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• 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

• Smart-seq 2 single cell sequencing of CD4 and CD8 T cells from the blood and synovial fluid of 4 psoriatic arthritis patients.

  This dataset was used to characterise T cell gene expression and clonality at sites of active inflammation within the joints of psoriatic arthritis (PsA) patients, and to compare these results with T cells from the peripheral blood of those same patients. Freshly sorted CD45RA negative CD3+CD4+ and CD3+CD8+ single cells from four patients were individually flow sorted into 96-well full-skirted plates (Eppendorf) containing 10µL of a 2% Dithiothreitol (DTT, 2M Sigma-Aldrich), RTL lysis buffer (Qiagen) solution. Cell lysates were sealed, mixed and spun down before storing at -80 ºC. Paired-end multiplexed sequencing libraries were prepared following the Smart-seq 2 protocol using the Nextera XT DNA library prep kit (Illumina). A pool of barcoded libraries from four different plates were sequenced across two lanes on the Illumina HiSeq 2500.

  Dataset EGAD00001006342

• Whole-genome sequences of single-cell derived clonal samples and bulk blood samples from human

  Human single cells were clonally expanded by culture and whole-genome sequenced. This dataset includes 334 clonal samples and 7 blood bulks from seven individuals (DB2, DB3, DB5, DB6, DB8, DB9, DB10). We extracted genomic DNA materials from clonally expanded cells and matched peripheral blood using DNeasy Blood and Tissue kits (Qiagen) according to the protocol. DNA libraries for WGS were generated by an Accel-NGS 2S Plus DNA Library Kit (Swift Biosciences) from 1 µg of genomic DNA materials. WGS was performed on either the Illumina HiSeq X platform or the NovaSeq 6000 platform to generate mean coverage of 25.2X for 374 clonally expanded cells and 94.8X for 7 matched blood tissues.

  Dataset EGAD00001007032

• Guardians of the genome: protecting DNA from endogenous sources of damage

  Mutational signatures are imprints of cell-intrinsic and extrinsic pathophysiological processes that have occurred through tumorigenesis. Experimental efforts to explore signature etiologies have produced a compendium of signatures of exogenous mutagens previously. Here, we unearth major sources of endogenous DNA damage and the genes that are critical to mitigating this innate stream of DNA damage under normal, physiological circumstances. We performed whole genome sequencing of 173 subclones of CRISPR-Cas9 knockouts of 43 genes in a human induced pluripotent stem cell system, in the absence of any added DNA damage. We reveal substitution and indel signatures that arise from those genes which are essential guardians of the genome. By detailed dissection and comparisons to cancer-derived signatures, we demonstrate interminable sources of constitutive DNA damage, and some mechanistic knowledge into how guardian genes preserve the genome. Based on these experimental insights, we develop and benchmark a tool for clinical classification of tumor samples.

  Dataset EGAD00001006055

• Atypical teratoid/rhabdoid tumors (ATRT) are comprised of three epigenetic subgroups with distinct enhancer landscapes

  Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants and young children. Although the prognosis of ATRT patients is poor, some patients respond very well to current treatments, suggesting inter-tumor molecular heterogeneity. To investigate this further, we genetically and epigenetically analyzed a large cohort of ATRTs (n = 170). Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location and type of SMARCB1 alterations, were identified using DNA-methylation or gene expression analyses. Whole genome DNA- and RNA-sequencing found no other recurrent mutations explaining the differences between subgroups. However, whole genome bisulfite-sequencing and H3K27Ac ChIP-sequencing of primary tumors revealed clear differences in methylation patterns and enhancer landscapes, leading to the identification of subgroup-specific regulatory networks.

  Dataset EGAD00001001444

• Reconstruction of human phylogenetic trees using single-cell genome sequencing

  The trillions of cells that constitute the human body are developed from a fertilized egg through embryogenesis. However, cellular dynamics and developmental outcomes of embryonic cells remain to be largely unknown due to the technical and ethical challenges. Here we sequenced whole-genomes single-cell-derived clones and various bulk tissues dissected from entire human bodies. Using the discovered somatic mutations as an intrinsic barcode, we reconstructed cellular phylogenetic trees that provide novel insights into early human embryogenesis.

  Study EGAS00001004824

• RNA sequencing of CD8 T cells from melanoma patients prior to and during checkpoint immunotherapy and untreated healthy controls

  We are interested in inter-individual variation in transcriptional response to immune checkpoint blockade. We have analysed poly A purified RNA expression from CD8 T cells (297 transcriptomes in total) isolated from metastatic melanoma patients (n=106) prior to and during treatment with either single agent (Pembrolizumab) or combination (Ipilimumab/ Nivolumab) immune checkpoint blockade. We compare expression at different stages of treatment and additionally contrast this with that from healthy controls (n=68).

  Study EGAS00001004081

• PEACE melanoma 14

  Understanding the evolutionary pathways to metastasis and resistance to immune checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here we present the most comprehensive intra-patient metastatic melanoma dataset assembled to date as part of the PEACE research autopsy programme, including exome, panel-sequenced, RNA-seq, and single-cell whole-genome sequencing samples from 14 ICI-treated patients. The main goals of the project are to decipher the evolutionary dynamics of melanoma metastases and to elucidate mechnisms of resistance to therapies.

  Study EGAS00001007081

• Aneurysmal Subarachnoid Hemorrhage patients with or without vasospasm

  Cerebellar vasospasm is a severe complication of aneurysmal subarachnoid hemorrhage (aSAH) occurring for 30% of aSAH patients. To date, no biomarker of vasospasm occurrence exists and thus all aSAH patients undergo a preventive and dangerous treatment. In this study, we explored the miRNome of aSAH patients to detect potential expression differences between the patients developing a vasospasm (VSP+) or not (VSP-). The shared data include raw and normalized count miRNA data in aneurysmal subarachnoid hemorrhage patients with or without vasospasm.

  Study EGAS00001003092

• MutWP5__CRUK_Mutographs_of_Cancer__Breast__Cancer_Mastectomy__Exome_

  Sequencing of LCM-derived microbiopsies from 30 women who underwent mastectomies due to a breast cancer diagnosis. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue. Exome data will be used as a driver and clonality screen, highly clonal or driver-containing samples will subsequently be sent for whole-genome sequencing. Results from this portion of the study will be compared to women who had cosmetic breast reduction surgeries and those with germline BRCA 1/2 mutations.

  Study EGAS00001003319

• Transcriptomic analysis of human hematopoietic populations sorted from umbilical cord blood.

  We isolated by fluorescence-activated cell sorting highly purified populations (long term hematopoietic stem cells (LT-HSCs), short term hematopoietic stem cells (ST-HSCs), multipotent progenitors (MPPs), common myeloid progenitor (CMPs), granulocyte and monocyte progenitors (GMPs), multilymphoid progenitors (MLPs), Myeloid-erythorid Progenitor (MEP), Granulocytes, Monocytes, B cells, T cells, Dendritic cells, Natural Killer cells and Erythrocyte Progenitors from 3 to 4 cord blood pools. We extracted RNA from 5K cells of each population and performed RNA-sequencing.

  Study EGAS00001004968

• 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

• Comprehensive molecular profiling of high-grade serous ovarian cancer

  The diversity and heterogeneity within high-grade serous ovarian cancer (HGSC) is not well understood. Here, we performed comprehensive molecular analysis, including high-pass whole genome sequencing, targeted deep sequencing, RNA sequencing, reverse phase protein arrays and immune assessment, on primary and metastatic sites from highly clinically annotated HGSC samples. Samples were obtained pre-treatment based on a laparoscopic triage algorithm from patients who underwent R0 tumor debulking, or received neoadjuvant chemotherapy (NACT) with excellent or poor response.

  Study EGAS00001003804

• USARC 10X Genomics Single Cell DNA Sequencing Data

  We investigated the impact of ploidy heterogeneity on copy number inference at a single cell level using fluorescence-activated cell sorted (FACS) nuclei from an undifferentiated soft tissue sarcoma. FACS revealed the presence of three aberrant subpopulations, including a haploid, a near diploid and a whole genome doubled population. Once sorted, single cell nuclei underwent whole genome sequencing using the chromium CNV single cell DNA library kit (10X Genomics). We sequenced single normal nuclei (2n) and single aberrant / tumour nuclei (1n, 2n and 2n+).

  Study EGAS00001006144

• Single cell multi-omic data of glioblastoma evolution under therapy

  We report a single-cell multi-omics atlas of GBM longitudinal specimens that represents decades of biobanking. We identify novel cell-intrinsic and cell-extrinsic targets for therapy development which we validate in situ and in low-passage patient-derived cell lines. We identify novel genetic correlates of the mesenchymal cellular phenotype. These studies integrate disparate findings in the literature around hypermutation status and immunogenicity as well as the source of the mesenchymal shift at recurrence.

  Study EGAS00001004909

• Single cell RNAseq of lung adenocarcinoma

  Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing as well as single-cell BCR sequencing of cells from 16 LUADs and 47 multi-region normal lung tissues of defined spatial proximities from the tumors. Our multi-region single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecological evolution LUAD from the lung that comprise high-potential targets for early interception.

  Study EGAS00001005021

• Identification of genomic aberrations in low-grade serous ovarian cancer

  Low-grade serous ovarian cancer (LGSOC) is a rare disease that occurs more frequently in younger women compared with high-grade disease. The current treatment is suboptimal, and better understanding of molecular pathogenesis of this disease is needed. In this study, we compared the whole genome sequences of LGSOCs from short-term and long-term survivors (defined as <40 and >60 months, respectively). Our goal was to identify novel genomic aberrations in LGSOC, especially in short-term survivors.

  Study EGAS00001006679

• Comprehensive single-cell genome analysis at nucleotide resolution using the PTA Analysis Toolbox

  We developed a comprehensive bioinformatic workflow, called the PTA Analysis Toolbox (PTATO), to accurately detect single base substitutions, insertions-deletions (indels) and structural variants in PTA-based WGS data. PTATO includes a machine learning approach and filtering based on recurrency to distinguish PTA-artefacts from true mutations with high sensitivity (up to 90%), outperforming existing bioinformatic approaches. Our results show that PTATO enables studying somatic mutagenesis in the genomes of single cells with unprecedented sensitivity and accuracy.

  Study EGAS00001007288

• Investigation of different library preparation and tissue of origin deconvolution methods for urine and plasma cfDNA methylome analysis

  In this study, a single- and a double-stranded library preparation approach was evaluated with respect to their technical biases when applied on cfDNA from plasma and urine. This study thus outlines potential limitations of double-stranded library preparation for methylation analysis of cfDNA especially for urinary cfDNA. While the double-stranded method allows jagged end analysis in addition to TOO analysis, it leads to significant methylation bias in urinary cfDNA, which single-stranded methods can overcome.

  Study EGAS00001007314

• H3K27ac ChIP-seq in primary inflammatory (TPP) macrophages

  We investigated an intergenic haplotype on chr21q22, linked to five different inflammatory diseases, and identified the molecular mechanism by which the risk haplotype increases expression of the causal gene, ETS2. This mechanism was predicted to alter enhancer activity at the disease-associated locus. We therefore performed H3K27ac ChIP-seq in inflammatory macrophages from minor and major allele homozygotes at the causal allele and investigated the effect on enhancer activity. In doing so, we mechanistically delineated how the risk haplotype increases expression of ETS2.

  Study EGAS00001007562

• Targeted DNA panel sequencing analysis of PanNEN tumors of varying grades using custom and commercial panels

  Targeted panel sequencing data from PanNEN samples. Sample ID is annotated in the following manner: each patient is given a number and "P" is appended to the patient number if it is a primary tumor, "M” if it is metastasis and "N" if it is normal (healthy tissue) sample. All NETG1 and NETG2 samples underwent panel sequencing using a custom panel (in-house PanNEN panel). All NEC and NETG3 samples (except PNET2, PNET77P and PNET77M) underwent panel sequencing using a commercial CCP panel.

  Dataset EGAD00001008432

• CcRCC_metabolic_heterogeneity

  Heterogeneity is a hallmark of clear cell renal cell carcinoma (ccRCC). In this study, hyperpolarized [1-13C]pyruvate MRI (HP-13C-MRI) was used to probe metabolic heterogeneity non-invasively in 6 ccRCC patients from which 58 tumor and healthy tissues biopsies were acquired postoperatively. MRI parameters were correlated with 146 metabolite concentrations and the expression of 2523 metabolic genes across 34 metabolic pathways. Using metabologram projections and pathway consensus scoring, several metabolic pathways were correlated with the metabolic MRI, including glycolysis, pentose phosphate pathway, and the TCA cycle. A simple thresholding approach applied to the imaging metrics was sufficient to provide meaningful metabolic pathway information. We also show that tissue metabolic heterogeneity increases in regions with higher pyruvate-to-lactate conversion on imaging. These results provide validation of the biological relevance of HP-13C-MRI and support the possibility of its clinical use to improve disease characterization, stratification, targeting of biopsies, and providing novel methods to monitor treatment response.

  Dataset EGAD00001015780

• Nasal epithelial cells of PCD and non-PCD patients grown at air-liquid interface for RNAseq analysis

  Nasal epithelial cells of PCD and non-PCD patients grown at air-liquid interface for RNAseq analysis. A total of 10 non-PCD patients (ALI day 14), 9 non-PCD patients (ALI day 21), 8 non-PCD patients (ALI day 28), 4 PCD patients (ALI day 14, day 21 and day 28), and 23 PCD patients (ALI day 21). Non-PCD patients and the 4 PCD patients on the three ALI days were sequenced at a depth of 100M reads, the remaining 23 PCD patients were sequenced at a depth of 70M. Overall sequencing design was rRNA depletion and 150bp paired-end.

  Dataset EGAD00001009498

• Platelets contain a repertoire of DNA fragments that map over the human nuclear genome, including tumour-derived DNA in patients with active malignancy.

  This dataset consists of WGS from six patients with a recent diagnosis of gastrointestinal adenocarcinoma. DNA-Seq libraries were prepared from platelet DNA (pDNA) and plasma cfDNA obtained from the same peripheral blood sample. pDNA was size selected into 2 groups (small, s-pDNA: less than 600 bp and long, b-pDNA: greater than 600 bp). The short fragments were further cleaned to remove <100 bp fragments and large platelet fragments were fragmented via sonication. Libraries were then prepared using the NEBNext Ultra II DNA Sample Preparation Kit for Illumina according to the manufacturer’s protocol and sequenced on an Illumina NextSeq 500 (300 cycle PE) at low-pass (0.1X) for all samples, and 10X for the cfDNA and s-pDNA, using four lanes in each sample.

  Dataset EGAD00001009856

• H3Africa - Consortium WGS

  To address gaps in sequence data for some of the African populations being studied in H3Africa projects, additional sequencing has been carried out through various projects and the data are being made available. The first dataset includes a high coverage whole genome sequence dataset generated at the Baylor College of Medicine with samples provided by H3Africa PIs and collaborators, funded by the National Institutes of Health. The sequence data files are accompanied by minimal metadata, including country, ethnic group (where available) and sex.

  Study EGAS00001005972

• Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples (T2D-GENES) Follow-Up Study: Research Studies in Hong Kong

  The ~52,000 sample Type 2 Diabetes Exome Sequencing project is a collaboration of six consortia with various funding mechanisms that have joined together to investigate genetic variants for type 2 diabetes (T2D) using the largest T2D case/control sample set compiled to date. This includes samples from: Type 2 Diabetes Genetic Exploration by Next-generation sequencing in Multi-Ethnic Samples (T2D-GENES) Genetics of Type 2 Diabetes (GoT2D) Exome Sequencing Project (ESP) Slim Initiative in Genomic Medicine for the Americas (SIGMA) Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care (LuCAMP) Progress in Diabetes Genetics in Youth (ProDIGY) This data generated from the Hong Kong cohort was part of the T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples) consortium, which is a NIDDK-funded international research consortium that seeks to identify genetic variants for type 2 diabetes (T2D) through multiethnic sequencing studies. The T2D-GENES Project is a multi-ethnic sequencing study designed to assess whether less common variants play a role in T2D risk and to assess similarities and differences in the distribution of T2D risk variants across ancestry groups. The individuals were obtained from over 20 cohorts across the 6 consortia that are listed in Table 1. The strategy was to perform deep exome sequencing of individuals, 24,991 with T2D and 24,953 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. The T2D-GENES, ProDIGY and SIGMA studies, sequencing was performed at the Broad Institute using the Agilent v2 capture reagent or Illumina Rapid Capture on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, two of the cohorts below are not in dbGaP, due to the samples not being consented for deposition. This includes the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study and Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care (LuCamp) study. The Exome Sequencing Project (ESP) was deposited in dbGaP as part of their initial study and the phs numbers for that project can be found here: https://esp.gs.washington.edu/drupal/dbGaP_Releases. Table 1. 52,000 sample T2D Case/Control Whole Exome Sequencing Studies Ancestry Consortia Study Countries of Origin # Cases # Controls African American T2D-GENES Project 1 Jackson Heart Study US 500 526 African American T2D-GENES Project 1 Wake Forest School of Medicine Study US 518 530 African American ESP Exome Sequencing Project (ESP) US 467 1374 African American T2D-GENES Follow-Up Study BioMe Biobank Program (BioMe) US 1297 1256 East Asian T2D-GENES Project 1 Korea Association Research Project Korea 526 561 East Asian T2D-GENES Project 1 and Follow-Up Study Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 1486 1568 East Asian T2D-GENES Follow-Up Study Korea SNUH South Korea 450 475 East Asian T2D-GENES Follow-Up Study Research Studies in Hong Kong (Hong Kong) Hong Kong 493 485 European T2D-GENES Project 1 Ashkenazi US, Israel 506 352 European T2D-GENES Project 1 Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European GoT2D Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European GoT2D Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European GoT2D UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European GoT2D Malmö-Botnia Study Finland, Sweden 478 443 European LuCamp Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care (LuCamp) Denmark 997 997 European ESP Exome Sequencing Project (ESP) US 390 2843 European T2D-GENES Follow-Up Study Genetics of Diabetes and Audit Research Tayside Study (GoDARTS) Scotland, UK 960 966 European T2D-GENES Follow-Up Study Framingham Heart Study (FHS) US 396 596 Hispanic T2D-GENES Project 1 San Antonio Family Heart Study, San Antonio Family Diabetes/ Gallbladder Study, Veterans Administration Genetic Epidemiology Study, and the Investigation of Nephropathy and Diabetes Study Family Component US 272 218 Hispanic T2D-GENES Project 1 and SIGMA v2 Starr County, Texas US 1762 1738 Hispanic SIGMA v1 Mexico City Diabetes Study Mexico 281 549 Hispanic SIGMA v1 and SIGMA v2 Multiethnic Cohort (MEC) US 1476 1443 Hispanic SIGMA v1 and SIGMA v2 UNAM/INCMNSZ Diabetes Study (UIDS) Mexico 1998 1977 Hispanic SIGMA v1 and SIGMA v2 Diabetes in Mexico Study (DMS) Mexico 1522 1546 Multiethnic ProDIGY Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) US 3097 0 Multiethnic ProDIGY SEARCH for Diabetes in Youth (SEARCH) US 553 0 South Asian T2D-GENES Project 1 London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 531 538 South Asian T2D-GENES Project 1 and Follow-Up Study Singapore Indian Eye Study Singapore (Indian Asian) 1640 1478 South Asian T2D-GENES Follow-Up Study Pakistan Risk of Myocardial Infarction Study (PROMIS) Pakistan 914 932 The research studies in Hong Kong contributed 493 cases and 485 controls to T2D-GENES Follow-Up study.

  Study phs001504

• Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples (T2D-GENES) Follow-Up Study: BioMe Biobank Program

  The ~52,000 sample Type 2 Diabetes Exome Sequencing project is a collaboration of six consortia with various funding mechanisms that have joined together to investigate genetic variants for type 2 diabetes (T2D) using the largest T2D case/control sample set compiled to date. This includes samples from: Type 2 Diabetes Genetic Exploration by Next-generation sequencing in Multi-Ethnic Samples (T2D-GENES) Genetics of Type 2 Diabetes (GoT2D) Exome Sequencing Project (ESP) Slim Initiative in Genomic Medicine for the Americas (SIGMA) Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care (LuCAMP) Progress in Diabetes Genetics in Youth (ProDIGY) This data generated from the BioMe Biobank cohort was part of the T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples) consortium, which is a NIDDK-funded international research consortium that seeks to identify genetic variants for type 2 diabetes (T2D) through multiethnic sequencing studies. The T2D-GENES Project is a multi-ethnic sequencing study designed to assess whether less common variants play a role in T2D risk and to assess similarities and differences in the distribution of T2D risk variants across ancestry groups. The individuals were obtained from over 20 cohorts across the 6 consortia that are listed in Table 1. The strategy was to perform deep exome sequencing of individuals, 24,991 with T2D and 24,953 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. The T2D-GENES, ProDIGY and SIGMA studies, sequencing was performed at the Broad Institute using the Agilent v2 capture reagent or Illumina Rapid Capture on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, two of the cohorts below are not in dbGAP, due to the samples not being consented for deposition. This includes the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study and Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care (LuCamp) study. The Exome Sequencing Project (ESP) was deposited in dbGAP as part of their initial study and the phs numbers for that project can be found here: https://esp.gs.washington.edu/drupal/dbGaP_Releases. Table 1. 52,000 sample T2D Case/Control Whole Exome Sequencing Studies Ancestry Consortia Study Countries of Origin # Cases # Controls African American T2D-GENES Project 1 Jackson Heart Study US 502 527 African American T2D-GENES Project 1 Wake Forest School of Medicine Study US 518 532 African American ESP Exome Sequencing Project (ESP) US 467 1374 African American T2D-GENES Follow-Up Study BioMe Biobank Program (BioMe) US 1294 1254 East Asian T2D-GENES Project 1 Korea Association Research Project Korea 526 561 East Asian T2D-GENES Project 1 and Follow-Up Study Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 1486 1568 East Asian T2D-GENES Follow-Up Study Korea SNUH South Korea 450 475 East Asian T2D-GENES Follow-Up Study Research Studies in Hong Kong (Hong Kong) Hong Kong 493 485 European T2D-GENES Project 1 Ashkenazi US, Israel 506 355 European T2D-GENES Project 1 Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European GoT2D Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European GoT2D Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European GoT2D UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European GoT2D Malmö-Botnia Study Finland, Sweden 478 443 European LuCamp Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care (LuCamp) Denmark 997 997 European ESP Exome Sequencing Project (ESP) US 390 2843 European T2D-GENES Follow-Up Study Genetics of Diabetes and Audit Research Tayside Study (GoDARTS) Scotland, UK 960 966 European T2D-GENES Follow-Up Study Framingham Heart Study (FHS) US 396 596 Hispanic T2D-GENES Project 1 San Antonio Family Heart Study, San Antonio Family Diabetes/ Gallbladder Study, Veterans Administration Genetic Epidemiology Study, and the Investigation of Nephropathy and Diabetes Study Family Component US 272 218 Hispanic T2D-GENES Project 1 and SIGMA v2 Starr County, Texas US 1762 1738 Hispanic SIGMA v1 Mexico City Diabetes Study Mexico 281 549 Hispanic SIGMA v1 and SIGMA v2 Multiethnic Cohort (MEC) US 1476 1443 Hispanic SIGMA v1 and SIGMA v2 UNAM/INCMNSZ Diabetes Study (UIDS) Mexico 1998 1977 Hispanic SIGMA v1 and SIGMA v2 Diabetes in Mexico Study (DMS) Mexico 1522 1546 Multiethnic ProDIGY Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) US 3097 0 Multiethnic ProDIGY SEARCH for Diabetes in Youth (SEARCH) US 553 0 South Asian T2D-GENES Project 1 London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 531 538 South Asian T2D-GENES Project 1 and Follow-Up Study Singapore Indian Eye Study Singapore (Indian Asian) 1640 1478 South Asian T2D-GENES Follow-Up Study Pakistan Genomic Resource (PGR) Pakistan 914 932 The BioMe Biobank study contributed 1294 cases and 1254 controls to T2D-GENES Follow-Up Study.

  Study phs001490

• Type 2 Diabetes Genetic Exploration by Next-generation Sequencing in Multi-Ethnic Samples (T2D-GENES) Follow up Study: Pakistan Genomic Resource (PGR)

  The ~52,000 sample Type 2 Diabetes Exome Sequencing project is a collaboration of six consortia with various funding mechanisms that have joined together to investigate genetic variants for type 2 diabetes (T2D) using the largest T2D case/control sample set compiled to date. This includes samples from: Type 2 Diabetes Genetic Exploration by Next-generation sequencing in Multi-Ethnic Samples (T2D-GENES) Genetics of Type 2 Diabetes (GoT2D) Exome Sequencing Project (ESP) Slim Initiative in Genomic Medicine for the Americas (SIGMA) Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care (LuCAMP) Progress in Diabetes Genetics in Youth (ProDIGY) This data generated from the Pakistan Genomic Resource (PGR) cohort was part of the T2-GENES (Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples) consortium, which is a NIDDK-funded international research consortium that seeks to identify genetic variants for type 2 diabetes (T2D) through multiethnic sequencing studies. The T2D-GENES Project is a multi-ethnic sequencing study designed to assess whether less common variants play a role in T2D risk and to assess similarities and differences in the distribution of T2D risk variants across ancestry groups. The individuals were obtained from over 20 cohorts across the 6 consortia that are listed in Table 1. The strategy was to perform deep exome sequencing of individuals, 24,991 with T2D and 24,953 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. The T2D-GENES, ProDIGY and SIGMA studies, sequencing was performed at the Broad Institute using the Agilent v2 capture reagent or Illumina Rapid Capture on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, two of the cohorts below are not in dbGAP, due to the samples not being consented for deposition. This includes the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study and Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care (LuCamp) study. The Exome Sequencing Project (ESP) was deposited in dbGAP as part of their initial study and the phs numbers for that project can be found here: https://esp.gs.washington.edu/drupal/dbGaP_Releases. Table 1. 52,000 sample T2D Case/Control Whole Exome Sequencing Studies Ancestry Consortia Study Countries of Origin # Cases # Controls African American T2D-GENES Project 1 Jackson Heart Study US 502 527 African American T2D-GENES Project 1 Wake Forest School of Medicine Study US 518 532 African American ESP Exome Sequencing Project (ESP) US 467 1374 African American T2D-GENES Follow-Up Study BioMe Biobank Program (BioMe) US 1297 1256 East Asian T2D-GENES Project 1 Korea Association Research Project Korea 526 561 East Asian T2D-GENES Project 1 and Follow-Up Study Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 1486 1568 East Asian T2D-GENES Follow-Up Study Korea SNUH South Korea 450 475 East Asian T2D-GENES Follow-Up Study Research Studies in Hong Kong (Hong Kong) Hong Kong 493 485 European T2D-GENES Project 1 Ashkenazi US, Israel 506 355 European T2D-GENES Project 1 Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European GoT2D Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European GoT2D Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European GoT2D UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European GoT2D Malmö-Botnia Study Finland, Sweden 478 443 European LuCamp Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care (LuCamp) Denmark 997 997 European ESP Exome Sequencing Project (ESP) US 390 2843 European T2D-GENES Follow-Up Study Genetics of Diabetes and Audit Research Tayside Study (GoDARTS) Scotland, UK 960 966 European T2D-GENES Follow-Up Study Framingham Heart Study (FHS) US 396 596 Hispanic T2D-GENES Project 1 San Antonio Family Heart Study, San Antonio Family Diabetes/ Gallbladder Study, Veterans Administration Genetic Epidemiology Study, and the Investigation of Nephropathy and Diabetes Study Family Component US 272 218 Hispanic T2D-GENES Project 1 and SIGMA v2 Starr County, Texas US 1762 1738 Hispanic SIGMA v1 Mexico City Diabetes Study Mexico 281 549 Hispanic SIGMA v1 and SIGMA v2 Multiethnic Cohort (MEC) US 1476 1443 Hispanic SIGMA v1 and SIGMA v2 UNAM/INCMNSZ Diabetes Study (UIDS) Mexico 1998 1977 Hispanic SIGMA v1 and SIGMA v2 Diabetes in Mexico Study (DMS) Mexico 1522 1546 Multiethnic ProDIGY Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) US 3097 0 Multiethnic ProDIGY SEARCH for Diabetes in Youth (SEARCH) US 553 0 South Asian T2D-GENES Project 1 London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 531 538 South Asian T2D-GENES Project 1 and Follow-Up Study Singapore Indian Eye Study Singapore (Indian Asian) 1640 1478 South Asian T2D-GENES Follow-Up Study Pakistan Genomic Resource (PGR) Pakistan 903 930 The PGR study contributed 903 cases and 930 controls to T2D-GENES Follow-Up Study.

  Study phs001552

• Angelman, Rett, Prader-Willi Syndrome Consortium (ARP) Rett Syndrome Natural History Protocol

  This observational study will involve the comprehensive assessment of the clinical features of Rett syndrome with this Rare Diseases Clinical Research Network. A clinical database of 1350 individuals with Rett syndrome including MECP2 mutation status for the purpose of elaborating phenotype-genotype correlations will be established. Eligible participants will be enrolled in the natural history study for 11 years from the 4 clinic sites currently involved with Rett syndrome (BCM, GGC, and UAB, CHB) as well as from the several thousand registrants in the International Rett Syndrome Foundation registry who will be invited to the nearest consortium site involved in Rett syndrome. Potential participants are expected to have had determination of their MECP2 mutation status, but will not be excluded should no mutation be present. All individuals who meet criteria and are currently receiving care from study sites will be invited to participate (N>600). Additional participants will be invited through the assistance of the International Rett Syndrome Foundation (IRSF). All individuals with RS registered with IRSF will be invited to participate in this study via the IRSF website and the IRSF newsletter. Potential participants will be apprised of the participating study sites and invited to contact one of the sites based on feasibility of travel. Inasmuch as the enrollment goal of 1350 participants is 40% of the current IRSF registry, we believe this will be a representative sampling. Bias can certainly occur based on travel requirements, level of interest, and other factors. However, inclusion of such a large sample should minimize sampling bias. No travel expenses will be covered, so it is likely that participants will be those with geographic proximity to Houston, Greenwood, Birmingham, or Boston. From the sample pool described above, the aim is to conduct the observational longitudinal (natural history) study on up to 1350 participants with classic Rett syndrome and variant forms of Rett syndrome, that is, participants who fully meet the established clinical criteria for Rett syndrome and those who meet some but not all of these criteria. All participants expressing MECP2 mutations irrespective of phenotype will be eligible for enrollment. For each of the eight common genetic mutations as well as those with large scale deletions, the prevalence of the following RS characteristics will be estimated for each age category and overall: seizure presence and frequency, ambulation status, scoliosis, ECG abnormality, breathing irregularities while awake, feeding difficulties, growth as measured in percentiles from NCHS standards curves, the presence of osteopenia as evidenced by bone fracture, and the presence of gallbladder disease. Both incidence and prevalence estimates will be made using a combination of data obtained at the regularly scheduled clinical visits and that obtained from the medical history. Incidence estimates will be calculated using time-to-event analyses (e.g., Kaplan-Meier survival curves) with appropriate calculations of standard errors and 95% confidence intervals. Cox proportional hazard regression models will be used to allow control for other factors, and t-tests will be calculated on the coefficients themselves. Appropriate transformations on explanatory variables will be used as deemed necessary in Cox models. Prevalence estimates will be calculated from estimates of proportions with exact confidence intervals. For a sample size of 275, the standard error of the estimate will not exceed 0.03 (3%) and for a sample size of 60, the standard error of the estimate will not exceed 0.06 (6%).

  Study phs000574

• Lineage Plasticity and Immune Cell Heterogeneity Are Coordinately Dysregulated Through Changes in FOXA1 Expression in Bladder Cancers with Squamous Differentiation

  We performed whole exome sequencing (WES) of paired, macrodissected regions of urothelial carcinoma (UC), not otherwise specified (NOS-UC) and squamous differentiation (SqD) from 21 bladder tumors in which distinct and separable NOS-UC and SqD regions were present (total 42 exomes, in addition to matched normal exomes). Mean tumor mutational burden (TMB) was higher in the SqD versus the NOS-UC regions. Consistent with the higher TMB, the SqD regions also had a higher neoantigen burden than the patient-matched NOS-UC regions. The SqD regions also exhibited higher karyotypic complexity with a higher median ploidy relative to the paired NOS-UC regions. Phylogenetic analysis of the WES data confirmed that the morphologically distinct regions of all 21 tumors arose from a shared precursor with a median of 68 (range 16 – 852) non-synonymous mutations shared between the NOS-UC and SqD regions, and the overall data were indicative of early branched evolution. As whole exome sequencing did not identify a shared mutational alteration or genomic signature unique to the SqD or NOS-UC components, we therefore performed expression profiling of separable SqD and NOS-UC regions of 12 bladder tumors from the WES cohort with RNA quality sufficient for whole transcriptome RNA-sequencing (RNAseq, total of 24 regions). Based on centroid clustering analysis of expression data, all 12 regions of SqD were basal-squamous subtype based on the TCGA molecular classification schema. Notably, 8 of the NOS-UC regions were also basal-squamous subtype, with only four pairs exhibiting discordant transcriptional subtypes (three NOS-UC regions were luminal-infiltrated, one luminal-papillary). To better quantify differences in the transcriptional profiles of the paired NOS-UC and SqD regions, we used single sample gene set enrichment analysis (ssGSEA) to assess for enrichment of luminal or basal-squamous gene expression. ssGSEA analysis revealed that the SqD regions expressed higher levels of basal-squamous genes based on the BASE47 gene set and UPK/KRT gene sets; whereas the matched NOS-UC regions expressed higher levels of luminal genes. These differences in the levels of expression of basal and luminal genes were observed even in cases in which both the NOS-UC and SqD regions were basal-squamous subtype based the TCGA molecular classification schema. Exomes from eight patients in this study have previously been deposited in dbGaP: accession number phs001783 as part of the study "Exome Recapture and Sequencing of Prospectively Characterized Clinical Specimens From Cancer Patients".

  Study phs002357

• Germline and Somatic Genetic Landscape of Pediatric Rhabdomyosarcoma

  Dynamic approaches that integrate population-based research and molecular biology are needed to explain the mechanisms underlying pediatric rhabdomyosarcoma (RMS) and to determine novel prevention strategies. RMS, the most common soft-tissue sarcoma in children and adolescents, has one of the poorest 5-year survival rates among all pediatric cancers (less than 65%). One of the strongest risk factors for RMS is having a cancer predisposition syndrome. The syndromes that are most commonly seen among those with RMS are Li-Fraumeni, neurofibromatosis type 1, Costello, Noonan, and DICER1. Based on smaller clinic-based studies, only about 7% of RMS cases are thought to be associated with the genes responsible for these syndromes. However, there have been no population-based assessments to support this estimate. Even in the most recent large-scale evaluations of germline mutations in predisposition genes among children with cancer, very few RMS cases were included (43 cases). Furthermore, no distinctions were made between the major histologic subtypes of RMS: embryonal (eRMS) and alveolar (aRMS), which display differences in terms of age distribution, incidence, and cytogenetics. For instance, nearly 80% of alveolar cases are driven by a chromosomal translocation between either PAX3 or PAX7 and FOXO1, whereas these fusions are not seen in embryonal cases. In fact, RMS research is shifting from categorization based on histology to fusion status (eRMS is overwhelmingly fusion-negative). Another limitation in previous studies has been the inability to evaluate the frequency of de novo germline mutations (DNMs) in cancer predisposition genes due to the absence of any well-characterized cohorts of RMS case-parent trios. Therefore, a major gap in our understanding of the role of cancer predisposition in pediatric RMS that limit translational impact is there have been no population-based assessments to determine the true impact of these mutations on pediatric RMS, which limits clinical sequencing guidelines and surveillance protocols in these children.Overall Project Strategy: The objective of this project is to advance our understanding of the relationship between cancer predisposition genes and pediatric RMS. Our central hypotheses are: 1) mutations in cancer predisposition genes are more common than expected in children with RMS; and 2) children with fusion-negative tumors have a higher burden of germline mutations than those with fusion-positive tumors. The framework for this study relies on >600 well annotated samples collected from newly diagnosed RMS patients and stored in the Children’s Oncology Group (COG) Biopathology Center.

  Study phs002304

• CSER: South-Seq: DNA Sequencing for Newborn Nurseries in the South

  SouthSeq, part of the Clinical Sequencing Evidence-Generating Research (CSER2) effort, aims to perform genome sequencing for infants in nurseries at hospitals in Alabama, Mississippi, Louisiana, and Kentucky. SouthSeq aims to sequence 600 newborn babies presenting with congenital anomalies, or other signs of a rare genetic disorder. The primary goals of SouthSeq are to provide early diagnoses to children with rare genetic conditions, to demonstrate the utility of genome sequencing as a frontline test with potential to improve intermediate and long-term clinical outcomes, and to equip non-genetics providers to deliver test results in order to facilitate the conduction of genome sequencing outside of major medical centers where patients may not have access to a genetics provider. SouthSeq also aims to ensure that genomic testing is applied across diverse communities; recruitment efforts focus on patients from rural and minority populations that have been historically under-represented in both medicine and genomics research. Sequencing and analysis for SouthSeq are being conducted at the HudsonAlpha Institute for Biotechnology in Huntsville, Alabama (https://www.hudsonalpha.org/). Enrollment of infants with signs of genetic disease is approved at five clinical sites, including nurseries at the University of Alabama at Birmingham, the University of Mississippi Medical Center, Woman's Hospital in Baton Rouge, Children's Hospital in New Orleans, and the University of Louisville. Both biological parents are enrolled when available so that follow-up testing can be performed to determine inheritance. 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 ACMG SFv3.0 genes.

  Study phs002307

• Mechanism of Action of Vitamin E in NAFLD

  We conducted a single-center prospective mechanistic randomized trial (clinicaltrials.gov NCT01792115). Adult patients with NAFLD were enrolled between May 2013 and November 2016. All patients underwent a 12 weeks run-in period of lifestyle intervention. Following the run-in phase, patients underwent a baseline evaluation including blood tests, glucose tolerance testing, measurement of liver fat content by 1H-magnetic resonance spectroscopy (MRS) and a percutaneous liver biopsy. Patients with no evidence of NAFLD on the entry liver biopsy ended their participation in the study at that point. Patients with histological confirmation of NAFLD (either NAFL or NASH) on the baseline biopsy were randomized at a 1:1:1 ratio to receive one of 3 doses of natural vitamin E (RRR-alpha-tocopherol, Pharmavite), 200, 400 or 800 IU/d, for 24 weeks, and were followed at a 1-8 week intervals in a parallel assigned design. While on vitamin E treatment, patients were encouraged to continue and adhere to the lifestyle and dietary guidelines of the run-in phase. On week 4 of vitamin E treatment, a repeat MRS and liver biopsy were performed. On week 24, a final MRS was performed to assess treatment response. The primary endpoint was the reduction of liver fat content by MRS from baseline (immediately prior to starting vitamin E) to week 24 of treatment, and a response was defined as a relative reduction of ≥25% in liver fat content by MRS between baseline and week 24. Early changes in the hepatic transcriptome were investigated at week 4 comparing non-responders to responder in a nested design.

  Study phs001930

• National Cancer Institute (NCI) Non-Hodgkin Lymphoma Genome-wide Association Study (GWAS)

  Within the framework of the International Lymphoma Epidemiology Consortium (InterLymph) Consortium and NCI-sponsored Cohort Consortium, investigators from 22 studies came together to conduct a genome-wide association study (GWAS) of non-Hodgkin lymphoma (NHL). The goal of the study was to identify common genetic variants associated with the risk of NHL. As described previously (Berndt SI et al., Nature Genetics, 2013, PMID: 23770605 ), cases and controls from 22 studies, including nine prospective cohort studies, eight population-based case-control studies, and five clinic or hospital-based case-control studies were included in this effort. Cases of NHL were ascertained from cancer registries, clinics or hospitals, or through self-report verified by medical and pathology reports. The phenotype information for all NHL cases was reviewed centrally at the InterLymph Data Coordinating Center and harmonized according to the hierarchical classification proposed by the InterLymph Pathology Working Group based on the World Health Organization (WHO) classification (2008). Controls were frequency matched to cases on age and gender by study, and the study was limited to subjects of European ancestry. Participants were genotyped using the Illumina Omni Express. The NCI Non-Hodgkin Lymphoma GWAS is utilized in the following dbGaP sub-studies. To view genotypes and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs000801 NCI Non-Hodgkin Lymphoma GWAS. phs000802 NCI Non-Hodgkin Lymphoma GWAS: CLL phs000818 NCI Non-Hodgkin Lymphoma GWAS: Controls phs000889 NCI Non-Hodgkin Lymphoma GWAS: DLBCL phs000890 NCI Non-Hodgkin Lymphoma GWAS: FL phs000891 NCI Non-Hodgkin Lymphoma GWAS: MZL

  Study phs000801

• Mechanisms of Risk for Sulfonamide Hypersensitivity

  Hypersensitivity (HS) reactions to sulfonamide antibiotics occur uncommonly, but with potentially severe clinical manifestations. A familial predisposition to sulfonamide HS is suspected, but robust predictive genetic risk factors have yet to be identified. Strongly linked genetic polymorphisms have been used clinically as screening tests for other HS reactions prior to administration of high-risk drugs. The purpose of this study was to evaluate for genetic risk of sulfonamide HS in the immunocompetent population using genome-wide association. Ninety-one patients with symptoms after trimethoprim-sulfamethoxazole (TMP-SMX) attributable to "probable" drug HS based on medical record review and the Naranjo Adverse Drug Reaction Probability Scale, and 184 age- and sex-matched patients who tolerated a therapeutic course of TMP-SMX, were included in a genome-wide association study using both common and rare variant techniques. Additionally, two subgroups of HS patients with a more refined clinical phenotype (fever and rash; or fever, rash and eosinophilia) were evaluated separately. For the full dataset, no single nucleotide polymorphisms were suggestive of or reached genome-wide significance in the common variant analysis, nor was any genetic locus significant in the rare variant analysis. A single, possible gene locus association (COL12A1) was identified in the rare variant analysis for patients with both fever and rash, but the sample size was very small in this subgroup (n=16), and this may be a false positive finding. No other significant associations were found for the subgroups. No convincing genetic risk factors for sulfonamide HS were identified in this population. These negative findings may be due to challenges in accurately confirming the phenotype in exanthematous drug eruptions, or to unidentified gene-environment interactions influencing sulfonamide HS. Reprinted under PLOS ONE's open access license, CC-BY (http://www.plos.org/open-access).

  Study phs001124

• A Polygenic Score for Acute Vaso-Occlusive Pain in Pediatric Sickle Cell Disease

  Recurrent acute pain, or vaso-occlusive pain crisis (VOP), is the most common complication of sickle cell disease and correlates strongly with increased hospital visits and early mortality (PMID: 1710777). While the genetics of VOP in sickle cell patients has been studied (PMID: 29205277, 27883292, 25102390, 30079801, 22925497, 29531649, 29620434, 19468207, 20172753, 22576309, 30031848, 24136375, 27603703, 29559808), it is not fully understood.Using whole genome sequencing, we interrogated the α-thalassemia deletion -α3.7 and 133 candidate single-nucleotide polymorphisms (SNPs) across 66 genes for associations with VOP in 327 SCCRIP participants followed longitudinally over 6 years. Twenty-one SNPs in 9 loci were associated with VOP, including 3 (BCL11A, MYB, and the β-like globin gene cluster) that regulate erythrocyte fetal hemoglobin (HbF) levels and 6 (COMT, TBC1D1, KCNJ6, FAAH, NR3C1, and IL1A) that were associated previously with various pain syndromes. An unweighted PGS integrating all 21 SNPs was associated with the VOP event rate (estimate, 0.35; standard error, 0.04; P = 5.9 × 10−14) and VOP event occurrence (estimate, 0.42; standard error, 0.06; P = 4.1 × 10−13). These associations were stronger than those of any single locus. Our findings provide insights into the genetic modulation of VOP in children with SCD. More generally, we demonstrate the utility of WGS for investigating genetic contributions to the variable expression of SCD-associated morbidities.For publications, written, and/or oral presentations resulting from use of this data, please cite the following information: "The original data description for A Polygenic Score for Acute Vaso-Occlusive Pain in Pediatric Sickle Cell Disease can be found here: (Journal Citation Blood Adv. 2021 Jul 27;5(14):2839-2851) (PMID: 34283174)."

  Study phs002470

• Identifying Novel Small RNA Biomarkers Unique to Patients with Gastric Cancer

  The biomarker development study consisted of two parts: discovery and validation. The first part was the discovery and verification phase of biomarkers using two different platforms: transcriptomic and miRNA. The salivary transcriptomes of 63 GC samples and 31 non-GC controls were profiled using Affymetrix HG U133+2.0 microarrays (Affymetrix, Santa Clara, CA). The identified exRNA candidates were verified by quantitative real-time PCR (RT-qPCR) using all 94 of the original samples. In the discovery phase for the miRNA biomarkers, 10 early-stage GC samples and 10 non-GC controls were selected. The salivary miRNAs of these samples (n=20) were profiled using the TaqMan MicroRNA Array (Applied Biosystems, Foster City, CA). MicroRNA candidates were verified using TaqMan miRNA Assay (Thermo Scientific, Grand Island, NY). The second part of the study was to validate these verified exRNA biomarker candidates with exRNA samples extracted from an independent cohort of 100 GC and 100 non-GC saliva samples. The cohort was not balanced for demographics on gender and smoking history but more accurately reflected the diagnostic setting where our proposed final model could be implemented. Reprinted from "Li F, Yoshizawa MJ, Kim K, Kanjanapangka J, Grogan T, Wang X, Elashoff D, Ishikawa S, Chia D, Liao W, Akin D, Yan X, Lee M, Choi R, Kim S, Kang S, Bae J, Sohn T, Lee J, Choi M, Min B, Lee J, Kim J, Kim Y, Kim S, Wong D. (2018) Development and Validation of Salivary Extracellular RNA Biomarkers for Noninvasive Detection of Gastric Cancer. Clin Chem. PMID: 30097497 DOI: 10.1373/clinchem.2018.290569", with permission from American Association for Clinical Chemistry (United States).

  Study phs001767

• Epigenetic Profiling of Human Colorectal Cancer

  DNA methylation, together with chromatin modifications, constitute the epigenome that functions to regulate gene expression and genome integrity. DNA methylation alterations are ubiquitous in human cancers, as many genes acquire DNA methylation in a cancer-specific manner. DNA methylation at these sites in the genome of cancer cells not only serves as a marker for tumor identification, but together with gene mutation and gene expression data, can also be used to describe subsets of tumors of the same organ source. We have previously shown distinct human colorectal cancer subtypes based on DNA methylation differences. Correlating these DNA methylation differences with clinical co-variates will serve to further understand how these distinct subtypes are generated. We have collected 100 colorectal tumor tissues (for which clinical information is known) and have obtained (unprotected) genome-wide DNA methylation and chromatin modification information for each sample for the purposes of identifying and classifying unique tumor subtypes of colorectal cancers. In addition, we have determined mutations of key genes relevant to colorectal cancer as well as gene expression profiles. We will use the clinical data for each de-identified sample to correlate with the DNA methylation, mutation and gene expression information so as to understand the driving forces behind these distinct colorectal subtypes. We have selected the most promising tumors for whole-genome bisulfite sequencing using next-generation sequencing technology to obtain complete maps of colon cancer methylomes. Researchers will be unable to identify the subjects because the samples and associated information have been de-identified and anonymized by the tissue source site. In addition, upon receipt by the USC Epigenome Center, we have assigned new random identifiers for each sample. The data generated using these new codes are not traceable to the patient identity.

  Study phs000385

• Genomic Answers for Kids (GA4K)

  Identification of complex genetic variants including defects in gene regulatory circuits and uncharacterized genes present challenges for rare disease diagnosis. In Genomic Answers for Kids program we apply the joint interpretation of patient genome sequence with genomic endophenotypes to expand the clinically actionable genome among pediatric cases of suspected genetic disease. Our objective is to examine the role of novel and under-interpreted sequence variation by combining complete DNA sequences, personal epigenetic variations and massively parallel functional screens. To achieve this we perform augmented whole genome sequence (WGS) interpretation including reanalysis of clinical exomes as well as generating WGS for patients with negative exome results all be subject to family-based semi-automated recall pipeline to discover missed diagnostic variation. We use linked-read and long-read sequencing technologies to focus on putative structural variants missed in short-read genome and exome analysis by the optimized integration of linked and long read technologies that also improve identification of transmission patterns of all variants, as well as resolving genomic regions resistant to standard alignment. We also include tissue DNA sequencing to investigate somatic mosaicism. To further assist with WGS interpretation for uncommon variation we capture snapshots of patient transcriptomes and epigenomes in individual cells using single-cell RNA (scRNA) and sc open chromatin (scATAC) as well as bulk whole genome bisulphite genome sequencing for methylome interpretation. Alternative splicing is functionally assessed in available patient tissues using RNA-seq, including full length cDNA sequences by IsoSeq (PacBio) methodology. Our overarching goal is an increase rate of diagnostic genomic findings up to two-fold among rare disease, resulting in the majority (>50%) of patient cases resolved by the integrated system developed in our program.

  Study phs002206

• Whole Exome Sequencing of Head and Neck Patients-Derived Tumor Organoids and Formalin Fixed Paraffin Embedded Tumor Tissue

  In this study, tissue specimens were procured from head and neck squamous cell carcinoma (HNSCC) patients undergoing routine diagnostic procedures as part of their standard of care. For surgical cases, only excess tissue remaining after allocation for essential pathological diagnosis was utilized for research purposes. We aimed to validate the genomic fidelity of patient-derived organoids (PDOs) compared to their originating tumors. Whole exome sequencing was performed on four paired sets of PDOs and matched surgical specimens preserved as formalin-fixed paraffin-embedded (FFPE) samples. The objective was to demonstrate that the in vitro PDO models maintain the genomic profile of the patient-specific tumors, thus supporting their potential application in identifying efficacious personalized treatment regimens. Comparative analyses of single nucleotide variants (SNVs) and copy number variants (CNVs) between matched PDO and FFPE pairs were conducted to assess global genomic similarity and shared HNSCC-relevant variants. The results indicated that the PDOs closely recapitulated the mutational landscape of the resected tumors from which they were derived. This finding supports the validity of the employed in vitro culture conditions for potential use in precision medicine approaches for HNSCC. The data submitted to dbGaP comprise eight whole exome sequencing profiles of matched pairs of HNSCC FFPE and PDO samples from four subjects. Novogene (Novogene Co., Ltd, CA, USA) generated these profiles from 1.0μg genomic DNA per sample, using the Agilent SureSelect Human All Exon kit (Agilent Technologies, CA, USA). Deposited files include raw BAM files of reads aligned to human genome Hg19 using BWA (v.0.7.8-r455), sorted with Samtools (v1.0), and filtered for duplicate reads using Picard (v1.111). Additionally, we've deposited VCF files of SNV variant calls from GATK (v3.8).

  Study phs003755

• Rapid Early Action for Coronary Treatment (REACT-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: This multicenter controlled community study developed and evaluated the impact of a community educational intervention program on participant delay time from onset of symptoms of an acute myocardial infarction (AMI) to arrival at a hospital emergency department.Background: Although early reperfusion or thrombolytic therapy can reduce morbidity and mortality following an AMI, delayed access to medical care in participants is relatively common. Mean delay times from symptom onset to hospital arrival range from more than 4 hours to 24 hours, and the largest component of prolonged delay is participant recognition and action.Participants: A total of 20 communities from 5 field centers in the U.S. were pair-matched (10 pairs) according to geographic proximity and demographic characteristics. After initiation of a 4 month baseline surveillance period, one community in each pair was randomly selected to receive the intervention. The baseline surveillance period was followed by an 18 month community intervention and surveillance period. The community surveillance captured a total of 59,944 adults aged 30 years or older presenting to hospital emergency departments with chest pain, of whom 20,364 met study criteria for suspected acute coronary heart disease (CHD) at admission and discharged with a CHD diagnosis.Conclusions: Delay times were decreased in the intervention and reference communities. The results showed that the multicomponent community intervention program did not differentially reduce delay time from onset of AMI symptoms to arrival at a hospital, but did significantly increase the use of Emergency Medical Services by these participants in the intervention communities. (PMID:10872014).

  Study phs003885

• A Personalized Neoantigen Vaccine Generates Anti-Tumor Immunity in High-Risk Renal Cell Carcinoma

  Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens. However, whether such responses can target cancer driver mutations, lead to immune recognition of a patient's tumor, and result in clinical activity are largely unknown, particularly in patients with lower mutation burden tumors. We conducted a phase I trial testing a neoantigen-targeting PCV in patients with high-risk, fully resected clear cell renal cell carcinoma (RCC; stage III or IV), with or without ipilimumab administered adjacent to the vaccine. At a median follow-up of 40.2 months from surgery, none of the 9 initial participants experienced a recurrence of RCC. No dose-limiting toxicities were observed. All patients generated T cell immune responses against PCV antigens, including RCC driver mutations in VHL, PBRM1, BAP1, KDM5C, and PIK3CA. Following vaccination, there was a durable expansion of peripheral T cell clones, and T cell reactivity against autologous tumor was detected in 7 of the 9 patients. Our results demonstrate that neoantigen-targeting PCVs in high-risk RCC are highly immunogenic, capable of targeting key driver mutations, and induce anti-tumor immunity. These observations, in conjunction with the absence of recurrence in all 9 vaccinated patients, highlights the promise of PCV as effective adjuvant therapy in RCC. We are submitting WES data from whole blood samples and tumor FFPE samples, and RNA-Seq data from tumor FFPE samples. We are also submitting RNA-Seq data from purified tumor samples. scRNA-seq data will be submitted for skin samples (vaccine site biopsies at Weeks 0, 4, and 13), tumor samples (including resected metastatic tumor samples for two patients), and normal kidney samples. Bulk TCR-seq data will be submitted for blood samples.

  Study phs003710

• HeLa Cell Genome Sequencing Studies

  HeLa is a human epithelial adenocarcinoma cell line that was derived from biopsy specimens of a 31-year old patient named Henrietta Lacks who was being treated for cervical cancer at The Johns Hopkins University Hospital in 1951. The specimens were obtained without her knowledge or consent just before her death in 1951. HeLa is the oldest and most widely used human cell line and has been an extraordinarily important resource for researchers throughout the world. HeLa cells have served as a standard for understanding many fundamental biological processes, such as testing the polio vaccine, establishing basic techniques for cloning and in vitro fertilization, identifying the cause of cervical cancer (HPV), and advancing the development of anti-cancer drugs.This study contains all authorized whole genome sequence data of the HeLa cell line from datasets currently in dbGaP. These data have been approved for health, medical, and/or biomedical research purposes. Access to these data can be granted for one year. Accessible data will include the studies listed on this page and any additional authorized datasets that become available during this one-year period. The HeLa Genome Data Access Working Group of the Advisory Committee to the Director (ACD) will review requests from the research community for access to these datasets and assess whether the requests align with the terms of use defined in the HeLa Genome Data Use Agreement. The Working Group's findings will be reported to the ACD, and the ACD will make recommendations to the NIH Director about whether a request should be approved or disapproved. The NIH Director will decide whether access to the data will be granted.

  Study phs000640

• CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory

  Foxp3-expressing CD25+CD4+ regulatory T cells (Tregs) are abundantly infiltrating into tumor tissues, hindering effective anti-tumor immunity. Here, assuming that such tumor Tregs were clonally expanding by recognizing tumor-associated antigens, we attempted to characterize them by their gene expression profiling and T-cell receptor (TCR) clonotyping at the single-cell level. We found that they predominantly expressed the chemokine receptor CCR8: ~40% of tumor Tregs, less than 10% of Tregs in other tissues, and few tumor-infiltrating conventional T cells expressed CCR8 in mice and humans. CCR8+ tumor Tregs were phenotypically highly differentiated and functionally stable. One injection of anti-CCR8 mAb with high antibody-dependent cellular cytotoxic activity was indeed able to specifically deplete clonally expanded tumor Tregs and thereby eradicate established tumors in mice. The depletion predominantly expanded tumor-infiltrating CD8+ effector T cells, which were different in activated or exhausted patterns from those seen after immune checkpoint blockade by anti-PD-1 mAb. The treatment also evoked potent secondary immune responses against the same tumor cell line inoculated several months after tumor eradication, indicating that the anti-CCR8-induced memory-type tumor-reactive effector T cells were, once induced, resistant to recovered Treg suppression. In contrast to such evocation of potent tumor immunity, anti-CCR8 treatment scarcely elicited discernable autoimmunity in mice, contrasting with a similar treatment for systemic whole Treg depletion, which induced histologically and serologically evident autoimmunity. Thus, temporary and specific depletion of clonally expanded Tregs in tumor tissues by cell-depleting anti-CCR8 mAb is sufficient to evoke potent tumor immunity with long-lasting memory and without serious autoimmunity.

  Study JGAS000312

• Distinct evolutionary trajectories of primary high grade serous ovarian cancers revealed through spatial mutational profiling

  High-grade serous ovarian cancer (HGSC) is characterized by poor outcome, often attributed to emergence of treatment-resistant sub-clones. We sought to measure the degree of genomic diversity within primary, untreated HGSC to examine the natural state of tumor evolution prior to therapy. We performed exome sequencing, copy number analysis, targeted amplicon deep sequencing and gene expression profiling on thirty-one spatially and temporally separated HGSC tumor specimens (six patients) including ovarian masses, distant metastases, and fallopian tube lesions. We found widespread intra-tumoral variation in mutation, copy number, and gene expression profiles, with key driver alterations in genes present in only a subset of samples (e.g. PIK3CA, CTNNB1, NF1). On average, only 51.5% of mutations were present in every sample of a given case (range: 10.2% to 91.4%), with TP53 as the only somatic mutation consistently present in all samples. Complex segmental aneuploidies, such as whole genome doubling, were present in a subset of samples from the same individual, with divergent copy number changes segregating independently of point mutation acquisition. Reconstruction of evolutionary histories showed one patient with mixed HGSC and endometrioid histology with common etiologic origin in the fallopian tube and subsequent selection of different driver mutations in the histologically distinct samples. In this patient, we observed mixed cell populations in the early fallopian tube lesion, indicating diversity arises at early stages of tumorigenesis. Our results reveal that HGSC exhibit highly individual evolutionary trajectories and diverse genomic tapestries prior to therapy, exposing an essential biological characteristic to inform future design of personalized therapeutic solutions and investigation of drug resistance mechanisms.

  Study EGAS00001000547

• Whole-exome sequencing of human pancreatic cancers and characterization of genomic instability caused by MLH1 haploinsufficiency and complete deficiency

  Whole-exome sequencing (Exome-Seq) has been successfully applied in several recent studies. We here performed Exome-Seq of 15 pancreatic tumor-normal pairs. We captured 162,073 exons of 16,954 genes and sequenced the targeted regions to a mean coverage of 56 folds. This study identified a total of 1,517 somatic mutations and validated 934 of them by transcriptome sequencing. We detected recurrent mutations in 56 genes. Among them, 41 have not been described. The mutation rates varied widely among tumors. The diversity of mutation rates was significantly correlated with the distinct MLH1 copy-number status. Exome-Seq revealed intensive genomic instability in a tumor with MLH1 homozygous deletion, indicated by a dramatically elevated mutation rate of somatic substitutions, small insertions/deletions (indels), as well as indels presented at microsatellites. Notably, we detected MLH1 allelic loss in 4 tumors. MLH1 expression was decreased by nearly half in these cases. While they were negative in the conventional microsatellite instability assay, they showed a 10.5-fold increase in the mutation rate of somatic indels, e.g. truncating indels in TP53 and TGFBR2, indicating MLH1 haploinsufficiency in correction of DNA indel errors. We further analyzed the exomes of 15 renal cell carcinomas (RCCs) and confirmed MLH1 haploinsufficiency. We observed a significant increase in the mutation rate of somatic indels in affected cases and identified recurrent truncating indels in several cancer genes such as VHL, PBRM1 and JARID1C. Together, our data suggest that MLH1 hemizygous deletion, through increasing the mutation rate of somatic indels, could drive the development and progression of sporadic cancers.

  Study EGAS00001000149

• Ultra-fast deep-learned pediatric CNS tumor classification.

  The primary treatment of CNS tumors starts with a neurosurgical resection in order to obtain tumor tissue for diagnosis and to reduce tumor load and mass effect. The neurosurgeon has to decide between radical resection versus a more conservative strategy to prevent surgical morbidity. The prognostic impact of a radical resection varies between tumor types. However due to a lack of pre-operative tissue-based diagnostics, limited knowledge of the precise tumor type is available at the time of surgery. Current standard practice includes preoperative imaging and intraoperative histological analysis, but these are not always conclusive. After surgery, histopathological and molecular tests are performed to diagnose the precise tumor type. The results may indicate that an additional surgery is needed or that the initial surgery could have been less radical. Using rapid Nanopore sequencing, a sparse methylation profile can be directly obtained during surgery, making it ideally suited to enable intraoperative diagnostics. We developed a state-of-the-art neural-network approach called Sturgeon, to deliver trained models that are lightweight and universally applicable across patients and sequencing depths. We demonstrate our method to be accurate and fast enough to provide a correct diagnosis with as little as 20 to 40 minutes of sequencing data in 45 out of 49 pediatric samples, and inconclusive results in the other four. In four intraoperative cases we achieved a turnaround time of 60-90 minutes from sample biopsy to result; well in time to impact surgical decision making. We conclude that machine-learned diagnosis based on intraoperative sequencing can assist neurosurgical decision making, allowing neurological comorbidity to be avoided or preventing additional surgeries.

  Study EGAS00001007475

• Tracking the evolution of Therapy-Related Myeloid Neoplasms using chemotherapy signatures

  Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms (tMN). Pre-leukemic clones (i.e., clonal hematopoiesis; CH) are detectable years before the development of these aggressive malignancies, though the genomic events leading to transformation and expansion are not well-defined. Here, leveraging distinctive chemotherapy-associated mutational signatures from whole-genome sequencing data and targeted sequencing of pre-chemotherapy samples, we reconstruct the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy is revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan are hypermutated and enriched for complex structural variants (i.e., chromothripsis) while neoplasms with non-mutagenic chemotherapy exposures are genomically similar to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as temporal barcodes linked to a discrete clinical exposure in each patient’s life, we estimate that several complex events and genomic drivers are acquired after chemotherapy is administered. For patients with prior multiple myeloma who were treated with high-dose melphalan and autologous stem cell transplantation, we demonstrate that tMN can develop from either a reinfused CH clone that escapes chemotherapy exposure and is selected following reinfusion, or from TP53-mutant CH that survives direct myeloablative conditioning and acquires melphalan-induced DNA-damage. Overall, we reveal a novel mode of tMN progression that is not reliant on direct mutagenesis or even exposure to chemotherapy. Conversely, for tMN that evolve under the influence of chemotherapy-induced mutagenesis, distinct chemotherapies not only select pre-existing CH, but also promote the acquisition of recurrent genomic drivers.

  Study EGAS00001006903

• Genomic landscape of oral cancers (Complete Genomics WGS)

  Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCC) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCC, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. By contrast, in HPV-negative OSCC, T>C substitutions in the sequence context 5’-ATN-3’ correlated with tobacco exposure. Universal expression of HPV E6*1 and E7 oncogenes was a sine qua non of HPV-positive OSCC. Significant enrichment of somatic mutations was confirmed or newly identified in PIK3CA, KMT2D, FGFR3, FBXW7, DDX3X, PTEN, TRAF3, RB1, CYLD, RIPK4, ZNF750, EP300, CASZ1, TAF5, RBL1, IFNGR1 and NFKBIA. Of these, many affect host pathways already targeted by HPV oncoproteins, including the p53 and pRB pathways, or disrupt host defenses against viral infections, including interferon and nuclear factor-B signaling. Frequent copy number changes were associated with concordant changes in gene expression. Chr. 11q (including CCND1) and 14q (including DICER1 and AKT1) were recurrently lost in HPV-positive OSCC, in contrast to their gains in HPV-negative OSCC. High-ranking variant allele fractions implicated ZNF750, PIK3CA and EP300 mutations as candidate driver events in HPV-positive cancers. We conclude that virus-host interactions cooperatively shape the unique genetic features of these cancers, distinguishing them from their HPV-negative counterparts.

  Study EGAS00001002393

• Exome sequencing in bipolar disorder families

  Bipolar disorder (BD) is a major psychiatric disorder affecting around 1% of the global population. BD is characterized by recurrent manic and depressive episodes, and has an estimated heritability of around 70% Research has identified the first BD susceptibility genes. However, the underlying pathways and regulatory networks remain largely unknown. Since research has shown that the cumulative impact of common alleles with small effect appears to explain only around 25-38% of the phenotypic variance for BD, rare variants of high penetrance may also contribute to BD risk. The present study investigated the role of rare, nonsynonymous, and potentially functional variants via whole exome sequencing in 15 BD cases from two large, multiply affected families from Cuba. The high prevalence of BD in these pedigrees renders them promising in terms of the identification of genetic risk variants with large effect sizes. In addition, SNP array data were used to calculate polygenic risk scores for affected and unaffected family members. After correction for multiple testing, polygenic risk scores for common, BD-associated genetic variants were not significantly higher in BD cases than in healthy relatives. Exome sequencing identified a total of 17 rare and potentially damaging variants in 17 genes. The identified variants were shared by all investigated BD cases in the respective pedigree. The most promising variant was located in the gene SERPING1 (p.L349F), which has been reported as a genome-wide significant risk gene for schizophrenia. A further promising variant was located in CAPN2, which has been implicated in synaptic plasticity. The present data suggest novel candidate genes for BD susceptibility, and may facilitate the discovery of disease-relevant pathways and regulatory networks.

  Study EGAS00001003085