrhea, vomiting, atopic dermatitis, dark discoloration patches on his skin and lip fissures; he suffered from anemia (megaloblastic), thrombocytopenia, hypogammaglobulinemia and lymphopenia; his growth and development are delayed. Whole exome sequencing identified only one variant predicted to have high impact and to potentially explain the patient’s phenotype, a homozygous missense chr21:46950793:C:T (hg19) SLC19A1 NM_194255:c.1042G>A (p.G348R). Sanger sequencing and segregation analysis confirmed the presence of the homozygous SLC19A1 c.1042G>A (G348R) missense variant in the proband, with a heterozygous state in his family. The same homozygous SLC19A1 variant was identified in a distantly-related male patient with a similar phenotype presentation, while his healthy family members were heterozygous. SLC19A1 is a folate transporter, and thus folic acid supplementation was performed for the proband: platelet counts normalized rapidly and anemia improved; hair and skin discoloration, mouth lesions and chronic diarrhea improved. In contrast, neurological and developmental issues remained unchanged and treatment had only a partial effect on the immune system. This further confirmed the causal role of SLC19A1 for the proband's condition.

  Study EGAS50000000356

• SardiNIA Medical Sequencing Discovery Project

  The SardiNIA Medical Sequencing Discovery Project studies the genetics of blood lipid levels and personality in a Sardinian population cohort. The project has generated draft genome sequences for approximately 2,000 individuals using whole genome shotgun sequencing. The draft sequences will allow investigators to evaluate the contribution of common and rare single nucleotide polymorphisms, short insertions and deletions, large copy number polymorphisms and other structural variants to blood levels of low density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c) and triglycerides (TG), all of which are key risk factors for cardiovascular disease, and to the 5 domains of personality as assessed by the NEO-PI-R questionnaire. The two traits represent different ends of the spectrum of medically interesting complex traits. Blood lipid levels are a risk factor for cardiovascular disease for which genetic studies have been very successful. In contrast, personality traits and other behavioral phenotypes represent a set of phenotypes that have proven more challenging to dissect using standard genetic tools. In both cases, we expect whole genome sequencing to improve our understanding of the underlying biology. The isolated Sardinian population is ideal for this type of study for several reasons, in particular because: (i) the bottleneck that occurred after colonization of the island attenuated natural selection against alleles with phenotypic consequences, increasing the odds that functional alleles will reach modest frequencies (0.5 - 5.0%) and will be detected in the present study and (ii) sharing of long haplotype stretches surrounding rare variants will facilitate imputation based analyses of shotgun sequence data, which improve the accuracy of individual genotype calls and thus increase power. This research helps advance NIH's mission by furthering our understanding of the genetic factors contributing to blood lipid levels and coronary heart disease and to personality, behavior and mental health. In addition, these data should facilitate development of analysis tools and strategies that can be used to study the genomes of hundreds to thousands of individuals and further our understanding of the genetics and biology of many different traits and conditions.

  Study phs000313

• PAGE: Global Reference Panel

  Stanford contributed samples to the PAGE study that can act as a population reference dataset across the globe. Therefore this dataset includes reference individuals, without phenotypes, chosen to help infer ancestry that will help us understand the diverse samples available in PAGE. The complete dataset comprises individuals of European, African, Asian, Oceanian, and Native American descent, from a total of over 50 populations. A subset of these individuals from Puno, Peru and Easter Island (Rapa Nui), Chile, are included in the PAGE samples that were whole genome sequenced in 2015. Additional details are available in the Study Acknowledgments. The Global Reference Panel comprises 6 sample sets: A population sample of Andean individuals primarily of Quechuan/Aymaran ancestry from Puno, Peru A population sample of Easter Island (Rapa Nui), Chile Individuals of indigenous origin from Oaxaca, Mexico Individuals of indigenous origin from Honduras Individuals of indigenous origin from Colombia Individuals of indigenous origin from the Nama and Khomani KhoeSan populations of the Northern Cape, South Africa In addition, we genotyped publicly available samples that will be hosted on the Bustamante lab website (https://bustamantelab.stanford.edu/). These comprise large public datasets to provide an open reference dataset for the world: The additional related individuals from the Americas in the Human Genome Diversity Panel (H952) plus all additional samples from the Americas A subset of the unrelated individuals from the Maasai in Kinyawa, Kenya (MKK) dataset from the International Hapmap Project hosted at Coriell Additional samples will be available for restricted use with a data access agreement with the Bustamante Lab. This study is part of the Population Architecture using Genomics and Epidemiology (PAGE) study (phs000356).

  Study phs001033

• Whole exome sequencing reveals the mutational spectrum of testicular germ cell tumours

  Testicular germ cell tumours (TGCTs) are the most common cancer in young men. Here we perform whole exome sequencing of 42 TGCTs to comprehensively study the mutational profile of TGCT. The mutation rate is uniformly low in all of the tumours (mean 0.5 mutations per megabase [Mb]) as compared to the common cancers, consistent with the embryological origin of TGCT. In addition to expected copy number gain of chromosome 12p and mutation of KIT we identify recurrent mutations in the tumour suppressor gene CDC27 (11.9%). Copy number analysis reveals recurring amplification of the spermatocyte development gene FSIP2 (15.3%) and a 0.4Mb region at Xq28 (15.3%). Two treatment-refractory patients are shown to harbour XRCC2 mutations, a gene strongly implicated in defining cisplatin resistance. Our findings provide further insights into genes involved in the development and progression of TGCT.

  Study EGAS00001001084

• Genomics characterization of primary central nervous system lymphoma

  Primary central nervous system lymphoma (PCNSL) is a rare malignancy confined to the central nervous system (CNS). Despite low tendency of systemic dissemination, its prognosis is poor with median overall survival of 2?4 years. Due to its rarity, knowledge of genomic alterations underling PCNSL pathogenesis is severely limited. Here we performed whole-exome sequencing on 44 PCNSL and paired normal specimens, revealing high penetrance of nonsynonymous somatic mutations in PIM1 (95.5%), BTG2 (88.6%) and MYD88 (81.8%). Interestingly we found oncogenic mutations in GRB2, and this effect was cancelled when transformed cells are treated with inhibitors to downstream kinases MAP2K1/2. Further, when tumor cells carries MYD88 mutations, the same mutations were also found at low frequency in peripheral blood mononuclear cells (PBMNC), implying that MYD88 mutation?positive precancerous cells originate outside CNS and develop to lymphoma with additional genetic hits that fit the CNS environment.

  Study JGAS000021

• Genomic_profiling_of_B_other_Adult_ALL_WGS

  Adult ALL is an aggressive leukaemia, affecting adults of all ages. It is associated with a rapid onset and poor outcomes. Our understanding of adult ALL genome has been limited to molecular markers first described in paediatric ALL and validated in adult ALL and to date there have been no studies investigating the genomics of Adult ALL. We will perform whole genome sequencing on at least 100 Adult ALL cases. Priority will be given on ALL cases without a known primary lesion by cytogenetic analysis which are categorised as “B-other”. We will also sequence representative cases of each known subtype. This will deliver a comprehensive annotation of the genomic landscape of Adult ALL to include acquired somatic mutations (substitutions, indels, structural variants/fusion genes) and copy number profiles. The focus on B-other Adult ALL is likely to result in new and previously undescribed genomic lesions.

  Study EGAS00001002474

• Genomic_profiling_of_B_other_Adult_ALL_RNA

  Adult ALL is an aggressive leukaemia, affecting adults of all ages. It is associated with a rapid onset and poor outcomes. Our understanding of adult ALL genome has been limited to molecular markers first described in paediatric ALL and validated in adult ALL and to date there have been no studies investigating the genomics of Adult ALL. We will perform whole genome sequencing on at least 100 Adult ALL cases. Priority will be given on ALL cases without a known primary lesion by cytogenetic analysis which are categorised as “B-other”. We will also sequence representative cases of each known subtype. This will deliver a comprehensive annotation of the genomic landscape of Adult ALL to include acquired somatic mutations (substitutions, indels, structural variants/fusion genes) and copy number profiles. The focus on B-other Adult ALL is likely to result in new and previously undescribed genomic lesions.

  Study EGAS00001003428

• Identification of High-Risk PHF19 Expressing Cells in Myeloma Single-Cell Multiomics

  The aim of this study is to identify novel subsets of cells that are associated with progression and response to treatment. In this project, we study the tumor fraction from 49 myeloma patients across stages of progression. Samples were collected from 10 smoldering multiple myeloma (SMM), 22 newly diagnosed multiple myeloma (NDMM), and 17 relapsed refractory multiple myeloma (RRMM) patients. These samples were then sorted using magnetic-activated cell sorting (MACS) for CD138+ cells that represent the tumor fraction of each sample. The CD138+ fraction then underwent whole genome sequencing (WGS), where possible, and single-cell multiomics. Single-cell multiomics can now measure scRNA-seq and scATAC-seq simultaneously, which we use in this project. Using single-cell multiomics, we will study subclonal changes in gene expression, chromatin accessibility, and identify novel regulatory relationships within myeloma tumors. Furthermore, we will apply state of the art single-cell and single-cell multiomic techniques to better identify the more high-risk components of myeloma.

  Study phs003220

• Chromosomal copy number heterogeneity predicts survival rates across cancers

  Survival rates of cancer patients vary widely within and between malignancies. While genetic aberrations are at the root of all cancers, individual genomic features cannot explain these distinct disease outcomes. In contrast, intra-tumour heterogeneity (ITH) has the potential to elucidate pan-cancer survival rates and the biology that drives cancer prognosis1,2. Unfortunately, a comprehensive and effective framework to measure ITH across cancers is missing3. Here, we introduce a scalable measure of chromosomal copy number heterogeneity that predicts patient survival across cancers. We show that the level of ITH can be derived from a single-sample copy number profile. Using gene-expression data we demonstrate that ongoing chromosomal instability underlies the observed heterogeneity. Analysing 11,534 primary cancer samples from 35 different malignancies, we find that copy number heterogeneity can be accurately deduced and predicts cancer survival across tissues of origin and stages of disease. Our results provide a unifying molecular explanation for the different survival rates observed between cancer types.

  Study EGAS00001004702

• DNA methylation-based classification of sinonasal tumors [DNA sequencing]

  This dataset contains raw exome sequencing data from nine sinonasal undifferentiated carcinoma FFPE samples and matched normal tissue that were assigned to a shared epigenetic class using DNA methylation-based classification. They were analyzed using the Twist Human Core Exome Plus Kit (Twist Bioscience) on a NovaSeq 6000 sequencer.

  Dataset EGAD00001009668

• Immune variation leads to diverse outcomes in human malaria (2020-01-15)

  Falciparum malaria is clinically heterogeneous and yet in most cases the risk of life-threatening disease dramatically declines after the first few infections of life because children rapidly acquire disease tolerance (resistance to severe malaria without improved control of parasite burden). Identifying the factors that determine clinical outcome in a malaria-naive host is therefore paramount to reduce malaria mortality. However, the relative contribution of disease-causing variants of the Plasmodium var gene family versus pathogenic inflammatory cytokine cascades remains fiercely debated - we sought to reconcile these conflicting arguments by studying their interaction in vivo. To this end, two human challenge models were used to reveal the parasite-host interactions that underpin variation in falciparum malaria. To capture the diversity of human immune responses, each individual was analysed independently by tracking dynamic changes in their whole blood transcriptome through time. And to uncover evidence of preferential expansion of disease-causing variants, var gene expression was tracked in vivo from the start to end of infection. In this way, we could show that group A var genes are always expressed upon liver egress but in a minority population that does not increase over 10-days of blood cycling; there is no selection of disease-causing variants in the naive host. In fact, parasites do not respond in any way to differences or changes in host environment. On the other hand, host-intrinsic variation determines the intensity of inflammation and progression to clinical malaria. And furthermore, regulation of the interferon signaling network controls host fate. These data emphasise the role of human immune decision-making in shaping course & outcome of infection. 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/ . This dataset contains all the data available for this study on 2020-01-15.

  Dataset EGAD00001005790

• 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

• Myelodysplastic_Syndrome_Exome_Sequnecing

  Cancer is driven by mutation. Illumina GA massively parallel sequencing technology will be applied to Agilent exome hybridisation capture libraries and total genomic paired-end libraries. Bespoke algorithms are being developed to identify the somatically acquired structural variants, point mutations, insertions and deletions in these samples. This project will give unprecedented insights into mutational processes, cellular repair pathways and gene networks associated with Myelodysplastic Syndrome development.

  Study EGAS00001000089

• Exome sequencing of Fibromyalgia patients

  Fibromyalgia is a complex disorder characterized by increased sensitivity to pain and extreme tiredness. It affects mostly women, and its causes are unknown. In this study we have performed exome sequencing of 87 fibromyalgia cases, including some sibling pairs, to perform rare variant association analysis and identify fibromyalgia risk factors. A few of the included samples have been also included in a previous GWAS study.

  Study EGAS00001003826

• cfDNA dataset from the urine supernatant of ovarian cancer patients and healthy controls

  Background Ovarian cancer is the deadliest gynecological malignancy worldwide, due to frequent diagnosis at advanced stage. Simple and non-invasive methods for earlier and accurate detection are urgently needed. Here, the presence of tumor-derived DNA in home-collected urine, cervicovaginal self-samples and clinician-taken cervical scrapes of ovarian cancer patients was explored by DNA methylation and copy number analysis. Methods A total of 428 samples (urine, cervicovaginal self-samples, and clinician-taken cervical scrapes) of 110 healthy controls and 54 patients with benign (n=25) or malignant (n=29) ovarian masses were analyzed. Different urine fractions were examined (full void urine, urine supernatant, and urine sediment). All samples were tested for 12 methylation markers by quantitative methylation-specific PCR. Shallow whole-genome sequencing was performed to detect copy number aberrations and verify the presence of tumor-derived DNA. Results Full void urine was most discriminatory between healthy controls and ovarian cancer patients (C2CD4D, p=0.008; CDO1, p=0.022; MAL, p=0.008), followed by cervical scrapes (C2CD4D, p=0.001; CDO1, p=0.004). A significant difference between benign and malignant ovarian masses was only observed for GHSR in the urine sediment (p=0.024). Methylation levels in cervicovaginal self-samples did not discriminate between healthy controls, benign and malignant ovarian masses. Copy number changes were identified in 17% of urine supernatant samples and smaller fragment sizes were seen in urine supernatant samples with a high tumor fraction. Conclusions This study demonstrates the presence of ovarian cancer-derived DNA in home-collected urine. Additional studies are warranted to further explore the clinical applicability of this approach.

  Study EGAS00001007238

• Mosaic structural variation sample

  Mosaic Normal-Tumor genomes are generated from real normal-tumor pairs with validated somatic variants. In this case, validated variants from the GRIDSS2 paper. Mosaic genomes were generated using GenomeMosaicMaker, an open-source software tool designed and implemented for this specific purpose. The variants provided in the VCF truth file for each mosaic tumor/normal pair were annotated using funnSV for SVs and VEP for SNVs and indels. All CRAM files are aligned to GRCh37. Please see https://github.com/EUCANCan/oncoliner and https://github.com/Computational-Genomics-BSC/GenomeMosaicMaker for more information.

  Study EGAS50000000460

• Exome sequencing of synchronous colorectal cancers

  Approximately 4% of colorectal cancer (CRC) patients have at least two simultaneous cancers in the colon. Due to the shared environment, these synchronous CRCs (SCRCs) provide a unique setting to study colorectal carcinogenesis. Understanding whether these tumors are genetically similar or distinct is essential when designing therapeutic approaches. We performed exome sequencing of 47 primary cancers and corresponding normal samples from 23 patients. Additionally, we carried out a comprehensive mutational signature analysis to assess whether tumors had undergone similar mutational processes and the first immune cell score analysis (IS) of SCRC to analyze the interplay between immune cell invasion and mutation profile in both lesions of an individual. The tumor pairs shared only few mutations, favoring different mutations in known CRC genes and signaling pathways, and displayed variation in their signature content. Two tumor pairs had discordant mismatch repair statuses. In majority of the pairs, IS varied between primaries. Differences were not explained by any clinicopathological variable or mutation burden.

  Study EGAS00001003474

• Idiopathic Pulmonary Fibrosis Network (IPFNet) Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis (IPFNet-STEP-IPF-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: The STEP-IPF study sought to evaluate whether treatment with sildenafil would improve walk distance, dyspnea, and quality of life in participants with advanced idiopathic pulmonary fibrosis (IPF).Background: IPF is a chronic, progressive lung disease of unknown cause that is characterized by the histopathologic pattern of usual interstitial pneumonia. Progression to end-stage respiratory insufficiency and death within 5 years after the onset of symptoms is characteristic. To date, no pharmacologic therapies have definitively been shown to improve survival or quality of life in participants with this disease.Participants with severe IPF have abnormalities of the pulmonary vasculature leading to decreased levels of resting and exercise-induced production of nitric oxide. Since nitric oxide is a potent pulmonary vasodilator, reduced levels are associated with pulmonary vasoconstriction and impaired gas exchange. Sildenafil (Revatio, Pfizer) is a phosphodiesterase-5 inhibitor that stabilizes the second messenger of nitric oxide, cyclic guanosine monophosphate, which leads to pulmonary vasodilatation. Such vasodilatation could improve ventilation–perfusion matching and thus gas exchange in with IPF.Design: STEP-IPF was a double-blind, randomized, placebo-controlled trial of oral sildenafil (20 mg three times daily). Participants meeting eligibility criteria were randomly assigned in a 1:1 ratio to receive sildenafil or matched placebo with the use of a permuted-block design, with stratification according to clinical center. The primary outcome was the presence or absence of an improvement of at least 20% in the 6-minute walk distance at 12 weeks, as compared with baseline. Key secondary outcomes included changes in the 6-minute walk distance, degree of dyspnea, and quality of life.Screening procedures included the taking of a detailed history, a physical examination, spirometry, echocardiography, CT imaging, and measurements of lung volume on plethysmography, carbon monoxide diffusion capacity, and arterial blood gases. Eligible participants returned for an enrollment visit within 6 weeks after screening. All participants received an initial dose of a study drug at this visit and were monitored for 60 minutes for adverse effects. Follow-up visits were scheduled at 1, 6, and 12 weeks. After completion of the 12-week visit, all participants were started on treatment with open-label sildenafil. Visits were scheduled at 13, 18, and 24 weeks; at 28 weeks, serious adverse events and vital status were documented. Testing of the 6-minute walk distance was performed with the use of a standardized protocol at the time of screening and enrollment and at study visits at 6, 12, 18, and 24 weeks. Participants with pulse oxygen saturation below 88% received supplemental oxygen. Conclusions: This study did not show a benefit for sildenafil for the primary outcome. The presence of some positive secondary outcomes creates clinical equipoise for further research. There were small but significant differences in arterial oxygenation, carbon monoxide diffusion capacity, degree of dyspnea, and quality of life favoring the sildenafil group.

  Study phs004085

• HudsonAlpha Long Read Sequencing Data of Individuals with Rare Suspected Genetic Conditions

  The data included in this project were generated from several IRB projects focused on the identification of the underlying genetic cause of undiagnosed rare conditions in infants, children and adults enrolled across the southeastern United States. Long read genome sequencing was performed on DNA samples collected as part of an IRB-approved study and findings from this testing was returned to enrolled study participants and the clinical team providing care. Proband participants in these studies were enrolled in both inpatient (neonatal intensive care units) and outpatient settings. When possible, biological relatives (including both biological parents) were also enrolled to help clarify inheritance of variants identified. Sequencing and analysis for SouthSeq is conducted at the HudsonAlpha Institute for Biotechnology in Huntsville, Alabama (https://www.hudsonalpha.org/). Results of testing are disclosed to participants by genetic counselors or trained non-genetics providers who also facilitate sharing of results with the participants' medical care teams when appropriate. Further, participant families may choose to opt-into return of secondary findings identified in the proband, which focus on pathogenic and likely pathogenic variation identified within the current ACMG gene list.

  Study phs003537

• Discrepancies in Tumour Mutation Burden (TMB) reporting from sequential Endobronchial ultrasound trans bronchial needle aspiration (EBUS TBNA) samples within single lymph node stations

  Introduction: Tumour Mutation Burden (TMB) is a potential biomarker for immune therapies. Identifying factors that may affect TMB prediction is key to its utility as biomarker for treatment options. Here we investigated parameters that might affect TMB using cytology smears obtained from endobronchial ultrasound transbronchial needle aspiration (EBUS TBNA)-sampled malignant lymph nodes, which are often the only diagnostic samples collected in patients with advanced lung cancer. Methods: Individual Diff-Quik cytology smears were prepared for each needle pass from the same enlarged malignant mediastinal lymph nodes. DNA extracted from smears of each pass underwent sequencing using a large gene panel sequencing (TSO500, Illumina). TMB was estimated for each individual needle pass using the TSO500 Local App v. 2.0 (Illumina). Results: Twenty patients had two or more Diff-Quik smears (total 45 smears) which passed sequencing quality control. Average TMB for all smears was 8.7 ± 5.0 mutations per megabase (Mb). Sixteen of the 20 patients had paired samples with minimal differences in TMB score (average difference 1.3 ± 0.85). Paired samples from 13 patients had concordant TMB in terms of scores being below or above a threshold of 10 mutations/Mb. Samples from seven patients had discrepant TMB, with four cases in particular exhibiting an average difference of 11.3 ± 2.7 mutations/Mb. Factors affecting TMB calling involved tumour content of the samples, the amount of DNA used in sequencing as well as bone fide intra tumour heterogeneity between paired samples. Conclusions: TMB assessment is feasible from EBUS-TBNA derived Diff-Quik slides from a single needle pass. Repeated samples of one or more lymph nodes have minimal variation in TMB in most cases (80%), suggesting accuracy of the test overall. To enhance accuracy of the result, care should be taken in relation to the tumour content of the cytology smear. Further, clinicians should be aware that even slight differences in lymph node site selection could give rise to variable genomics and discrepant TMB due to tumour heterogeneity. Therefore, it would be reasonable for multi-lymph node site analysis of TMB to be performed using EBUS TBNA aspirates from different easily accessible lymph nodes. Further investigations need to determine whether these samples should be combined as one sample or tested separately.

  Study EGAS00001007484

• Low_coverage_whole_genome_sequencing_of_samples_from_the__Cretan_Greek_isolate_collection_HELIC_MANOLIS

  Whole-genome sequencing at 1x of samples from the Cretan Greek isolate collection HELIC-MANOLIS. Genome-wide association studies of complex traits have been successful in identifying common variant associations, but a substantial heritability gap remains. The field of complex trait genetics is shifting towards the study of low frequency and rare variants, which are hypothesised to have larger effects. The study of these variants can be empowered by focusing on isolated populations, in which rare variants may have increased in frequency and linkage disequilibrium tends to be extended. This work focuses on an isolated population from Crete, Greece. Sequencing is very efficient in isolated populations, because variants found in a few samples will be shared by others in extended haplotype contexts, supporting accurate imputation.

  Study EGAS00001000392

• Single cell RNA-seq of two rare cases of human glioblastoma at multiple sampling points

  Glioblastoma is characterized by large cellular diversity whose complexity and organizing principles are only starting to be uncovered. Both neurodevelopment-like and mesenchymal-like cell states have been described in glioblastoma but the nature of the mesenchymal-like cell states remains unresolved. Here, we performed deep single-cell RNA sequencing of two rare glioblastoma cases where tissue could be sampled from tumor core to macroscopically normal cortex with the aim of understanding these tumor cell states.

  Study EGAS50000001030

• Chromosome contacts in activated T cells identify autoimmune disease-candidate genes

  Autoimmune disease-associated DNA variants are preferentially found in regions with putative regulatory function in immune cells, particularly CD4+ T cells. Linking such regulatory elements to gene promoters in disease-relevant cells and contexts is essential to identify disease candidate genes. Here we show that the activation of CD4+ T cells invokes changes in the activity of regulatory elements and transcription of RNAs that correspond to changes in the expression of their interacting genes identified by promoter capture Hi-C (PCHi-C).

  Study EGAS00001001961

• RNAseq data from the study - Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML

  This study assessed molecular determinants of response in a cohort of patients with AML that were treated with venetoclax in combination with either DNA methyltransferase inhibitors or low dose cytarabine. RNA sequencing was performed on 31 patients from three different response classes [10 Group A - Durable remission (n=10), Group B - Relapsed (n=10) and Group C - Refractory (n=11)]. Library preparation and sequencing was performed at the Australian Genome Research Facility, using the Truseq Stranded mRNA library kit. Technical and batch replicate samples are included. Gene count data are provided with the original publication. The use of the sequencing data is subject to a data transfer agreement and is restricted to ethically approved research into blood cell malignancies and cannot be used to assess germline variants.

  Dataset EGAD00001005949

• Drug Development against Tumor Microtube Networks in Glioblastoma

  Glioblastomas are aggressive brain tumors that resist current therapies by hijacking neurodevelopmental programs to invade the brain and form resilient multicellular networks. Tumor Microtubes (TMs), neurite-like processes extended by cancer cells, drive this pathobiology, but TM-inhibiting drugs are lacking. Here we developed a comprehensive, combined in vitro and in vivo drug screening approach, including novel AI-based analysis tools of TM parameters. Two Protein Kinase C (PKC) activators, TPPB and PMA, exhibited robust inhibition of TM formation in cell-based assays. Since unconnected glioblastoma cells exhibit increased sensitivity to cytotoxic therapy in vivo, brain tumor-bearing mice received TPPB, the most consistent TM-inhibiting compound, in combination with radiotherapy. Long-term intravital 2-photon microscopy confirmed anti-TM and anti-tumor effects of the co-treatment. Mechanistically, TPPB treatment inhibited several key molecular and functional components of TM-related glioblastoma cell network communication and decreased the expression of TTYH1, a key driver of invasive TMs. By establishing a novel screening pipeline for anti-TM drug development, our study identifies a druggable TM master regulator pathway and a small molecule with robust anti-TM effects. It provides a proof-of-principle that disrupting TMs and disconnecting tumor networks is a pharmacologically feasible strategy to make therapies against glioblastoma more effective.

  Study EGAS50000000477

• T1DGC GWAS 1958 British Birth Cohort controls

  T1DGC genome-wide case-control association study for Type 1 Diabetes (T1D) using the 1958 British Birth Cohort as controls. The cases for this study are made available from the NCBI dbGAP.

  Study EGAS00000000038

• Lipid Research Clinics - Prevalence Study (LRC-PS-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: The LRC Program began in 1971 under the sponsorship of the National Heart, Lung, and Blood Institute, National Institutes of Health. Part of this program was the Lipid Research Clinics Prevalence Study, a standardized series of cross-sectional surveys of various North American populations designed to determine the prevalence of dyslipidemias and to describe the distributions of lipids and lipoproteins in major ethnic and social groups. In addition to contributing to the aggregate analysis, each independent population-based study was designed with capabilities for separate analyses of lipid and lipoprotein distributions. The participating populations were not selected to be a probability sample representative of the North American population per se, but by virtue of their size and economic and geographical diversity, they provide a useful cross-sectional group. The Family Study was the third phase of the Lipids Research Clinics North American Population Studies. The Family Study was designed to obtain knowledge of the distribution of lipids and lipoproteins among family members and of the association of familial and genetic attributes to dyslipoproteinemias. Background: An association between serum cholesterol and coronary heart disease is well established. A system was developed for classifying hyperlipoproteinemias into six types of patterns, as a basis for characterizing lipoprotein disorders. The Lipid Research Clinics was thus created to improve the detection of and clinical management of hyperlipoproteinemias. The three primary objectives were: 1) to acquire data on the prevalence of different types of hyperlipoproteinemia in various age and ethnic groups, with special emphasis on the nature and frequency of genetic forms; 2) to collect reliable data on the prevalence and incidence of atherosclerosis in different types of hyperlipoproteinemia; and 3) to conduct an intervention trial to determine if lowering plasma lipid levels would reduce the risk of CHD. Participants: There were 60,495 participants. Conclusions: Data from this study confirm findings from earlier studies in developed countries, showing age-related differences in plasma lipid levels. However, for overall distributions, the LRC data showed slightly lower cholesterol and markedly higher trigylceride values than those previously reported for North America. Some variation in plasma lipid values was evident among the clinic populations. The large number of participants within most subgroups permitted a variety of analytic and comparative studies. For example, data from the large pediatric population revealed a drop in plasma cholesterol levels in adolescent males and females. Males aged 20-50 years had higher cholesterol levels than females in the same age group, and higher trigylceride levels between ages 20-70 years. Numbers were also significient for meaningful comparisons between lipid distributions of females who were taking sex hormones and those who were not; in females taking sex hormones, cholesterol and triglyceride levels were higher for subjects younger than 45 years, but slightly lower after age 45, than lipid levels in females not taking hormones (Circulation 1979; 60(2):427-439).

  Study phs003995

• Type I Interferon and Cycling Lymphocytes in Macrophage Activation Syndrome

  We performed immune profiling of peripheral blood mononuclear cells from patients with Still's disease and macrophage activation syndrome (MAS) using bulk RNA sequencing and single-cell RNA sequencing. Three groups were included in the study: healthy controls, patients with Still's disease without macrophage activation syndrome, and patients with Still's disease and macrophage activation syndrome. We found that macrophage activation syndrome is associated with transcriptomic signatures of interferon upregulation and cell cycling. We identified cycling lymphocytes within T cell and NK cell populations that are correlated with MAS disease activity. All sequencing data are available through dbGaP.

  Study phs003310

• Professors Colin Palmer and Ewan Pearson, from University of Dundee, are both members of the Access Group panel for the GoDARTS bioresource, which provided the data for the current study. The current Study used genotypes (EGAD00010000282) generated by the WTCCC2 (EGAS00000000121), on which both Colin and Ewan are also DAC panel members.

  Dac EGAC00001000504

• Transposable Elements Shape Stemness in Normal and Leukemic Hematopoiesis

  Despite most acute myeloid leukemia (AML) patients achieving complete remission after induction chemotherapy, two-thirds will relapse with fatal disease within five years. AML is organized as a cellular hierarchy sustained by leukemia stem cells (LSC) at the apex, with LSC properties directly linked to tumor progression, therapy failure, and disease relapse 1–5. Despite the central role of LSC in poor patient outcomes, little is known about the genetic determinants driving their stemness properties. As LSCs share many functional and molecular properties with normal hematopoietic stem cells (HSC) 6, we investigated accessible chromatin unique across normal hematopoietic and cancer cell states and identified transposable elements (TEs) as genetic determinants of both primitive populations in comparison with their downstream mature progeny. A clinically-relevant TE chromatin accessibility-based LSCTE121 signature was developed that enabled patient classification based on survival outcomes. Through functional assays, primitive cell specific-TE subfamilies were found to serve as docking sites for stem cell-associated regulators of genome topology or lineage-specific transcription factors, including LYL1 in LSCs. Finally, using chromatin editing tools, we establish that chromatin accessibility at LTR12C elements in LSCs are necessary to maintain stemness properties. Our work identifies TEs as genetic drivers of primitive versus mature cell states, where distinct TE subfamilies account for stemness properties in normal versus leukemic hematopoietic stem cells.

  Study EGAS50000001141

• Transposable Elements Shape Stemness in Normal and Leukemic Hematopoiesis

  Despite most acute myeloid leukemia (AML) patients achieving complete remission after induction chemotherapy, two-thirds will relapse with fatal disease within five years. AML is organized as a cellular hierarchy sustained by leukemia stem cells (LSC) at the apex, with LSC properties directly linked to tumor progression, therapy failure, and disease relapse 1–5. Despite the central role of LSC in poor patient outcomes, little is known about the genetic determinants driving their stemness properties. As LSCs share many functional and molecular properties with normal hematopoietic stem cells (HSC) 6, we investigated accessible chromatin unique across normal hematopoietic and cancer cell states and identified transposable elements (TEs) as genetic determinants of both primitive populations in comparison with their downstream mature progeny. A clinically-relevant TE chromatin accessibility-based LSCTE121 signature was developed that enabled patient classification based on survival outcomes. Through functional assays, primitive cell specific-TE subfamilies were found to serve as docking sites for stem cell-associated regulators of genome topology or lineage-specific transcription factors, including LYL1 in LSCs. Finally, using chromatin editing tools, we establish that chromatin accessibility at LTR12C elements in LSCs are necessary to maintain stemness properties. Our work identifies TEs as genetic drivers of primitive versus mature cell states, where distinct TE subfamilies account for stemness properties in normal versus leukemic hematopoietic stem cells.

  Study EGAS50000001147

• Novel CNV contribution to schizophrenia from a genome wide study of 41,321 subjects

  Genomic copy number variants (CNVs) have been strongly implicated in the etiology schizophrenia (SCZ). However, apart from a small number of risk variants, elucidation of the CNV contribution to risk has been difficult due to the very low frequencies of risk alleles, all occurring in less than 1% of patients. We sought to address this obstacle through a collaborative effort unprecedented in psychiatry in which we applied a centralized analysis pipeline to a large SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden is observed in SCZ patients (OR=1.11, P=5.7e-15), and persists after excluding loci implicated in previous studies (OR=1.07, P=1.7e-6). CNV Burden is also enriched for genes associated with synaptic function (OR = 1.68, P = 2.8e-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3e-05). While only previously implicated loci surpass strict genome-wide testing correction, we identify “novel” CNVs (BH-FDR < 0.05) that confer both protective and risk effects on SCZ and are predominantly mediated by non-allelic homologous recombination (NAHR). Our combined data find genome-wide significant support for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2.

  Study EGAS00001001960

• Genetic Risk for Subsequent Neoplasms among Long-term Survivors of Childhood Cancer in the St. Jude Lifetime Cohort

  While childhood cancer survivors are known to be at increased risk of subsequent neoplasms (SNs), the contribution of germline mutations in cancer predisposition genes to the risk of SN is largely unknown. Whole-genome sequencing (30X) was performed on 3,006 5+ year survivors of childhood cancer (median age, 35.8 [range: 7.1-69.8] years) from the St. Jude Lifetime Cohort. Survivors underwent a comprehensive clinical assessment. Germline mutations in 156 cancer predisposition genes (SJCPG156), including a subset of 60 (SJCPG60) autosomal dominant genes with moderate to high penetrance, were classified for their pathogenicity. Piecewise exponential regression, stratified by radiation exposure, was used to evaluate the relative rate (RR) and 95% confidence interval (95% CI) of SN occurrence by mutation status. Pathogenic or likely pathogenic mutations in SJCPG156 and SJCPG60 were identified in 11.7% and 5.8% of survivors, respectively. The most frequently mutated SJCPG60 genes included RB1 (n=43), NF1 (n=22), BRCA2 (n=14), BRCA1 (n=12) and TP53 (n=10). Mutations in SJCPG60 were associated with the rate of subsequent sarcoma (RR, 10.3; 95% CI, 4.2 to 25.6) and breast cancer (RR, 13.3; 95% CI, 5.8 to 30.5) among irradiated survivors, and the rate of developing any SN (RR, 4.8; 95% CI, 2.4 to 9.4) and breast cancer (RR, 7.8; 95% CI, 2.5 to 24.0) among non-irradiated survivors. The rate of developing ≥2 histologically distinct SNs was increased 17.8-fold (95% CI, 3.5 to 89.8) among SJCPG60 mutation carriers treated without radiotherapy. Similar but attenuated associations were observed for mutations in SJCPG156. Survivors who develop a SN without prior radiotherapy or who are diagnosed with a subsequent sarcoma or breast cancer within a site of prior radiotherapy should be referred to genetic counseling.

  Study EGAS00001002499

• Add Health: Longitudinal Study of a Nationally Representative Sample of Adolescents in Grades 7-12 in the United States during the 1994-95 School Year, Followed into Adulthood with Five Interviews/Surveys in 1995, 1996, 2001-02, 2008, and 2016-18

  The National Longitudinal Study of Adolescent to Adult Health [Add Health] is an ongoing longitudinal study of a nationally representative U.S. cohort of more than 20,000 adolescents in grades 7-12 (aged 12-19 years) in 1994 followed into adulthood with five interviews/surveys in 1995, 1996, 2001-02, 2008, and 2016-18. Add Health was designed to understand how social environments and behaviors in adolescence are linked to health and achievement outcomes in young adulthood. Add Health contains unprecedented environmental, behavioral, psychosocial, biological, and genetic data from early adolescence and into adulthood on a large, nationally representative cohort with unprecedented racial, ethnic, socioeconomic, and geographic diversity. Add Health has a large, multidisciplinary user base of over 50,000 researchers around the world who have published over 3,400 research articles. Add Health is housed at the Carolina Population Center of the University of North Carolina at Chapel Hill. Add Health datasets are distributed according to a tiered data disclosure plan designed to protect the data from the risk of direct and indirect disclosure of respondent identity. Add Health's large sample size, population diversity and rich longitudinal database of psychosocial, physical, and contextual data will permit investigation of an exceptionally broad range of phenotypes with known genetic variation. Prospective longitudinal measures are available to document change over time in each of these phenotypes, as well as change in the social environment and life experiences, making the Add Health sample ideal for understanding genetic linkages with health and behavior across the life course. The original design of Add Health included important features for understanding biological processes in health and developmental trajectories across the life course of young people, including an embedded genetic sample with more than 3,000 pairs of adolescents with varying biological resemblance (e.g., twins, full sibs, half sibs, and adolescents who grew up in the same household but have no biological relationship), testing of saliva and urine for sexually transmitted infections and HIV, and biomarkers of cardiovascular health, metabolic processes, immune function, renal function, and inflammation. Add Health therefore has critical objective indicators of health status and disease markers in young adulthood, well before chronic illness or its complications emerge in later adulthood. Because DNA has been collected on the full sample at Wave IV, it is possible to link genetic profiles with social, behavioral, and biological measures over time from adolescence into adulthood. Add Health sampled the multiple environments in which young people live their lives, including the family, peers, school, neighborhood, community, and relationship dyads, and provides independent and direct measurement of these environments over time. Add Health contains extensive longitudinal information on health-related behavior, including life histories of physical activity, involvement in risk behavior, substance use, sexual behavior, civic engagement, education, and multiple indicators of health status based on self-report (e.g., general health, chronic illness), direct measurement (e.g., overweight status and obesity), and biomarkers. No other data resource with this expanse of genotype and phenotype data on a large nationally representative longitudinal sample with race, ethnic, socioeconomic, and geographic diversity exists. A complete reference guide on study design and accomplishments can be found on the Add Health website: https://cdr.lib.unc.edu/concern/articles/6t053j27s.

  Study phs001367

• H3Africa - Kidney Disease Research Network

  Chronic kidney disease (CKD) affects an estimated 14% of adults in sub-Saharan Africa but very little research has been done on the etiology, progression and prevention of CKD on the continent. As part of the Human Heredity and Health in Africa (H3A) Consortium, the H3Africa Kidney Disease Research Network was established to study prevalent forms of kidney disease in sub-Saharan Africa and increase the capacity for genetics and genomics research. The study is performing comprehensive phenotypic characterization with analysis of environmental and genetic factors from seven clinical centers in two African countries (Ghana and Nigeria) over a five-year period. Approximately 4,000 participants with specified kidney disease diagnoses and 4000 control participants will be enrolled in the four African countries. In addition, approximately 50 families with hereditary glomerular disease will be enrolled. The study includes both pediatric and adult participants ages <1 to 74yrs across a broad spectrum of kidney diseases secondary to hypertension, diabetes, human immunodeficiency virus, sickle cell disease, biopsy-proven glomerular disease and CKD of unknown origin. Clinical and demographic data with biospecimens are collected for assessment of clinical, biochemical and genetic markers of kidney disease.

  Study EGAS00001006558

• Asian Immune Diversity Atlas (AIDA) sQTL

  Current efforts within the Human Cell Atlas (HCA) are largely focused on defining reference human cell types using a relatively small number of samples of predominantly European origin. However, the next phase of the HCA is likely to address the topic of human diversity by comprehensively characterizing variation in cell states across age, sex, population groups, diseases and environments. To spur this next phase, and also expand the geographical scope of the HCA, we propose an HCA-Asia seed network to generate an Asian Immune Diversity Atlas (AIDA). AIDA will generate transcriptome variation datasets from 5 major Asian population groups (Chinese, Japanese, Korean, Indian, Malay), define an atlas of Asian cell types and states, and characterize their variation associated with ethnicity, age and sex. We will also formalize a study design based on common controls that can in principle reduce technical artifacts in a broad range of comparative single cell studies. This study design will be complemented with novel algorithms designed to normalize datasets of interest against the common controls, to increase the robustness of biological inferences. In addition to providing new tools and resources to the HCA, this seed network will serve as a template for future comparative studies in the single cell field.The AIDA dataset consists of scRNA-seq (10x 5′ v2 scRNA-seq) and genotype (Illumina Infinium Global Screening Array v.3) data. In the AIDA splicing quantitative trait loci (sQTL) project, we identified 11,577 independent cis-sQTLs, 607 trans-sQTLs, and 107 dynamic sQTLs. The post-imputation genotype for the Japanese and Korean cohort will be available through dbGaP. The Singaporean (ethnically Chinese, Indian and Malay) genotypes require a data access application to the HELIOS Data Access Committee (helios_science@ntu.edu.sg). European samples are used as control.

  Study phs003848

• WGS of Biobank iPSC lines

  WGS data from healthy reference iPSC lines. The median coverage is 41-50x. >85% have a coverage of >30x. 97% of the variants are known.

  Dataset EGAD00001008769

• Scalable whole-genome single-cell library preparation without pre-amplification

  Single-cell genomics is critical for understanding cellular heterogeneity in cancer, but existing library preparation methods are expensive, require sample preamplification and introduce coverage bias. Here we describe direct library preparation (DLP), a robust, scalable, and high-fidelity method that uses nanoliter-volume transposition reactions for single-cell whole-genome library preparation without preamplification. We examined 782 cells from cell lines and triple-negative breast xenograft tumors. Low-depth sequencing, compared with existing methods, revealed greater coverage uniformity and more reliable detection of copy-number alterations. Using phylogenetic analysis, we found minor xenograft subpopulations that were undetectable by bulk sequencing, as well as dynamic clonal expansion and diversification between passages. Merging single-cell genomes in silico, we generated "bulk-equivalent" genomes with high depth and uniform coverage. Thus, low-depth sequencing of DLP libraries may provide an attractive replacement for conventional bulk sequencing methods, permitting analysis of copy number at the cell level and of other genomic variants at the population level.

  Study EGAS00001002170

• Efficacy of two different FGFR-inhibitors in a patient with extrahepatic cholangiocarcinoma harboring an FGFR2 mutation

  Cholangiocarcinomas (CCAs) is a type of cancer with few effective systemic therapies. Elucidation of the molecular landscape of the disease from genomic studies based on next generation sequencing (NGS) has contributed to the introduction of new targeted therapies. One of these treatments consists of a class of small molecules that target members of the FGFR family of receptor tyrosine kinases. These drugs are effective and have been approved for cholangiocarcinomas with fusions or rearrangements of FGFR genes. In contrast, the role of these inhibitors in cholangiocarcinomas with mutations in FGFR genes is less well defined. We report here a patient with a cholangiocarcinoma bearing a FGFR2 p.Ser252Trp mutation. The patient was treated with two different FGFR inhibitors, as the first caused ocular toxicity. She obtained clinical benefit from both. This case illustrates the efficacy of FGFR inhibitors on cholangiocarcinoma with specific point mutations. This is the first case to report the clinical benefit of these drugs in FGFR2 p.Ser252Trp mutation. Clinical benefit can be sustained, as seen in our patient. Our case also shows that FGFR inhibitors-induced adverse effects, such as ocular toxicities, may not recur after re-challenge with an alternative drug of the same class.

  Dataset EGAD50000000021

• Memory-like HCV-specific CD8+ T cells retain a chronic scar after cure of chronic HCV infection

  Chronic hepatitis C virus (HCV) infection is associated with CD8+ T-cell exhaustion characterized by limited effector functions and thus compromised anti-viral activity. Exhausted HCV-specific CD8+ T cells are comprised of memory-like and terminally exhausted CD8+ T-cell subsets. So far, little is not known about the molecular profile and fate of these cells after elimination of chronic antigen stimulation by direct acting antiviral therapy (DAA). Here, we report an antigen-driven molecular core signature underlying exhausted CD8+ T-cell subset heterogeneity in chronic viral infection with a progenitor/progeny relationship of memory-like and terminally exhausted HCV-specific CD8+ T cells via an intermediate stage. Furthermore, transcriptional profiling reveals that the memory-like cells remain after DAA-mediated cure while terminally exhausted HCV-specific CD8+ T-cell subsets are lost. Thus, the memory polarization of the overall HCV-specific CD8+ T-cell response after cure does not result from re-differentiation of exhausted T cells. Consequently, antigen elimination has little impact on the exhausted core signature of memory-like CD8+ T cells that remains clearly different from bona fide T-cell memory. These results identify a molecular signature of T-cell exhaustion that is imprinted like a chronic scar in HCV-specific CD8+ T cells even after HCV cure, highlighting the requirement of re-programming to elicit full effector potential of exhausted T cells.

  Study EGAS00001004538

• Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications Study (EDIC)

  The Diabetes Control and Complications Trial (DCCT, 1982-93) and the Epidemiology of Diabetes Interventions and Complications follow-up study (EDIC, 1994-2016) have been ongoing for more than twenty years. After a mean follow-up of approximately 16 years, the DCCT-EDIC cohort of 1,441 Type 1 diabetics had remained remarkably complete with more than 90% of the original cohort being actively followed. Taken together, the DCCT clinical trial and subsequent EDIC longitudinal follow-up provide a uniquely rich source of information on the impact of intensive therapy on glycemia and the its long-term complications for persons with Type 1 diabetes. The DCCT was a multicenter, randomized clinical trial (1, 2) designed to compare intensive with conventional diabetes therapy with regard to their effects on the development and progression of the early complications of Type 1 diabetes. The DCCT trial found that "intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy" in patients with Type 1 diabetes (1). The goal of the EDIC follow-up was to examine the longer term effects of the original DCCT interventions, especially as they apply to late-occurring complications, such as cardiovascular disease and more advanced stages of retinal and renal disease (3). The EDIC study has been remarkably fruitful in discovering the long term "imprinting" effects (metabolic memory) of the previous intensive therapy, and in delineating the interactions among risk factors with regard to microvascular complications (4-6). In addition, EDIC established, for the first time, the role of intensive therapy and chronic glycemia on atherosclerosis (7-9). Note: This study description has been prepared using materials authored by the DCCT-EDIC Data Coordinating Center. DETAILED DESCRIPTION OF STUDY

  Study phs000086

• Genome-Wide Association Study of HCC in Non-Asian USA Population

  This GWAS of HCC relied on existing biological and data resources from 7 USA sites and one Canadian site which allows for the integration of genetic and environmental data. Total of 2199 case patients and 1103 non cancer controls were genotyped. Case patients are defined as patients with pathological or radiological diagnosis of HCC with and without chronic hepatitis C virus infection. Study was restricted to Caucasian population without prior infection with chronic HBV infection. All DNA samples were extracted from peripheral blood. Study population of the participated sites are: Site-1: University of Texas MD Anderson Cancer Center A hospital based-case-control study was initiated at UT MD Anderson Cancer Center in 2000 and approved by the Institutional Review Board of The University of Texas M. D. Anderson Cancer Center. Study design was previously described in detailed (1-3). Written informed consent for an interview and for a biological sample was obtained from each participant. At time of diagnosis prior to treatment exposure. Case patients were recruited from the population of patients with newly diagnosed HCC who were evaluated and treated at the institution's gastrointestinal medical and surgical oncology outpatient clinics. Inclusion criteria were as follows: a pathologically confirmed diagnosis of HCC, U.S. residency, and the ability to communicate in English. Patients with concurrent or past history of other types of cancers were excluded. Control subjects were healthy spouses of patients with cancers other than liver, gastrointestinal, lung, or head and neck (smoking-related cancers) undergoing treatment at our institution. Eligibility criteria for control subjects were the same as those for patients, except that control subjects could not have ever had cancer. A short, structured questionnaire was used to screen potential control subjects on the basis of eligibility criteria. Control subjects and patients were recruited simultaneously. Case patients and control subjects were interviewed by well-trained interviewers who followed a written protocol to guide ascertainment and reduce surveillance, interviewer, and recall bias. No proxy interviews were conducted. The interviewers used a structured and validated questionnaire to collect information about demographic characteristics and potential risk factors for HCC such as personal smoking history, alcohol use, medical history, occupational history, and family history of cancer. Blood samples from cases and controls were tested for HBV and HCV. HCV antibodies, hepatitis B surface antigen, and antibodies to hepatitis B core antigen were detected by use of a third-generation enzyme-linked immunosorbent assay (ELISA) (Abbott Laboratories, North Chicago, IL). Important clinical information were retrieved from patients' medical records. Total of 1188 case patients and 278 controls from MD Anderson study were genotyped. Site-2: Mayo Clinic Case patients and controls included in the study from Mayo clinic were recruited as part of Mayo International Hepatobiliary Neoplasia Register and Biorepository. Only USA patients and controls were participated. All cases and controls signed informed consent indicating their willingness to participate in genetic studies. Epidemiological and clinical data were collected from participants and retrieved from medical records. Total of 522 HCC case patients and 182 controls were genotyped in this study. Site-3: Toronto University Molecular Epidemiology of Hepatobiliary Tumors (HBT study, CAPCR 09-0289) is a hospital-based study that includes 1710 patients diagnosed with liver, bile duct or gallbladder adenocarcinoma (Hepatocellular carcinoma - HCC; cholangiocarcinoma - CCA; and gall bladder adenocarcinoma -GBCa) recruited at University Health Network (UHN) between 2009 and 2018. HBT study is a prospective study of cancer patients that collects self-reported demographic and epidemiological data, medical records/clinical information and blood samples for research purposes. Eligible patients recruited between 2009 and March 15 2016 were selected to participate in the Genome-Wide Association Study in Patients with Hepatocellular Carcinoma (GWAS in HCC, CAPCR 15-9943-CE), a sub-study of the HBT study. Eligible prospective patients recruited after March 15 2016 signed the Addendum to the HBT consent form and became eligible to participate in the GWAS in HCC study. Total of 271 cases and 21 controls were genotyped from Toronto University Site-4: University of Pittsburgh The design of the study has been described previously (4-6). Briefly, this population-based study enrolled 120 HCC patients and 230 matched controls from black, Hispanic, and non-Hispanic white residents of Los Angeles County who were between 18 and 74 years of age at diagnosis from January 1995 through December 2001. HCC Cases were identified through the Los Angeles County Cancer Surveillance Program. We sought to recruit up to two control subjects per case from the neighborhoods where HCC patients resided at the time of diagnosis, who were matched to the index case by sex, age (within 5 years), and race (Hispanic white, non-Hispanic white, black). Blood samples (plasma and buffy coat), medical and lifestyle factors were collected from all consenting participants. Total of 65 cases and 60 controls were genotyped in this study Site-5: South Western Dallas Under IRB approval, HCC Cases and controls were prospectively collected since 2015 from the outpatient Liver clinics from Parkland Health and Hospital System and UT Southwestern Medical Center, two large health systems in Dallas TX. A Total of 31 cases and 29 controls were genotyped from site 5. Site-6: Columbia University HCC patients from Columbia are those recruited as part of the Herbert Irving Comprehensive Cancer Center Database Shared Resource which seeks to recruit all cancer patients for potential future studies. The PI is Dr. Katherine Crew AAAL5871. This resource collects sociodemographic, lifestyle and clinical data on patients as well as a blood sample. Those who indicated on their consent form that they would participate in genetic studies were included. Total of 79 case patients with HCC were genotyped from Columbia University. Site-7: University of Michigan The study population included from University of Michigan were included from a prospective study of with chronic HCV infection recruited in Ann Arbor Patients who had under- gone liver transplantation, known coinfection with HIV, life expectancy <12 months due to extra-hepatic illnesses, or were receiving HCV treatment at enrolment, were excluded. Protocol, surveys, and data forms were developed where each enrolled patient completed the same questionnaire All patients provided written informed consent before enrolment in the study. The study was approved by the institutional review board or ethics committee at the University of Michigan. Detailed study description was previously published (7). Total of 44 cases and 347 controls were genotyped Site-8: Veteran Administration Medical Center in Houston This research including written informed consent form was jointly approved by Institutional Review Boards for the Baylor College of Medicine and the Michael E. DeBakey VA Medical Center in Houston, Texas. Study details have been previously published (8). Briefly, we prospectively recruited consecutive HCV-infected veterans prior to their previously scheduled HCV clinic visit at a large tertiary care VA medical center between May 1, 2009 and December 31, 2012. Patients completed a research assistant (RA) administered survey interrogating medical and risk factor history including lifetime alcohol use, had anthropometric measurements taken, and completed a fasting venipuncture for performance of the FibroSure-ActiTest as a measure of hepatic pathology. We restricted our current analysis to individuals who were: (1) White male veterans between 18 and 70 years; (2) had no history of HCC, liver transplant, decompensated liver disease including ascites, dementia, or psychosis; (3) were serologically-confirmed to have chronic HCV and to be negative for both HIV and active HBV infection; (4) were not currently receiving anti-HCV pharmacotherapy; and (5) had FibroSURE testing shown F3/F4 fibrosis consistent with cirrhosis.

  Study phs001744

• METABRIC

  Solid tumors are complex tissues composed of a mixture of cancer and normal cells, which complicates the interpretation of their molecular profiles. Normal cell contamination can dilute cancer cell information and tissue architecture is generally not reflected in molecular assays. To address these challenges, we developed a computational approach based on standard Haematoxylin and Eosin-stained sections and demonstrated its power in a discovery cohort of 323 breast tumors and an independent validation cohort of 241 tumors. First, to deconvolute cellular heterogeneity and detect subtle genomic aberrations, we introduced an algorithm based on tumor cellularity to increase the comparability of copy-number profiles between samples. Second, we demonstrated that a predictor for survival integrating image-based and molecular features significantly outperforms classifiers based on single data types. Third, we described and validated a novel, independent prognostic factor based on quantitative analysis of spatial patterns between stromal cells, which are not detectable by molecular assays. Our quantitative methods refine and complement molecular assays of tumor samples and could benefit all large-scale cancer studies.First, to deconvolute cellular heterogeneity and detect subtle genomic aberrations, we introduced an algorithm based on tumor cellularity to increase the comparability of copy-number profiles between samples. Second, we demonstrated that a predictor for survival integrating image-based and molecular features significantly outperforms classifiers based on single data types. Third, we described and validated a novel, independent prognostic factor based on quantitative analysis of spatial patterns between stromal cells, which are not detectable by molecular assays. Our quantitative methods refine and complement molecular assays of tumor samples and could benefit all large-scale cancer studies.

  Study EGAS00000000098

• High Altitude Pulmonary Hypertension

  The Central Asian Kyrgyz highland population provides a unique opportunity to address genetic diversity and understand the genetic mechanisms underlying hypoxia-induced high altitude pulmonary hypertension (HAPH). While a significant fraction of the population is unaffected, there are susceptible individuals who display HAPH in the absence of any lung, cardiac or hematologic disease. We report herein the analysis of the whole genome sequencing of healthy individuals compared with HAPH patients and other controls. In this study, 34 male individuals from Central Asian Kyrgyz highland are sequenced with Illumina HiSeq 2000 with mean-coverage of 30X.

  Dataset EGAD00001004308