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• The Role of Germline Mutation and Parental Age in Autism Spectrum Disorders

  <p>We will apply whole genome sequencing of trio families to determine how patterns of germline mutation throughout the genome determine risk for Autism Spectrum Disorder (ASD). We will investigate the nature intrinsic hypermutability and the extrinsic forces, such as paternal age, that influence rates of germline mutation. We will accomplish these goals through the following specific aims: Specific Aim 1 will characterize germline de novo mutations (DNMs) by whole genome sequencing in families. These studies will identify and validate ~8,000 de novo point mutations and structural variants in trios and controls to determine the parent of origin of DNMs. Specific Aim 2 will identify hot spots for germline mutation based on the regional density of DNMs in the genome, and determine the effects of DNA sequence features on rates of mutation. We will determine the association of mutation hotspots with ASD in the discovery sample and in genomic datasets from an independent sample of 2700 cases and 2700 controls. Specific Aim 3 will characterize the effects of extrinsic factors, including parental age and environment, on genome-wide rates of mutation. We will quantify the effect of paternal age on pathogenic and neutral alleles in sperm and investigate whether some DNMs confer a germline selective advantage. The findings of this study will provide fundamental insights into the genetic basis of autism risk and the genetic mechanism of the observed parental age effects in ASD. We will identify genes that confer significant risk for autism, and we will determine how intrinsic properties of the genome interact with extrinsic forces to determining risk for disease in offspring.

  Study phs001164

• Phylogenetic analysis of treatment-naive metastases using whole exome and genome sequencing data

  Metastases are responsible for the majority of cancer related deaths and are often difficult to treat successfully. Even for metastases that occur subsequent to treatment, we do not know whether such relapsing metastases were originally heterogeneous or if the observed heterogeneity is a consequence of therapy. Given that treatment can influence evolutionary dynamics by selecting resistant clones, imposing bottlenecks on cancer cell populations, and even inducing novel somatic mutations, characterizing the prior standing variation among metastases remains an important goal to predict initial therapeutic response. To quantify the heterogeneity at clinical presentation of advanced disease, we surveyed the literature for patients in which at least two treatment-naïve metastases underwent genome/exome-wide sequencing. Across all cancer types surveyed, only 18 subjects were found to fulfill this requirement. Including previously unpublished data from two subjects, we analyzed data of 74 untreated metastases and inferred cancer phylogenies. Putative driver gene mutations were acquired at a 2-fold higher rate on the trunk of all metastases than on branches. Mutations in driver genes along the trunk were strongly enriched for predicted functional consequences. Using a stochastic mathematical model, we find that driver gene heterogeneity among metastases mostly occurs in slowly growing cancers for highly advantageous driver gene mutations. Seeding efficiency only weakly affects the heterogeneity among metastases. These results explain why functional driver gene heterogeneity is uncommon in advanced disease prior to treatment, thus providing optimism for future therapies that depend on mutations across metastases.

  Study EGAS00001002777

• ATAC-seq in KMS11 vs TKO cells

  ATAC-seq to determine chromatin accessibility in t(4;14) Myeloma cell line KMS11 and KMS11 cells with knock-out of the translocated NSD2 allele.

  Study EGAS50000000076

• Genomewide association studies in ankylosing spondylitis

  The aim of this study was to identify genes associated with ankylosing spondylitis susceptibility in British and Australian individuals of European descent.

  Study EGAS00000000104

• Kids First: Pediatric Research Project on the Genomic Analysis of Congenital Diaphragmatic Hernia

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). 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. WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. In collaboration with the University of Utah, DNA from four families were selected for high-depth WGS (60X) including diaphragm and skin tissue to identify mosaicism. In collaboration with the Broad Institute, DNA from four families underwent linked long read sequencing using 10X Genomics technology. Probands with congenital diaphragmatic hernia/defects and both biological parents enrolled as part of the DHREAMS study.

  Study phs001110

• Comprehensive Genomic Characterization of Gene Therapy-Induced T-cell Acute Lymphoblastic Leukemia (H007)

  Six out of ten patients in a hematopoietic stem cell gene therapy (GT) trial for Wiskott-Aldrich syndrome (WAS) developed T-cell acute lymphoblastic leukemia (T-ALL) associated with gamma-retroviral vector integration at the LMO2 locus. We hypothesized that detailed molecular analysis of T-ALL driven by temporally defined first deregulation of LMO2 might offer valuable insights into the pathogenesis of GT-associated and sporadic T-ALL (HIPO project 007). In all six patients whole-genome and transcriptome sequencing demonstrated that in addition to oncogenic chromosomal translocations involving the T-cell receptor loci, retrovirally induced leukemias faithfully recapitulated secondary genomic events observed in sporadic T-ALL. Multiple genetic events culminated in the development of a rapidly proliferating leukemic clone and onset of clinical manifestation at 1.3 to 5 years after infusion of the gene corrected transplant. These genetic alterations affected NOTCH1 and PI3K signaling, cell cycle regulation as wells as T-cell transcription factors LEF1 and TCF1. Two of the six cases displayed a phenotype reminiscent of early immature T-ALLs, and lacked additional T-ALL typical alterations. Our analysis shows that insertional mutagenesis involving the LMO2 locus triggers T-ALL development due to diverse genetic alterations in large parts, but not exclusively, in known T-ALL driver genes, demonstrating the molecular diversity of GT-associated T-ALL.

  Study EGAS00001003870

• A Protein Neddylation Inhibitor MLN4924 Suppresses Patient-Derived Glioblastoma Cells via Inhibition of ERK and AKT Signaling

  Glioblastoma is a highly aggressive and lethal brain tumor, with limited treatment options. Abnormal activation of the neddylation pathway is observed in glioblastoma, and the NEDD8-activating enzyme (NAE) inhibitor, MLN4924 was previously shown to be effective in glioblastoma cell line models. However, its effect has not been tested in patient-derived glioblastoma stem cells. Immunohistochemistry and public data were analyzed to determine whether NEDD8 pathway proteins are important in glioblastoma development and patient survival. The effects of MLN4924 were evaluated in 4 glioblastoma cell lines and 15 patient-derived glioblastoma stem cells using high content analysis. Immunoblot analysis assessed the NEDD8 pathway proteins and biomarkers. Whole transcriptome analysis identified pathways associated with MLN4924 sensitivity. NAE1 and UBA3 levels increased in glioblastoma patients; high NEDD8 levels were associated with poor clinical outcomes. Glioblastoma cell lines and patient-derived stem cells were highly susceptible to MLN4924, while normal human astrocytes were resistant. Genomic analyses indicated that MLN4924 sensitive cells exhibited enrichment of ERK and AKT signaling. We verified that MLN4924 inhibits ERK and AKT phosphorylation in MLN4924 sensitive cells. Our findings suggest that patient-derived glioblastoma stem cells in the context of ERK and AKT activation are sensitive and highly regulated by neddylation inhibition.

  Study EGAS00001004018

• Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples (T2D-GENES) Project 1: KARE

  T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples) is a NIDDK-funded international research consortium which seeks to identify genetic variants for type 2 diabetes (T2D) through multiethnic sequencing studies. T2D-GENES Project 1 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 14 cohorts that are listed in Table 1. The strategy was to perform deep exome sequencing of 12,940 individuals, 6,504 with T2D and 6,436 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. Sequencing was performed at the Broad Institute using the Agilent v2 capture reagent on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study does not have a sub study, as it is not consented to be deposited in dbGAP. Table 1. T2D-GENES Whole Exome Sequencing Studies Ancestry Study Countries of Origin # Cases # Controls African American Jackson Heart Study US 502 527 African American Wake Forest School of Medicine Study US 518 532 East Asian Korea Association Research Project Korea 526 561 East Asian Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 486 592 European Ashkenazi US, Israel 506 352 European Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European Malmö-Botnia Study Finland, Sweden 478 443 Hispanic 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 272 219 Hispanic Starr County, Texas US 749 704 South Asian London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 530 538 South Asian Singapore Indian Eye Study Singapore (Indian Asian) 563 585 The Korea Association Research Project (KARE) studies contributed 526 cases and 561 controls to T2D-GENES Project 1.

  Study phs001096

• Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples (T2D-GENES) Project 1: Ashkenazi

  T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples) is a NIDDK-funded international research consortium which seeks to identify genetic variants for type 2 diabetes (T2D) through multiethnic sequencing studies. T2D-GENES Project 1 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 14 cohorts that are listed in Table 1. The strategy was to perform deep exome sequencing of 12,940 individuals, 6,504 with T2D and 6,436 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. Sequencing was performed at the Broad Institute using the Agilent v2 capture reagent on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study does not have a sub study, as it is not consented to be deposited in dbGAP. Table 1. T2D-GENES Whole Exome Sequencing Studies Ancestry Study Countries of Origin # Cases # Controls African American Jackson Heart Study US 502 527 African American Wake Forest School of Medicine Study US 518 532 East Asian Korea Association Research Project Korea 526 561 East Asian Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 486 592 European Ashkenazi US, Israel 506 352 European Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European Malmö-Botnia Study Finland, Sweden 478 443 Hispanic 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 272 219 Hispanic Starr County, Texas US 749 704 South Asian London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 530 538 South Asian Singapore Indian Eye Study Singapore (Indian Asian) 563 585 The Ashkenazi study contributed 506 cases and 352 controls to T2D-GENES Project 1.

  Study phs001095

• Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples (T2D-GENES) Project 1: Singapore

  T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples) is a NIDDK-funded international research consortium which seeks to identify genetic variants for type 2 diabetes (T2D) through multiethnic sequencing studies. T2D-GENES Project 1 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 14 cohorts that are listed in Table 1. The strategy was to perform deep exome sequencing of 12,940 individuals, 6,504 with T2D and 6,436 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. Sequencing was performed at the Broad Institute using the Agilent v2 capture reagent on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study does not have a sub study, as it is not consented to be deposited in dbGAP. Table 1. T2D-GENES Whole Exome Sequencing Studies Ancestry Study Countries of Origin # Cases # Controls African American Jackson Heart Study US 502 527 African American Wake Forest School of Medicine Study US 518 532 East Asian Korea Association Research Project Korea 526 561 East Asian Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 486 592 European Ashkenazi US, Israel 506 352 European Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European Malmö-Botnia Study Finland, Sweden 478 443 Hispanic 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 272 219 Hispanic Starr County, Texas US 749 704 South Asian London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 530 538 South Asian Singapore Indian Eye Study Singapore (Indian Asian) 563 585 The Singapore studies contributed 1049 cases and 1177 controls to T2D-GENES Project 1.

  Study phs001097

• Type 2 Diabetes Genetic Exploration by Next-generation Sequencing in Multi-Ethnic Samples (T2D-GENES) Project 1: London Life Sciences Population Study (LOLIPOP) UK South Asian

  T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples) is a NIDDK-funded international research consortium which seeks to identify genetic variants for type 2 diabetes (T2D) through multiethnic sequencing studies. T2D-GENES Project 1 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 14 cohorts that are listed in Table 1. The strategy was to perform deep exome sequencing of 12,940 individuals, 6,504 with T2D and 6,436 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. Sequencing was performed at the Broad Institute using the Agilent v2 capture reagent on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study does not have a sub study, as it is not consented to be deposited in dbGAP. Table 1. T2D-GENES Whole Exome Sequencing Studies Ancestry Study Countries of Origin # Cases # Controls African American Jackson Heart Study US 502 527 African American Wake Forest School of Medicine Study US 518 532 East Asian Korea Association Research Project Korea 526 561 East Asian Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 486 592 European Ashkenazi US, Israel 506 352 European Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European Malmö-Botnia Study Finland, Sweden 478 443 Hispanic 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 272 219 Hispanic Starr County, Texas US 749 704 South Asian London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 530 538 South Asian Singapore Indian Eye Study Singapore (Indian Asian) 563 585 The London Life Sciences Population Study (LOLIPOP) contributed 530 cases and 538 controls to T2D-GENES Project 1.

  Study phs001093

• Genetic and Phenotypic Analysis of Multiple Sclerosis in Hispanics

  We sought to identify MS susceptibility variants specific to the Major Histocompatibility Complex and to assess the effect of ancestral risk modification within 2652 Latinx and Hispanic individuals, as well as 2435 Black and African American individuals ascertained in collaboration with the Alliance for Research in Hispanic MS (ARHMS). All DNA samples were obtained through whole blood extraction and were genotyped on the MS Chip, an Illumina Infinium custom genotyping array that contains targeted and dense coverage of the extended MHC, specifically designed for imputation. Classical HLA alleles, SNPs, and amino acid residues were imputed simultaneously from genotyped SNPs using HLA-TAPAS and a multi-ethnic reference panel of 2504 samples from the 1000 Genomes Project. We have identified several novel susceptibility alleles which are rare in European populations including HLA-B*53:01, and we have identified an independent role for HLA-DRB1*15:01 and HLA-DQB1*06:02 on MS risk. We found a decrease in Native American ancestry in MS cases vs controls across the MHC, peaking near the previously identified MICB locus; and we have identified several susceptibility variants for which MS risk is modified by global or local ancestry. We are making data on all genotyped and imputed SNPs, classical HLA alleles, and amino acid residues available through dbGaP for the Hispanic and African American samples utilized in these analyses.

  Study phs003105

• GECCO: Detecting Common and Rare Genetic Loci and GxE Interactions in Colorectal Cancer

  COLON, Colorectal Cancer: Longitudinal Observational study on Nutritional and lifestyle factors that influence colorectal tumor recurrence, survival and quality of life: The COLON study is a multi-center prospective cohort study to assess the role of diet and other lifestyle factors in cancer recurrence and survival among incident colorectal cancer patients in the Netherlands. DACHS, Darmkrebs: Chancen der Verhütung durch Screening:This German study was initiated as a large population-based case-control study in 2003 in the Rhine-Neckar-Odenwald region (southwest region of Germany) to assess the potential of endoscopic screening for reduction of colorectal cancer risk and to investigate etiologic determinants of disease, particularly lifestyle/environmental factors and genetic factors. During an in-person interview, data were collected on demographics, medical history, family history of CRC, and various life-style factors, as were blood and mouthwash samples. EPIC, European Prospective Investigation into Cancer: EPIC is an on-going multicenter prospective cohort study designed to investigate the associations between diet, lifestyle, genetic and environmental factors and various types of cancer. HPFS, Health Professionals Follow-up Study: HPFS is a parallel prospective study to the NHS. The HPFS cohort comprised 51,529 men aged 40-75 who, in 1986, responded to a mailed questionnaire. Participants provided information on health related exposures, including current and past smoking history, age, weight, height, diet, physical activity, aspirin use, and family history of colorectal cancer. Colorectal cancer and other outcomes were reported by participants or next-of-kin and were followed up through review of the medical and pathology record by physicians. Overall, more than 97% of self-reported colorectal cancers were confirmed by medical record review. Information was abstracted on histology and primary location. Follow-up evaluation has been excellent, with 94% of the men responding to date. NHS, Nurses' Health Study: The NHS cohort began in 1976 when 121,700 married female registered nurses age 30-55 years returned the initial questionnaire that ascertained a variety of important health-related exposures [PMID:248266]. Since 1976, follow-up questionnaires have been mailed every 2 years. Colorectal cancer and other outcomes were reported by participants or next-of-kin and followed up through review of the medical and pathology record by physicians. Overall, more than 97% of self-reported colorectal cancers were confirmed by medical-record review. Information was abstracted on histology and primary location. The rate of follow-up evaluation has been high: as a proportion of the total possible follow-up time, follow-up evaluation has been more than 92%. NQplus, Nutrition Questionnaires plus: NQplus is a longitudinal observational study on diet and health in the general Dutch population.

  Study phs001315

• NHLBI TOPMed: Children's Health Study (CHS) Integrative Genomics and Environmental Research of Asthma (IGERA)

  The Integrative Genomics and Environmental Research of Asthma (IGERA) Study was proposed to collect immortalized cell lines, RNA, cDNA and DNA from 400 well-characterized subjects who participated in the southern California Children's Health Study (CHS) and to develop an accompanying database for these samples consisting of extensive phenotype, exposure, genome-wide genotype, gene expression, and methylation data. A subset of Hispanic-White participants (n=160) were included in the TOPMed project, including 77 asthma cases and 83 controls.

  Study phs001603

• Genomic Characterization of African-American Prostate Cancer

  African-American men have the highest incidence and mortality rate from prostate cancer. This study represents a whole exome sequencing study of prostate cancer samples from African-American men. We performed exome sequencing and analysis of prostate tumors and matched normal tissues to identify somatic mutations and insertion/deletions across this cohort. All sequencing was performed at the Broad Institute. This study has the potential to identify novel recurrently mutated genes in prostate cancer and improve our understanding of prostate cancer in African-Americans.

  Study phs000945

• WES of breast cancer patients and controls

  This study assessed the variant profiles of 408 samples from 126 breast cancer patients with various survival outcomes, including paired uninvolved mammary gland samples collected at proximal distances from primary lesions. As a reference, control samples from 15 mammoplasty individuals without cancer history were studied. Whole exome sequencing was performed to identify post-zygotic and germline variants present in the studied samples. Variant annotation in known databases, interpretation, and statistical analyses followed to discern the clinical relevance of called variants.

  Study EGAS50000000539

• 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

• The molecular landscape of colorectal cancer reveals genetic mutations.

  We performed whole-exome sequencing of tumor samples and adjacent normal mucosae from 46 patients to characterize the genetic alterations in China.

  Study EGAS00001001893

• The molecular landscape of colorectal cancer （17 cases）

  We performed whole-exome sequencing of tumor samples and adjacent normal mucosae from 17 cases to characterize the genetic alterations in china.

  Study EGAS00001002174

• The molecular landscape of colorectal cancer （5 cases）

  We performed whole-exome sequencing of tumor samples and adjacent normal mucosae from 5 patients to characterize the genetic alterations in china.

  Study EGAS00001002374

• GATCI whole exome germline variants

  Exome sequences were aligned to the GRCH38 reference genome. Aligned sequence was analyzed with GATK Haplotype Caller to generate germline variant calls. Variant calls are in VCF format. Details for the call can be found in the VCF header

  Dataset EGAD00001005916

• GATCI whole exome somatic variants (MuTect)

  Exome sequences were aligned to the GRCH38 reference genome. Aligned sequence was analyzed with GATK/MuTect, to generate somatic variant calls. Somatic variant calls are in VCF format. Details for the mutect call can be found in the vcf header.

  Dataset EGAD00001005917

• GATCI whole exome somatic variants (SomaticSniper)

  Exome sequences were aligned to the GRCH38 reference genome. Aligned sequence was analyzed with GATK/SomaticSniper, to generate somatic variant calls. Somatic variant calls are in VCF format. Details for the mutect call can be found in the vcf header.

  Dataset EGAD00001005918

• UNC Tumor Donation Program Set 2021

  The goal of this study is to study gene expression patterns in primary, metastatic tumors, and normal tissues.

  Study phs002429

• DAC for lymphoma IFZ Essen

  This DAC is set in place to handle acess to data on lymphomas and immune cells submitted by scientists from the Institute of Cell Biology (Cancer Research) at the University of Duisburg-Essen in Essen, Germany.

  Dac EGAC50000000521

• Myeloproliferative_Neoplasms__MPN__Exome_Validation_Study

  Experiments using targeted pulldown methods will be sequenced to validate findings in the exomes of patients with Myeloproliferative Neoplasms (MPN).

  Study EGAS00001000404

• Initial WGS of plasma cell neoplasms in fire fighters exposed to the WTC attack

  Initial WGS of plasma cell neoplasms in fire fighters exposed to the WTC attack

  Dataset EGAD00001006896

• Project for Development of Innovative Research on Cancer Therapeutics; Identifiying the predictive factors for response to chemoherapy in ovarian cancer

  To identify novel predictive biomarkers of response to chemotherapy for clear cell carcinoma of the ovary

  Study JGAS000076

• Dynamic human admixture histories over the past ~1,300 years at the northern Himalayan frontier

  Archaeological and paleogenomic evidence from the Tibetan Plateau and high-altitude Central Himalayas suggest biocultural connections with each other and with lowland East, Central, and South Asia. However, genetic histories at the northern frontier of the Indian Himalayas, which is geographically more proximal to Central and lowland South Asia, remain underexplored. We analyzed genome-wide data from 7 ancient (~2300 to 100 years old) and 10 present-day individuals from the northern Indian Himalayas and one ~3370-year-old individual from the Central Himalayas in Nepal. Ancient and present-day individuals from the northern Himalayas predominantly have Tibetan-related genetic ancestry, likely the source of high-altitude adaptive variants in these individuals, with substantial Steppe-related genetic ancestry that is observed in all individuals dating between ~1300 years and present day. In addition, some present-day individuals have lowland South Asian admixture. Our analyses reveal a dynamic interplay between genetic admixture and continuity in the northern Himalayas.

  Study EGAS50000001342

• NHLBI TOPMed: Genome-Wide Association Study of Adiposity in Samoans

  The individuals sequenced here represent a small subset of the parent study (described below) and were carefully selected for the purpose of creating a Samoan-specific reference panel for imputation back into the parent study. The INFOSTIP algorithm of Gusev et. al. (2012) (PMID: 22135348) was used to optimally choose the individuals for sequencing. The research goal of the parent study (dbGaP ID phs000914) is to identify genetic variation that increases susceptibility to obesity and cardiometabolic phenotypes among adult Samoans using genome-wide association (GWAS) methods. DNA from peripheral blood and phenotypic information were collected from 3,119 adult Samoans, 23 to 70 years of age. The participants reside throughout the independent nation of Samoa, which is experiencing economic development and the nutrition transition. Genotyping was performed with the Affymetrix Genome-Wide Human SNP 6.0 Array using a panel of approximately 900,000 SNPs. Anthropometric, fasting blood biomarkers and detailed dietary, physical activity, health and socio-demographic variables were collected. We are replicating the GWAS findings in an independent sample of 2,500 Samoans from earlier studies. After replication of genomic regions and informative SNPs in those regions, we will determine sequences of the important genes, and determine the specific genetic variants in the sequenced genes that are associated with adiposity and related cardiometabolic conditions. We will also identify gene by environment interactions, focusing on dietary intake patterns and nutrients.

  Study phs000972

• Whole exome sequencing in patients with ALS and concomitant FTD lacking the C9orf72 repeat expansion

  Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a clinical, pathological and genetic continuum. The purpose of the present study was to assess the mutation burden that is present in ALS and/or FTD known disease-causing genes in 54 patients (16 with available postmortem neuropathological diagnosis) with concurrent ALS and FTD (ALS/FTD) not-carrying the C9orf72 hexanucleotide repeat expansion, the most important genetic cause in both diseases.

  Study EGAS00001002439

• Whole-exome sequencing performed on a patient with chronic myelomonocytic leukemia and B cell acute lymphoblastic leukemia

  We studied the rare case of a patient who underwent transformation of myelodysplastic syndrome to chronic myelomonocytic leukemia and B cell acute lymphoblastic leukemia. We used fluorescence-activated cell sorting and whole-exome sequencing to identify driver mutations in the various clones. This allowed us to propose a model of branching clonal evolution with a possible germline predisposition to cancer.

  Study EGAS00001005117

• DNA methylomes of monozygotic twins clinically discordant for multiple sclerosis

  Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Although genetic susceptibility is important, a modest concordance rate for MS in monozygotic (MZ) twins suggests that interaction with other risk factors is required to develop clinical symptoms. In this study, we examined whether DNA methylation differences contribute to the discordant clinical manifestation of MS in MZ twins, and studied the impact of MS treatments on the DNA methylome. Genome-wide DNA methylation profiles of peripheral blood mononuclear cells (PBMCs) of 45 MZ twins clinically discordant for MS were generated using the Illumina HumanMethylationEPIC array. Repetitive element methylation and selected differentially methylated positions (DMPs) were validated using targeted deep bisulfite sequencing (TDBS). In addition, we performed whole genome bisulfite sequencing (WGBS) to profile CD4+ memory T-cells of a subset of four MS discordant MZ twins. Our results show that interferon treatment causes robust DNA methylation changes and several epigenetic biomarkers for interferon treatment response were identified. However, overall the PBMC-based methylomes of the MS discordant MZ twins were highly similar, since large systematic methylation differences (>5%) were absent in the data. This suggests that previously reported large methylation changes are probably caused by genetic rather than epigenetic differences. In addition, our data does not support the hypothesis that the observed maternal parent-of-origin effect in MS is due to genomic imprinting errors, and no evidence was found that copy number variations explain the discordant phenotype in these MZ twins. Although not genome-wide significant, a couple of DMPs associated with the MS phenotype were identified and successfully technically replicated using TDBS, including a differentially methylated region (DMR) in the promoter of the transmembrane protein encoding gene TMEM232. Another MS-associated DMP, located in an enhancer in the gene body of the transcription factor ZBTB16, was also associated with medium-term glucocorticoid treatment history. WGBS analysis confirmed this DMP as a promising epigenetic biomarker for glucocorticoid treatment. In conclusion, this epigenome-wide association study (EWAS) in genetically identical twins identified a DMR in the TMEM232 promoter as a candidate loci associated with the clinical manifestation of MS. In addition, epigenetic biomarkers for MS treatments were identified, revealing that not only short-term, but also medium-term treatment effects are detectable in immune cells, which should be taken into account in future EWAS designs.

  Study EGAS00001003147

• The clinical utility of genomics in childhood cancer extends beyond targetable mutations - WGS data

  We deeply sequenced 864 cancer-associated genes and the complete genomes and transcriptomes for 300 pediatric and adolescent/young adult (AYA) patients with poor prognosis or rare tumors. Using integrative somatic-germline analyses, we assessed the clinical utility of cancer genomics in this population. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants, found in 54% of patients, were of unanticipated timing and type, with over 20% of these derived from the germline. Enrichment in corroborating mutational signature 3 (‘BRCAness’) in patients with germline homologous recombination defects suggests they are drivers of pediatric cancers and potential targets for PARP inhibition. Comprehensive somatic-germline cancer genomic profiling is useful at multiple points in the care trajectory for pediatric/AYA patients, supporting its integration into early clinical management. Re-biopsy at the time of relapse should be considered, and specific attention to mutational burden is indicated. Defective DNA repair genes in the germline may represent important targetable drivers.

  Study EGAS00001006610

• Bone Microarchitecture

  Osteoporosis affects more than 28 million people in the United States and the lifetime risk for osteoporosis-related morbidity is higher than a woman's combined risk for breast cancer, endometrial cancer and ovarian cancer. Health care expenditures for osteoporotic patients in this country are currently nearly 13 billion dollars per annum and are predicted to increase markedly in the next decades due the aging of the population; therefore, it is important to understand the factors that contribute to bone strength and fracture risk. With the advent of skeletal imaging modalities such as high resolution peripheral quantitative computed tomography (HR-pQCT), it is now possible to study the genetics of more highly refined peripheral skeletal microarchitecture phenotypes. Because these refined phenotypes have not been measured in many cohort studies, this project was a collaborative effort to include almost all the existing data on HR-pQCT of the radius and tibia, and genetics from around the world. Cohorts involved in the discovery included: 1) Framingham Osteoporosis Study, 2) Mayo Clinic cohort; 3) Geneva Retirees cohort; 4) OFELY cohort from Lyon France; 5) STRAMBO cohort from Lyon France; 6) Swedish Male cohorts. Replication cohorts undergoing de novo genotyping include: 1) QUALYOR cohort from Lyon France; 2) CaMOS cohort from Canada. Other than the Framingham cohort and the Swedish male cohorts, all discovery cohorts underwent genome wide genotyping with the Affymetrix Axiom Biobank array that had common variants along with exome content based on the early findings from the Exome Sequencing Project. All genotype data from the discovery cohorts were then imputed using the Haplotype Reference Consortium reference panel. Variants for replication genotyping using the Kasp technology were selected based on novelty compared with previously identified loci using DXA phenotypes, minor allele frequency, underlying LD structure within a locus, and likelihood of a variant being functional as assessed using various algorithms for coding and non-coding variants.    

  Study phs002102

• Genomics-based personalized oncology in cancer of unknown primary (CUP, project H021)

  To perform a comprehensive genomic characterization of 70 patients suffering from cancer of unknown primary (CUP) we used whole-exome, whole-genome, transcriptome and methylome analysis. We detected a substantial mutational heterogeneity with genes most commonly affected by SNVs, indels and fusions being TP53, TTN, MUC16, ABCA13, COL6A3, KRAS, LRP1B, XIRP2 and CSMD3. The most common fusion involved FGFR2, the most common focal deletion affected CDKN2A. A molecular tumor board recommended genomics-based therapies in 56/70 (80%) patients which were applied in 20/56 (35.7%) cases. Entity predictions based on transcriptome and methylome data could be made in up to 62/70 (88.6%) cases but were conclusive in only 16/48 (33.3%) cases. Germline analysis revealed 6 (likely) pathogenic mutations in 5 patients. Recommended therapies translated into a mean PFS2/1 ratio of 3.61 (median=2.25) with a median PFS1 of 89 days (n=17) compared to a median PFS2 of 182.5 days (n=20). Our data emphasize the clinical benefit of comprehensive genetic approaches in diagnostic and therapeutic management and underline the need for innovative, mechanism-based clinical trials in this heterogeneous group of diseases.

  Study EGAS00001004786

• Application of organoid culture system of human gastrointestinal and thoracic cancer in genome medicine

  In order to establish preclinical models, we have established a kind of lung cancer tumoroids derived from a mucus-producing solid pulmonary adenocarcinoma patient. We performed whole exome sequencing and RNA sequencing to analyze genetic background of the tumoroids.

  Study JGAS000664

• Application of organoid culture system of human gastrointestinal and thoracic cancer in genome medicine

  In order to establish preclinical models, we have established a kind of lung cancer tumoroids derived from a mucus-producing solid pulmonary adenocarcinoma patient. We performed whole exome sequencing and RNA sequencing to analyze genetic background of the tumoroids.

  Study JGAS000653

• Determinants of DNA methylation patterning in human placental development and trophoblast stem cell models.

  To assess whether the DNA methylation landscape of human trophoblast stem cells resembles an in vivo cell type, we used post-bisulfite adaptor-tag sequencing to measure genome-wide DNA methylation of preimplantation human trophectoderm and sorted first trimester cytotrophoblast.

  Study EGAS50000000661

• Nucleosome footprinting in plasma cell-free DNA for diagnosis of ovarian cancer

  Fragmentation patterns of plasma cell-free DNA (cfDNA) are known to reflect nucleosome positions of cell types contributing to cfDNA. Based on cfDNA fragmentation patterns, the deviation in nucleosome footprints was quantified between diagnosed ovarian cancer patients and healthy individuals.

  Study EGAS00001005361

• COVID_19_UK_CIC_Spatial

  Understanding the immune response to SARS-CoV-2 is critical to our ability to control the coronavirus pandemic. Spatial transcriptomics will be performed on COVID-19 post-mortem tissues in collaboration with the UK - Coronavirus Immunology Consortium (UK-CIC). UK-CIC encompasses a concerted effort by the UK's world-leading immunology community to deliver a co-ordinated and agile national research programme to increase our understanding of how the immune system interacts with SARS-CoV-2. UK-CIC is led by Professor Paul Moss (University of Birmingham) and brings together 20 UK immunology centres of excellence, with support from the British Society for Immunology.

  Study EGAS00001005817

• A Prospective Multicenter Study of Exploring Genomic Correlates of Clinical Outcome in Patients with Metastatic Castration-Sensitive Prostate Cancer Receiving Enzalutamide.

  This study aims to characterize the somatic mutational landscape of metastatic castration-sensitive prostate cancer (mCSPC) in a Japanese population using whole-exome sequencing of tumor and matched germline DNA. The objective is to provide a comprehensive catalog of somatic mutations and a resource for understanding prostate cancer genomics and supporting future research.

  Study JGAS000902

• ERDERA Diagnostic Research Workstream - WES reanalysis (distributed approach)

  The ERDERA Diagnostic Research Workstream – WES reanalysis (distributed approach) aims to improve diagnostic yield by systematically reanalyzing existing whole exome sequencing (WES) data from rare disease cases. The goal is to apply updated bioinformatics pipelines, novel variant interpretation tools, and the latest reference databases to detect clinically relevant variants that may have been missed in earlier analyses. By using a distributed approach across multiple expert groups, the project fosters collaborative interpretation and knowledge sharing to enhance diagnostic outcomes for patients.

  Study EGAS50000001514

• Cancer Affected Patients - Data Access Committee

  Access to the cancer cohort is made available by completing the data access agreement for review by the data access committee and will be granted to qualified investigators for appropriate use. Individuals requesting access to the data need to comply with the terms of a Data Access Agreement (DAA) and are requested to use the data only in approved and ethical ways.

  Dac EGAC50000000037

• RNA Sequencing of AD OM cells exposed to traffic-related air pollutants

  Total RNA sequencing of olfactory mucosa (OM) cells derived from individuals diagnosed with Alzheimer's disease exposed to traffic-related ultrafine particles (UFPs) for 24-h and 72-h in submerged cultures. The UFPs used for exposures were: A0, A20 and Euro6. Exposures were compared to the corresponding blank samples.

  Study EGAS50000000448

• Case Report: Precision medicine target revealed by in-vitro modelling of relapsed, refractory ALL from a child with neurofibromatosis

  Children with neurofibromatosis have a higher risk of developing juvenile myelomonocytic leukaemia and acute myeloid leukaemia, but rarely develop B-cell acute lymphoblastic leukaemia (B-ALL). Through in-vitro modelling, a novel NF1 p.L2467 frameshift (fs) mutation identified in a relapsed/refractory Ph-like B-ALL patient with neurofibromatosis demonstrated cytokine independence and increased RAS signalling, indicative of leukaemic transformation. Furthermore, these cells were sensitive to the MEK inhibitors trametinib and mirdametinib. Bi-allelic NF1 loss of function may be a contributing factor to relapse and with sensitivity to MEK inhibitors, suggests a novel precision medicine target in the setting of neurofibromatosis patients with B-ALL.

  Study EGAS00001006187

• Reliable assessment of telomere maintenance mechanisms in neuroblastoma

  Telomere maintenance mechanisms (TMM) are a hallmark of high-risk neuroblastoma, and are conferred by activation of telomerase or alternative lengthening of telomeres (ALT). However, detection of TMM is not yet part of the clinical routine, and consensus on TMM detection, especially on ALT assessment, remains to be achieved. We here propose a workflow to reliably detect TMM in neuroblastoma. We show that unambiguous classification is feasible following a stepwise approach that determines both, activation of telomerase and ALT. The workflow proposed in this study can be used in clinical routine and provides a framework to systematically and reliably determine telomere maintenance mechanisms for risk stratification and treatment allocation of neuroblastoma patients.

  Study EGAS00001006510

• Genomic stratification and liquid biopsy in a rare adrenocortical carcinoma (ACC) case, with dual lung metastases

  Adrenocortical carcinoma is a rare malignancy with a poor prognosis and few treatment options. Molecular characterization of this cancer remains limited. We present a case of an adrenocortical carcinoma (ACC) in a 37-yr-old female, with dual lung metastases identified 1 yr following commencement of adjuvant mitotane therapy. As standard therapeutic regimens are often unsuccessful in ACC, we undertook a comprehensive genomic study into this case to identify treatment options and monitor disease progress. We performed targeted and whole-genome sequencing of germline, primary tumor, and both metastatic tumors from this patient and monitored recurrence over 2 yr using liquid biopsy for ctDNA and steroid hormone measurements. Sequencing revealed the primary and metastatic tumors were hyperhaploid, with extensive loss of heterozygosity but few structural rearrangements. Loss-of-function mutations were identified in MSH2, TP53, RB1, and PTEN, resulting in tumors with mismatch repair signatures and microsatellite instability. At the cellular level, tumors were populated by mitochondria-rich oncocytes. Longitudinal ctDNA mutation and hormone profiles were unable to detect micrometastatic disease, consistent with clinical indicators of disease remission. The molecular signatures in our ACC case suggested immunotherapy in the event of disease progression; however, the patient remains free of cancer. The extensive molecular analysis presented here could be applied to other rare and/or poorly stratified cancers, to identify novel or repurpose existing therapeutic options, thereby broadly improving diagnoses, treatments, and prognoses.

  Study EGAS00001003497

• Bioinformatic Methods and Bridging of Assay Results for Reliable Tumor Mutational Burden Assessment in Non-Small Cell Lung Cancer

  Tumor mutational burden (TMB) has emerged as a predictive biomarker of response to immune checkpoint inhibitors. Standardization of TMB measurement is essential for implementing diagnostic tools to guide treatment. Here we evaluate bioinformatic TMB analysis by whole exome sequencing (WES) in formalin-fixed, paraffin-embedded samples. In CheckMate 026, TMB was retrospectively assessed in 312 patients with non-small cell lung cancer (58% of the intent-to-treat population) who received first-line nivolumab treatment or chemotherapy. We examined the sensitivity of TMB assessment to bioinformatic filtering methods and assessed concordance between TMB data derived by WES and the FoundationOne CDx™ assay. TMB scores comprising synonymous, indel, frameshift, and nonsense mutations (all mutations) were 3.1-fold higher than data including missense mutations only, but values were highly correlated (Spearman’s r = 0.99). Scores from CheckMate 026 samples including missense mutations only were similar to those generated from data in The Cancer Genome Atlas, but those including all mutations were generally higher. Using databases for germline subtraction (instead of matched controls) showed a trend for race-dependent increases in TMB scores. Parameter variation can therefore impact TMB calculations, highlighting the need for standardization. Encouragingly, WES and FoundationOne CDx outputs were highly correlated (Spearman’s r = 0.90) and differences could be accounted for by empirical calibration, suggesting that reliable TMB assessment across assays, platforms and centers is achievable.

  Study EGAS00001003661

• Kids First: Genomic Studies of Orofacial Cleft Birth Defects

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). 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. WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. The Kids First study of nonsyndromic orofacial cleft birth defects (OFCs) is a whole genome sequencing study of 415 White parent-case trios drawn from ongoing collaborations led by Dr. Mary L. Marazita of the University of Pittsburgh Center for Craniofacial and Dental Genetics, including collaborations with Dr. George Wehby of the University of Iowa, Dr. Jacqueline Hecht of the University of Texas, and Dr. Terri Beaty of Johns Hopkins University. Sequencing was done by the Washington University McDonell Genome Institute. The case in each of the Kids First trios has cleft lip (CL, Figure A), cleft palate (CP, Figure B), or both (CL+CP, Figure C): OFCs are genetically complex structural birth defects caused by genetic factors, environmental exposures, and their interactions. OFCs are the most common craniofacial anomalies in humans, affecting approximately 1 in 700 newborns, and are one of the most common structural birth defects worldwide. On average a child with an OFC initially faces feeding difficulties, undergoes 6 surgeries, spends 30 days in hospital, receives 5 years of orthodontic treatment, and participates in ongoing speech therapy, leading to an estimated total lifetime treatment cost of about $200,000. Further, individuals born with an OFC have higher infant mortality, higher mortality rates at all other stages of life, increased incidence of mental health problems, and higher risk for other disorders (notably including breast, brain, and colon cancers). Prior genome-wide linkage and association studies have now identified at least 18 genomic regions likely to contribute to the risk for nonsyndromic OFCs. Despite this substantial progress, the functional/pathogenic variants at OFC-associated regions are mostly still unknown. Because previous OFC genomic studies (genome-wide linkage, genome-wide association studies (GWAS), and targeted sequencing) are based on relatively sparse genotyping data, they cannot distinguish between causal variants and variants in linkage disequilibrium with unobserved causal variants. Moreover, it is unknown whether the association or linkage signals are due to single common variants, haplotypes of multiple common variants, clusters of multiple rare variants, or some combination. Finally, we cannot yet attribute specific genetic risk to individual cases and case families. Therefore, the goal of the current study is to identify specific OFC risk variants in Whites by performing whole genome sequencing of parent-case trios.

  Study phs001168