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• RNA-sequencing of six Pilocytic astrocytoma tumors

  Total stranded TruSeq RNA sequencing by Illumina of six tumor samples from six cases of pediatric Pilocytic astrocytoma. The data is published in the following paper: Tomic TT, Olausson J, Wilzen A, Sabel M, Truve K, Sjogren H, Dosa S, Tisell M, Lannering B, Enlund F, Martinsson T, Aman P, Abel F. A new GTF2I-BRAF fusion mediating MAPK pathway activation in pilocytic astrocytoma. PLoS One. 2017 Apr 27;12(4):e0175638.

  Dataset EGAD00001003143

• Transcriptomic sequences of small intestinal Plasma cells from Celiac disease patients

  Transcriptomic sequences of small intestinal Plasma cell (PCs)s from Celiac disease patients. RNAseq data produced using Illumina paired-end (75bp) reads. Includes only raw data of sequences (fastq format). Samples from seven Celiac disease patients and four healthy controls. Samples from Celiac disease patients contain sub-groups of PCs that are either specific or not specific to autoantigen of the disease (TG2).

  Dataset EGAD00001004481

• Benchmarking CRISPR Whole-genome Drop-out Screen - B&S (2019-08-07)

  This study is a benchmarking exercise to explore potential source of variation between different CRISPR drop out libraries. . This dataset contains all the data available for this study on 2019-08-07.

  Dataset EGAD00001005233

• Whole transcriptome and 97 antibodies of one healthy bone marrow

  Whole transcriptome sequencing using BD Rhapsody with 97 antibodies of a healthy young adult bone marrow (Young3/BM3) mononuclear cells from iliac crest aspirations. Please note raw and integrated gene expression data, cell type annotation, metadata and dimensionality reduction are available as Seurat v3 objects through figshare. Access links is https://figshare.com/s/901bcddb9ee18e226031.

  Dataset EGAD00001008186

• Targeted sequencing of healthy blood and bone marrow

  Targeted sequencing using BD Rhapsody with 462 mRNA and 197 antibodies of healthy young adult bone marrow mononuclear cells from iliac crest aspirations. Please note raw and integrated gene expression data, cell type annotation, metadata and dimensionality reduction are available as Seurat v3 objects through figshare. Access link is https://figshare.com/s/313b5739ff469dac8c01

  Dataset EGAD00001008189

• Targeted seqencing of serrated lesions of the colorectum

  Dataset consists of Oncomine Comprehensive Cancer Panel v3 sequencing of 16 tumor-normal mucosa pairs. Tumors include 8 sessile serrated lesions (SSL), 3 sessile serrated lesions with dysplasia (SSL/D), 2 traditional serrated adenomas (TSA) and 3 tubular adenoma s(TA).

  Dataset EGAD00001008191

• The Genomic Analysis of Medulloblastoma

  Medulloblastoma is a heterogenous disease made up of at least four distinct subtypes of disease which appear to exploit and disrupt naturally occurring developmental pathways of cellular growth and hindbrain development. To better understand the driver mutations of this disease, we performed whole genome sequencing of 37 medulloblastomas and the corresponding normal DNA of the 37 affected children treated at St. Jude Children's Research Hospital. We have found several novel mutations which appear subtype specific. These mutations were checked for frequency in a separate tumor cohort of 56 children with medulloblastoma, also treated on the St. Jude Medulloblastoma 2003 trial, and were tested in several animal models of medulloblastoma for proof of oncogenic potential.

  Study phs000409

• CADD/GADD centers on Antisocial Drug Dependence

  CADD (Center for Antisocial Drug Dependence): Funded through NIDA 011015 to study genetic influences on, and treatment of, antisocial drug dependence, studying both clinical probands and their families, and community samples of matched controls, twins, and participants in an ongoing longitudinal adoption study. A collaboration between three organizations at two campuses of the University of Colorado. Longitudinal with three waves of data collection completed. GADD (Genetics of Adolescent Antisocial Drug Dependence): Funded originally through NIDA 012845, s multisite collaboration including adolescent subjects at high-risk for antisocial drug dependence and their siblings, recruited in Denver, CO and San Diego, CA. Longitudinal with two waves of data collection completed, one in progress as of May, 2018.

  Study phs001841

• Whole genome sequencing of 25 South African individuals with myasthenia gravis

  This study investigated the genetic basis of an ophthalmoplegic subphenotype of MG (OP-MG) which occurs in a proportion of myasthenics with juvenile symptom onset and African genetic ancestry. This OP-MG subphenotype is characterised by treatment resistant weakness of the extraocular muscles (EOMs) and the pathogenetic mechanism(s) underlying its development is unknown. The aim of this study was to use a hypothesis-generating genome-wide case-control analysis to identify candidate OP-MG susceptibility genes and pathways. Whole genome sequencing (WGS) was performed on 25 AChR-antibody positive myasthenic individuals of African genetic ancestry sampled from the phenotypic extremes: 15 with OP-MG (cases) and 10 individuals with control MG (EOM treatment-responsive).

  Study EGAS00001003462

• Alzheimer's Disease Sequencing Project (ADSP)

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

  Study phs000572

• Study of Osteoporotic Fractures (SOF)

  The Study of Osteoporotic Fractures (SOF) is a prospective multicenter study of risk factors for vertebral and non vertebral fractures. The cohort is comprised of 9704 community-dwelling women 65 years old or older recruited from populations-based listings in four U.S. areas: Baltimore, Maryland; Minneapolis, Minnesota; Portland, Oregon; and the Monongahela Valley, Pennsylvania. Women enrolled in the study were 99% Caucasian with African American women initially excluded from the study due to their low incidence of hip fractures. (A cohort of AA women was recruited at the 6th Visit.) The SOF participants were followed up every four months by postcard or telephone to ascertain the occurrence of falls, fractures and changes in address. To date, follow-up rates have exceeded 95% for vital status and fractures. All fractures are validated by x-ray reports or in the case of most hip fractures, a review of pre-operative radiographs. Blood samples were collected in 6795 women at their Year 2 exam (Visit 2) and with written consent for use of DNA in genetic studies. Of these, we have GWAS data on 3625 Caucasian participants. As a separate study, the SOF Osteoarthritis Project was funded separately to collect data about risk factors for osteoarthritis (OA) and analyze baseline hip and hand films for the presence and severity of OA. Raw GWAS data is housed at the study's coordinating center and not released as part of the dbGaP release. The raw data can be requested from the study's coordinating center. Only QC cleaned PLINK files are available at dbGaP. Auxiliary files are also available for duplicates and HapMap participants.

  Study phs000510

• The Breast and Prostate Cancer Cohort Consortium (BPC3) GWAS of Aggressive Prostate Cancer and ER- Breast Cancer

  The Breast and Prostate Cancer Cohort Consortium (BPC3) was established in 2003 to pool data and biospecimens from nine large prospective cohorts to conduct research on gene-environment interactions in cancer etiology. The BPC3 initially focused on the association of >70 candidate genes in the Steroid Hormone Metabolism and IGF pathways with risk of breast and prostate cancer. The Consortium's work expanded in 2007 to include genome-wide association studies of estrogen receptor negative (ER-) breast cancer and aggressive prostate cancer. ER- breast cancers have specific epidemiologic characteristics and greater lethality, suggesting ER- breast cancer has a different etiology than ER+ breast cancer. Similarly, aggressive forms of prostate cancer, characterized by extraprostatic extension (Stage C/D) or high histologic grade (Gleason score 8+), differ epidemiologically from the vastly more common indolent forms of prostate cancer and are of the greatest clinical importance. By restricting cases to these specific subtypes, the BPC3 GWAS increased power to detect loci associated with ER- and aggressive prostate cancer (Kraft P and Haiman CA, Nature Genetics 2010 Oct;42:819-20, PMID: 20877320 ). The BPC3 GWAS includes the following cohorts: the American Cancer Society Cancer Prevention Study-II (CPS-II); the European Prospective Investigation of Cancer (EPIC); the Physician's Health Study (PHS); the Nurses' Health Studies I and II (NHS and NHSII); the Health Professionals Follow-up Study (HPFS); the Multiethnic Cohort (MEC); the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial; and the Alpha-Tocopherol, Beta-Carotene (ATBC) Study. For the GWAS of ER- cancer, the BPC3 was expanded to include the Polish Breast Cancer Study (PBCS), a population-based case-control study.

  Study phs000812

• Genetic Epidemiology Network of Arteriopathy (GENOA)

  The Genetic Epidemiology Network of Arteriopathy (GENOA) is one of four networks in the NHLBI Family-Blood Pressure Program (FBPP). GENOA's long-term objective is to elucidate the genetics of target organ complications of hypertension, including both atherosclerotic and arteriolosclerotic complications involving the heart, brain, kidneys, and peripheral arteries. The longitudinal GENOA Study recruited European-American and African-American sibships with at least 2 individuals with clinically diagnosed essential hypertension before age 60 years. All other members of the sibship were invited to participate regardless of their hypertension status. Participants were diagnosed with hypertension if they had either 1) a previous clinical diagnosis of hypertension by a physician with current anti-hypertensive treatment, or 2) an average systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg based on the second and third readings at the time of their clinic visit. The Family Blood Pressure Program (FBPP), GENOA's parent program, is an unprecedented collaboration to identify genes influencing blood pressure (BP) levels, hypertension, and its target-organ damage. This program has conducted over 21,000 physical examinations, assembled a shared database of several hundred BP and hypertension-related phenotypic measurements, completed genome-wide linkage analyses for BP, hypertension, and hypertension associated risk factors and complications, and published over 130 manuscripts on program findings. The FBPP emerged from what was initially funded as four independent networks of investigators (HyperGEN, GenNet, SAPPHIRe and GENOA) competing to identify genetic determinants of hypertension in multiple ethnic groups. Realizing the greater likelihood of success through collaboration, the investigators created a single confederation with program-wide and network-specific goals.

  Study phs001238

• Epigenetics of Cocaine and Nicotine Addiction

  This project characterizes DNA methylation and gene expression changes that occur in the human brain, specifically in neurons from the rostral striatum. Major advances from NIDA funded initiatives for noninvasive neuroimaging studies have made it possible to study neuroanatomical, neurochemical and functional changes in the human brain that contribute to the vulnerability to abuse drugs, together with the neurotoxic consequences of years of drug misuse. Animal models have been developed to explain the fundamental behavioral and biological mechanisms of addiction, including reward, tolerance and dependence. From these studies, we learned that cocaine abuse not only alters the epigenetic status of genes, but also induces particular epigenetic modifications depending on the frequency of the drug's administration. Certain genes are switched on by infrequent (short-term exposure) administration, while others are switched on only after chronic administration (addiction/dependence). Animal studies have also suggested that cocaine-seeking habits modeling chronic cocaine addiction in humans depend upon dopamine-dependent serial connectivity linking the ventral (nucleus accumbens) with the dorsal striatum (caudate nucleus). The primary goal of this study is to identify DNA methylation and gene expression changes that occur in the transition from recreational cocaine use to cocaine addiction. High throughput sequencing studies were designed to investigate unique postmortem human brain specimens from individuals that met criteria for cocaine dependence, as compared to unaffected age-matched controls. Brain biospecimens were available from the University of Miami Brain Endowment BankTM, from a collection of phenotypically well-characterized postmortem tissues sampled from chronic cocaine abusers that came to autopsy. This biobank of postmortem brain specimens and annotated genomic data serve as a research resource to support NIDA's scientific mission.

  Study phs001377

• Target sequencing of 27 cancer-predisposing genes and 13 renal cell carcinoma-related genes in Japanese renal cell carcinoma patients

  Identifying causative genes via genetic testing is useful for the screening, prevention, and treatment of cancer. Several hereditary syndromes are known to occur in renal cell carcinoma (RCC). However, these evidences came from the European population; it remains unclear how the RCC-related genes and other cancer-predisposing genes contribute to the development RCC in the Japanese population. A case-control study of 14 RCC-related genes and 26 cancer-predisposing genes was performed using 1,563 Japanese patients with RCC and 6,016 controls. Patients were divided into two major histological subtypes of clear cell RCC (ccRCC) or non-clear cell RCC (nccRCC). Gene-based analysis of germline pathogenic variants in patients with each subtype and cancer-free subjects was performed. Following quality control, 1,532 patients with RCC and 5,996 controls were further analyzed. For ccRCC, 52 of 1,283 (4.05%) patients carried pathogenic variants mainly in the cancer-predisposing genes such as TP53 (P = 1.73 �� 10-4; OR, 5.8; 95% CI, 2.2���15.7). Approximately 80% of patients with pathogenic variants in TP53 had p.Ala189Val that was specific in East Asian population. For nccRCC, 14 of 249 (5.62%) patients carried pathogenic variants mainly in the RCC-related genes such as BAP1 (P = 6.27 �� 10-5; OR, Inf; 95% CI, 10.0���Inf), and FH (P = 6.27 �� 10-5; OR, Inf; 95% CI, 10.0���Inf). Our study showed different and population-specific contributions of risk genes between ccRCC and nccRCC in Japanese for better-personalized medicine.

  Study JGAS000414

• Tremelimumab +/- durvalumab in combination with paclitaxel as immune induction in metastatic urothelial cancer: clinical and translational results of the ICRA trial

  DESCRIPTION: New therapeutic strategies for therapy-refractory metastatic urothelial carcinoma (mUC) patients are still needed. In the phase I-II ICRA trial, we evaluated whether paclitaxel plus tremelimumab (T; anti-CTLA-4), with or without durvalumab (D; anti-PD-L1), could induce a tumor response in mUC patients who had already received platinum chemotherapy and immune checkpoint inhibition (ICI). After a dose-escalation safety phase, patients were randomized between three arms: A (n=20 after expansion) paclitaxel plus T750mg (cycles 2-8); B (n=12) paclitaxel plus T300mg (cycle 2) plus D1500mg (cycles 2-13); C (n=12) T750mg (cycles 1-7). The objective response rate in arm A was 26% (88% confidence interval (CI) = [14,36%]) versus 17% (88% CI = [3,42%]) in arm B and 8% (88% CI = [0.3,33%]) in arm C. Grade 3-4 treatment-related adverse events occurred in (A) 45%, (B) 75%, and (C) 25% of patients. Murine experiments showed attenuated tumor outgrowth for paclitaxel plus anti-CTLA-4 compared to monotherapy with either agent. Transcriptomic analyses showed upregulation of inflammation signatures in on-treatment tumor tissue biopsies. This study demonstrated encouraging antitumor activity in therapy-refractory mUC treated with paclitaxel plus high-dose anti-CTLA-4 and suggests immune induction may still be possible after failure to anti-PD-(L)1 therapy. PROJECT GOAL: We aimed to explore both potential biomarkers for response to combination ICB, as well as treatment dynamics to gain a better understanding of the effects of ICB on the urothelial cancer tumor microenvironment (TME).

  Study EGAS50000001574

• Cerebrospinal fluid cfDNA sequencing for classification of central nervous system glioma

  Primary central nervous system (CNS) gliomas can be classified by characteristic genetic alterations. In addition to solid tissue obtained by surgery or biopsy, cell-free DNA (cfDNA) derived from cerebrospinal fluid (CSF) is an alternative source of material for genomic analyses. Experimental design: We performed targeted next-generation sequencing (NGS) of CSF cfDNA in a representative cohort of 85 patients presenting with with suspicion of primary or recurrent glioma at two neurooncological centers. Copy-number variation (CNV) profiles, single nucleotide variants (SNVs), and small insertions/ deletions (indels) were combined into a molecular-guided tumor classification. Comparison with the solid tumor was performed for 38 cases with matching solid tissue available. Results: Cases were stratified into four groups: glioblastoma (n = 32), other glioma (n = 19), non-malignant (n = 17) and no confirmed diagnosis available (n = 17). We introduce a molecular-guided tumor classification, enabling identification of tumor entities and/ or cancer specific alterations in 75.0 % (n = 24) of glioblastoma and 52.6 % (n = 10) of other glioma cases. The overlap between CSF and matching solid tissue was highest for CNVs (26-48 %) and SNVs at pre-defined gene loci (44 %), followed by SNVs/indels identified via uninformed variant calling (8-14 %). A molecular-guided tumor classification was made 23.5 % (n = 4) of cases with no confirmed diagnosis available. Conclusions: We developed a workflow for targeted sequencing of CSF cfDNA as well as a strategy for interpretation and reporting of sequencing results based on a molecular-guided tumor classification in glioma.

  Study EGAS50000000060

• Exome sequencing of uterine leiomyosarcomas

  Uterine leiomyosarcomas (ULMSs) are aggressive smooth muscle tumors associated with poor clinical outcome. Despite previous cytogenetic and molecular studies, their molecular background has remained elusive. To examine somatic variation in ULMS, we performed exome sequencing on 19 tumors. Altogether 43 genes were mutated in at least two ULMSs. Most frequently mutated genes included tumor protein P53 (TP53; 6/19; 33%), alpha thalassemia/mental retardation syndrome X-linked (ATRX; 5/19; 26%), and mediator complex subunit 12 (MED12; 4/19; 21%). Unlike ATRX mutations, both TP53 and MED12 alterations have repeatedly been associated with ULMSs. All the observed ATRX alterations were either nonsense or frameshift mutations. ATRX protein levels were reliably analyzed by immunohistochemistry in altogether 44 ULMSs, and the majority of tumors (23/44; 52%) showed clearly reduced expression. Loss of ATRX expression has been associated with alternative lengthening of telomeres (ALT), and thus the telomere length was analyzed with telomere-specific fluorescence in situ hybridization. The ALT phenotype was confirmed in all ULMSs showing diminished ATRX expression. Exome data also revealed one nonsense mutation in death-domain associated protein (DAXX), another gene previously associated with ALT, and the tumor showed ALT positivity. Aberrant expression of both TP53 and ATRX were associated with poor overall survival. In conclusion, exome sequencing revealed that TP53, ATRX, and MED12 are frequently mutated in ULMSs. ALT phenotype was commonly seen in tumors, indicating that ATR inhibitors, which were recently suggested as possible new drugs for ATRX-deficient tumors, could provide a potential novel therapeutic option for ULMS.

  Study EGAS00001001612

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

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

  Study EGAS00001002207

• Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes

  Aberrant DNA repair processes are a hallmark of human tumours. How these deficiencies variously impact the genomes of ovarian cancer between and within histotypes remains unknown. We studied the whole genome pointmutation and structural variation patterns of 133 tumours (59 high grade serous (HGSC), 35 clear cell (CCOC), 29 endometrioid (ENOC), and 10 adult granulosa cell tumours (GCT)) as a substrate for class discovery in ovarian cancer. Ab-initio clustering of integrated point mutation and structural variation signatures revealed seven novel subgroups, comprising between and within histotype stratification. Prevalence of fold-back inversions (FBI) co-localised with high level amplification events divided HGSC into two prognostically significant subgroups. This finding was recapitulated in two additional independent cohorts (total n=576 cases), and transcended gene based mutation status and gene expression as prognostically relevant features of HGSC. CCOC were divided into one group harbouring a signature reflective of active genome editing via APOBEC enzymes (26%) and a complementary group with an age-relatedmutational signature. ENOC were divided intomicrosatellite instable (MSI) cases (28%) with a distinctmismatch repairmutation signature and an outlying mutation rate, with the remainder of cases distributed amongst the remaining six groups. We suggest the FBI, MSI, and APOBEC groups represent biologic strata that could direct treatment strategies. Taken together, our work establishes the efficacy of the somatic genome as a biomarker to stratify ovarian cancers, simultaneously identifying patients that may benefit from emerging therapeutics and distinct subgroups within classic ovarian cancer histotypes.

  Study EGAS00001002390

• PD-L1 blockade in combination with carboplatin as immune induction in metastatic lobular breast cancer: the GELATO-trial

  Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype but published data on trials specific for ILC are so far lacking. Translational research revealed that a subset of ILCs may be immune-related and more sensitive to DNA-damaging agents such as platinum. In murine ILC models, synergy between immune checkpoint blockade and platinum has been observed. Here, we tested this concept in the phase II, GELATO-trial (NCT03147040), in which patients with metastatic ILC were treated with weekly carboplatin (AUC 1.5) as immune induction treatment for 12 weeks and atezolizumab (PD-L1 blockade; every three weeks) from the third week onwards until disease progression. Four out of 23 evaluable patients had a partial response (17%, 95%CI 5-39%) and two patients had stable disease for at least 24 weeks, resulting in a clinical benefit rate of 26% (95%CI 10-48%). Out of these six patients, four patients had triple-negative ILC (TN-ILC). In serial biopsies of metastatic lesions, we observed higher CD8 T-cell infiltration, expression of immune checkpoints, and exhausted T cells upon carboplatin/PD-L1 blockade. This is the first report of a clinical trial specifically for ILC and we demonstrate promising anti-tumor activity of atezolizumab with carboplatin as immune induction, in particular for TN-ILC. While activity of carboplatin/PD-L1 blockade in classical ER+ ILC was limited, our translational data yield important insights for the design of highly needed clinical trials in ILC.

  Study EGAS00001006902

• Exome-wide mutation analysis of cell-free DNA to simultaneously monitor the full spectrum of cancer treatment outcomes

  Purpose: Cell-free DNA (cfDNA) offers a non-invasive approach to monitor cancer. Here we develop a method using whole-exome sequencing (WES) of cfDNA for simultaneously monitoring the full spectrum of cancer treatment outcomes, including MRD, recurrence, evolution, and second primary cancers. Experimental Design: Three simulation datasets were generated from 26 cancer patients to benchmark the detection performance of MRD/recurrence and second primary cancers. For further validation, cfDNA samples (n=76) from cancer patients (n=35) with six different cancer types were used for performance validation during various treatments.Results: We present a cfDNA-based cancer monitoring method, named cfTrack. Taking advantage of the broad genome coverage of WES data, cfTrack can sensitively detect MRD and cancer recurrence by integrating signals across known clonal tumor mutations of a patient. In addition, cfTrack detects tumor evolution and second primary cancers by de novo identifying emerging tumor mutations. A series of machine learning and statistical denoising techniques are applied to enhance the detection power. On the simulation data, cfTrack achieved an average AUC of 99% on the validation dataset and 100% on the independent dataset in detecting recurrence in samples with tumor fraction ≥0.05%. In addition, cfTrack yielded an average AUC of 88% in detecting second primary cancers in samples with tumor fraction ≥0.2%. On real data, cfTrack accurately monitors tumor evolution during treatment, which cannot be accomplished by previous methods.Conclusion: Our results demonstrated that cfTrack can sensitively and specifically monitor the full spectrum of cancer treatment outcomes using exome-wide mutation analysis of cfDNA.

  Study EGAS00001005906

• Prevention and Early Treatment of Acute Lung Injury (PETAL) Acetaminophen in Sepsis: Targeted Therapy to Enhance Recovery (ASTER) (PETAL ASTER-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL ASTER include plasma, urine and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis participants compared with placebo.Background: Acetaminophen (paracetamol) has many effects that can be beneficial in sepsis treatment, including analgesia, antipyresis, cyclooxygenase-2 inhibition, as well as a potent and specific hemoprotein reduction that can block hemoglobin-induced oxidation of lipids and other substrates. The majority of sepsis participants experience elevated circulating cell-free hemoglobin levels, which is associated with development of organ dysfunction including acute respiratory distress syndrome (ARDS) and death.Acetaminophen has been found in observational studies to be associated with improved survival in critically ill sepsis participants with elevated plasma cell-free hemoglobin, and small clinical trials have had positive sepsis participant outcomes such as reduced plasma biomarkers of lipid peroxidation and improved kidney function. However, a large, randomized trial of acetaminophen administration for treatment of fever in participants with suspected infection did not show a mortality benefit. The NHLBI PETAL Network initiated ASTER as a larger phase trial to examine the utility of plasma cell-free hemoglobin level as a biomarker for future sepsis trials and whether acetaminophen would increase the number of days alive and free of organ support for participants with sepsis and respiratory or circulatory organ dysfunction. Participants: A total of 447 participants were enrolled and randomized, 227 to the acetaminophen arm and 220 to the placebo arm. Data from 40 participants who were randomized to the Vitamin C arm, which was stopped early (see Design section below), is also included.Design: ASTER was a phase 2b multicenter, randomized, double-blind trial. The study originally had a 3-arm platform trial in which participants were randomized 1:1:1 to treatment with intravenous acetaminophen, vitamin C, or a common placebo. The vitamin C arm of the trial was stopped after enrolling 79 participants due to external clinical trial data for vitamin C.Participants randomized to the acetaminophen arm received acetaminophen at the dose of 1 g in 100 mL diluent (or 15 mg/kg if actual body weight was Conclusions: Intravenous acetaminophen was considered to be safe but did not significantly improve days alive and free of organ support in critically ill sepsis participants. There was no significant interaction between cell-free hemoglobin levels and acetaminophen.

  Study phs003900

• A Phase I Study of the Treatment of Recurrent Malignant Glioma with CAN-3110 (AKA rQNestin34.5v.2), a Genetically Engineered HSV-1 Virus

  This study is a "first-in-human" phase 1 trial of recurrent, IDH wild-type glioblastoma (rGBM) patients treated with CAN-3110 (aka rQNestin34.5v.2), a genetically modified oncolytic herpes simplex virus 1 (HSV-1). The study was a 3+3 dose-escalation study starting at a single intra-tumoral injection of 106 PFU CAN-3110 going up to 1010 PFU in half-log increments (cohorts 1-9). An expansion cohort (cohort 10) was treated with 109 PFU injected into up to 5 sites within a single tumor. Principal findings of the study conclude that:CAN-3110 was safe at all tested doses (no dose-limiting toxicities reached)HSV-1 seropositive patients survived significantly longer than HSV-1 seronegative patients in this study - longer than expected based on historical rGBM controlsHSV-1 seropositive patients were significantly more likely to clear CAN-3110 (HSV-1) antigen from their tumors based on immunohistochemical stainingCAN-3110 treatment-induced CD8+/CD4+ T-cell recruitment to injected tumor sites altered TCR beta diversity in both tumor infiltrating leukocytes (TILs) and PBMCs, and initiated changes in specific TCR beta clonotypes and immune gene signatures which were associated with post-treatment survival.Data provided in dbGaP for this study include:Bulk RNA-Seq data for 13 pre/post-treatment pairs of rGBM tumors corresponding to 12 unique patients (patient 28 was treated with CAN-3110 at two different timepoints). This data is provided as raw sequencing reads (.fastq), kallisto pseudoalignment transcript-level read counts (abundance.tsv files), gene-level abundance matrix (Gene_Level_Expression_Matrix.tsv), and immune gene signature scores matrix (Immune_Gene_Signatures_Matrix.tsv). Sequencing was performed as paired 150bp sequencing on NovaSeq6000 S4 Illumina flow cells. Library preparation varied by batch as described in the included RNAseq_Metadata.xlsx table.TCR beta DNA sequencing performed by Adaptive Biotechnologies for 21 pre/post-treatment pairs of rGBM tumors and PBMCs representing 20 unique patients (patient 28 was treated with CAN-3110 at two different timepoints). Note that all tumor pairs with TCR beta sequencing data also have available bulk RNA-Seq data. The TCR beta sequencing data is provided as an excel spreadsheet (TCRbeta_Sample_Overview.xslx), which provides a broad level summary of the sequencing on a per-sample basis (# of TCRbeta templates, T cell fraction, TCR beta diversity metrics, etc.) and as a large tab separated value file (Full_TCRbeta_Rearrangement_Details.tsv), which provides information per sample at the level of each unique TCR beta sequence (amino/nucleic acid sequence, VDJ gene usage, etc.).An excel table of de-identified metadata for the patients involved in this study.

  Study phs003378

• Providing safe access to sensitive human data across borders: Federated EGA becomes a reality

  Enabling discovery and access to sensitive data across national boundaries is vital for improving human health. It enables more powerful and efficient research by increasing the volume and diversity of data available for analysis. It allows us to better understand the causes of diseases – cancer, rare diseases, infectious diseases like COVID-19 – and develop new medicines and treatments. Sensitive human omics data are typically generated by research initiatives and shared using specialist repositories which provide services for data submission, discovery, and access. The EGA is one such repository. Established in 2008 at EMBL’s European Bioinformatics Institute (EMBL-EBI) in the UK, since 2012 the EGA (“Central EGA”) has been jointly managed by EMBL-EBI and the Centre for Genomic Regulation (CRG) in Spain. Many countries have emerging personalised medicine programmes which generate data from national initiatives. These programmes are driving a transition in human genomics from being research-driven to receiving funding through healthcare. Data generated in a clinical context are subject to stricter governance than research data and must follow national data protection legislation. To solve these challenges, the Federated EGA provides a network of connected resources to enable transnational discovery of and access to human omics data for research, while also respecting jurisdictional data protection regulations. In this way, the Federated EGA infrastructure supports the goals of European initiatives such as the 1+ Million Genomes initiative (1+MG), the European Health Data Space, and a number of EU-funded 1+MG implementation projects including Beyond 1 Million Genomes. The Federated EGA is made up of “Nodes” – typically nationally funded and operated – which store and manage data locally while allowing global discovery within the Federated EGA network. Since 2016, multiple parallel efforts, supported by ELIXIR and other transnational and national initiatives, have created technical and legal frameworks for establishing the Federated EGA. In 2022, the first five Nodes – Finland, Germany, Norway, Spain, and Sweden – officially joined the Federated EGA by signing Federated EGA Collaboration Agreements with Central EGA. The Finnish FEGA Node is operated by CSC - IT Center for Science and provides data management services according to national laws and the requirements of the EU General Data Protection Regulation (GDPR). These services provide tools and support for the whole life-cycle of sensitive research data from collating to analysis, publication, and authorised re-use. The development of the services has been a joint effort with the other Nordic nodes within NeIC's Tryggve and Heilsa projects, and funded by Finnish Ministry of Education and Culture and projects coordinated by ELIXIR Finland. Read more about Finnish FEGA signing. The German Human Genome-Phenome Archive (GHGA) strives to provide a national infrastructure as well as an ethical and legal framework that balances FAIR omics data usage and data protection needs for Germany. As a Germany-wide consortium funded by the German Research Foundation under the umbrella of the NFDI association, GHGA combines the expertise of 21 universities and research institutions to form a federated national infrastructure. Read more about GHGA signing. The German Human Genome-Phenome Archive (GHGA) strives to provide a national infrastructure as well as an ethical and legal framework that balances FAIR omics data usage and data protection needs for Germany. As a Germany-wide consortium funded by the German Research Foundation under the umbrella of the NFDI association, GHGA combines the expertise of 21 universities and research institutions to form a federated national infrastructure. Read more about GHGA signing. In Norway, a key component of the infrastructure is the services of The Sensitive Data Service (TSD) offered by USIT at University of Oslo. The Federated EGA Norway Node is developed by ELIXIR Norway and operated by the University of Oslo as the responsible legal entity. Core software modules are developed jointly with the other Nordic nodes in the NeIC Tryggve and Heilsa projects. Read more about FEGA Norway signing. The Spanish FEGA (es-FEGA) is a national service for storing sensitive biomedical data in Spain. Supported by the Spanish Institute of Bioinformatics (INB) in collaboration with Central EGA, sensitive research datasets are primarily hosted at the Barcelona Supercomputing Centre facilities. The Swedish Sensitive Data Archive is a secure data archive and sharing platform for sensitive datasets. It was developed by the National Bioinformatics Infrastructure Sweden (NBIS) in collaboration with other Nordic ELIXIR Nodes through the Tryggve and Heilsa projects funded by NeIC and coordinated with Central EGA through ELIXIR. Read more about the Swedish Node signing. The Swedish Sensitive Data Archive is a secure data archive and sharing platform for sensitive datasets. It was developed by the National Bioinformatics Infrastructure Sweden (NBIS) in collaboration with other Nordic ELIXIR Nodes through the Tryggve and Heilsa projects funded by NeIC and coordinated with Central EGA through ELIXIR. Read more about the Swedish Node signing. By providing a solution for secure and efficient management of human omics data, the Federated EGA aims to foster data reuse, enable reproducibility, accelerate biomedical research, and improve human health. Find out more Interested in setting up your own Federated EGA Node? Check out the FEGA Onboarding Knowledge Base for more information. The ELIXIR Federated Human Data Community is a great entry point for anyone interested in learning more about the Federated EGA. You can: Join the ELIXIR Federated Human Data Community mailing list (select “Human Data”) Attend the ELIXIR Federated Human Data Community calls

  Blog safe-access-to-sensitive-human-data-federated-ega

• imputed_bacterial_meningitis

  This study includes 1146 samples of host genotyping data (imputed) from Illumina Omni arrays, using https://imputation.sanger.ac.uk/ with the Haplotype Reference Consortium v1.1. Samples were collected from adults (>16 yrs) patients with CSF confirmed bacterial meningitis in the Netherlands between 2006 and 2015. Metadata includes patient outcome, species of bacteria, and for 467 samples a link to an ENA run with the associated bacterial genome (S. pneumoniae only).

  Dataset EGAD00010002327

• WGS and RNA-seq data of PC9 erlotinib-resistant and sensitive cell lines

  This dataset contains whole genome sequencing (WGS) and RNA sequencing (RNA-seq) FASTQ files from two PC9 NSCLC cell lines: erlotinib-resistant (PC9-ER-R) and erlotinib-sensitive parental (PC9-ER-S). A total of 4 paired-end FASTQ file pairs were generated using Illumina NovaSeq 6000, comprising 2 WGS and 2 RNA-seq libraries. Data were generated to investigate RAF1 ecDNA-mediated acquired erlotinib resistance mechanisms.

  Dataset EGAD50000002658

• Barcelona kids with melanoma

  This set of samples is composed of eight young people (7-16 years old) that have developed melanoma with first-degree relatives that have also developed cancer, which suggests a genetic component to their disease. Here we want to sequence these samples in order to find the causative mutations. As these samples do not carry any of the high-penetrance mutations known to date, finding the genes(s) responsible will offer new insights into the genetic mechanisms underlying predisposition to melanoma.

  Dataset EGAD00001002198

• NIDDK IBD Genetics Consortium Repository Exome Chip

  The Illumina Infinium HumanExome+ BeadChip contains putative functional exonic variants selected from individual exome and whole-genome sequences from diverse populations. It includes nonsynonymous variants, splice variants and stop-altering variants. It also includes tags for previous GWAS-identified loci, ancestry informative markers, markers designed for identity by descent analyses, synonymous variants, fingerprint SNPs common to major genotyping platforms, mitochondrial SNPs, chromosome Y SNPs, and HLA tag SNPs. For more information as well as a detailed description of the variant calling and QC procedures, see Li et al. (2016). Li, D., et al. (2016) A pleiotropic missense variant in SLC39A8 is associated with Crohn's disease and human gut microbiome composition. Gastroenterology, 151, 1-9. PMID: 27492617.

  Study phs001723

• Exome sequencing of autosomal recessive progressive external ophthalmoplegia (arPEO)

  Progressive external ophthalmoplegia (PEO) is an inherited mitochondrial disease that follows either autosomal dominant or recessive forms of inheritance (adPEO or arPEO). AdPEO is a genetically heterogeneous disease and several genes including POLG1 and C10orf2/Twinkle have been identified as responsible genes. On the other hand, POLG1 was the only established gene causing arPEO with mitochondrial DNA deletions. We previously reported a case of PEO with unidentified genetic etiology. The patient was born of a first-cousin marriage. Therefore, the recessive form of inheritance was suspected. To identify the disease causing variant in this patient, we subjected the patient's DNA to whole-exome sequencing and narrowed down the candidate variants using public data and runs of homozygosity analysis.

  Study phs000392

• Prostate Cancer and Normal Adjacent Prostate RNA-seq samples, NGS-ProToCol

  The dataset "Prostate Cancer and Normal Adjacent Prostate RNA-seq samples, NGS-ProToCol" includes 41 Normal Adjacent Prostate and 51 ribo-depleted Prostate Cancer RNA-seq samples. ---- Detection of fusion transcripts and their genomic breakpoints from RNA sequencing data Youri Hoogstrate, Malgorzata A. Komor, René Böttcher, Job van Riet, Harmen J. G. van de Werken, Stef van Lieshout, Ralf Hoffmann, Evert van den Broek, Anne S. Bolijn, Natasja Dits, Daoud Sie, David van der Meer, Floor Pepers, Chris H. Bangma, Geert J. L. H. van Leenders, Marcel Smid, Pim French, John W.M. Martens, Wilbert van Workum, Peter J. van der Spek, Bart Janssen, Eric Caldenhoven, Christian Rausch, Mark de Jong, Andrew P. Stubbs, Gerrit A. Meijer, Remond J.A. Fijneman, Guido Jenster

  Study EGAS00001002816

• DPY30_ChIP_seq

  H9 human embryonic stem cells (hESCs) were cultured in feeder-free chemically-defined conditions in medium containing 10ng/ml Activin A and 12ng/ml FGF2 (Vallier L. 2011, Methods in Molecular Biology, 690: 57–66). Chromatin immunoprecipitation was performed as described in Brown S. et al. 2011. Stem Cells 29: 1176–85 by using 5ug of anti-DPY30 antibody (Sigma, cat. number HPA043761). This protocol was performed in control hESCs (expressing a scrambled shRNA) and in hESCs stably expressing an shRNA against DPY30 (Sigma, clone n. TRCN0000131112).This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001001132

• Cell motility and migration as determinants of stem cell efficacy

  Limited stem cell migration capacities and undirected homing hamper their therapeutic efficacy. We report here the novel technology to isolate stem cell subpopulations with high migration potential. Hereby, we identified podoplanin-dependent stem cell mobility as important mechanism for their in vivo homing capacities and therapeutic efficacy as validated in preclinical models of Alzheimer´s disease and mouse glioma. In vivo applications of highly migrating stem cells resulted in remarkable improvement of targeted homing and engraftment rates. Moreover, animals receiving highly migrating stem cells showed higher recovery rates compared to unselected stem cells. This novel technology provides useful tool to improve therapeutic efficacy of stem cells and give insights into stem cell subpopulations heterogeneity with the potential of general applicability for cellular therapies.

  Study EGAS00001002478

• TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism

  DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism/Seckel syndrome. We establish that TRAIP relocalizes to sites of DNA damage where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to UV irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a novel component of the DNA damage response to replication-blocking DNA lesions.

  Study EGAS00001001501

• PCa-LINES

  PCa-LINES: Ribo-minus RNA-seq of 4 patient samples and 2 PCa cell lines ---- Detection of fusion transcripts and their genomic breakpoints from RNA sequencing data Youri Hoogstrate, Malgorzata A. Komor, René Böttcher, Job van Riet, Harmen J. G. van de Werken, Stef van Lieshout, Ralf Hoffmann, Evert van den Broek, Anne S. Bolijn, Natasja Dits, Daoud Sie, David van der Meer, Floor Pepers, Chris H. Bangma, Geert J. L. H. van Leenders, Marcel Smid, Pim French, John W.M. Martens, Wilbert van Workum, Peter J. van der Spek, Bart Janssen, Eric Caldenhoven, Christian Rausch, Mark de Jong, Andrew P. Stubbs, Gerrit A. Meijer, Remond J.A. Fijneman, Guido Jenster bioRxiv 2021.05.17.441778; doi: https://doi.org/10.1101/2021.05.17.441778 https://www.biorxiv.org/content/10.1101/2021.05.17.441778v1

  Study EGAS00001004613

• Determination of Cross-Reactive Immunological Material (CRIM) status and longitudinal follow-up of individuals with Pompe disease

  Infantile-onset Pompe disease is an inherited disorder that is normally diagnosed within the first months of life. It is caused by lack of or defect in an enzyme (a special protein that carries out normal chemical reactions within the body) called acid alpha-glucosidase (GAA). GAA normally breaks down glycogen (stored sugar) in lysosomes (the part of the cell that digests food and other chemicals). Pompe disease is one of many lysosomal storage diseases (LSDs). LSDs are diseases caused by the malfunction of the lysosome or one of their digestive enzymes. Patients with Pompe disease cannot break down lysosomal glycogen. This causes glycogen to build up and damage cells throughout the body, especially in the heart and muscles. Current treatment for Pompe disease involves enzyme replacement therapy (ERT). In this treatment, the drug alglucosidase alfa (Myozyme) is put into your blood. The drug provides a form of the GAA enzyme to replace the enzyme that is missing or not working properly in the patient's blood. This treatment has allowed babies to live longer and achieve developmental milestones. In this study, researchers will learn about the patient's ability to tolerate ERT. Cross-Reactive Immunological Material (CRIM) is a measurement of natural GAA production. A patient's CRIM status (either positive or negative) is an important factor that affects how he or she responds to ERT with Myozyme. Children who produce some natural GAA are classified as CRIM+, while children who do not produce any natural GAA are classified as CRIM-. Children who are CRIM+ generally tolerate ERT well. But, children who are CRIM-, and some children classified as CRIM+, have a poor response to ERT. Patients who have a poor response to ERT have complications because their body sees Myozyme as "foreign" and triggers an immune response to try to remove it from the body. Treatments are currently being developed to stop this immune response and prevent complications from ERT. We will enroll patients with Infantile Pompe disease in this longitudinal natural history (observational) study. The specific aims of this study are: To determine and correlate Cross-Reactive Immunological Material (CRIM) status with the GAA gene mutations found on these patients To validate an approach for determining CRIM status from whole blood sample, with the gold standard determination of CRIM status by skin fibroblasts and mutation analysis To explore the clinical treatment response and natural history of CRIM-positive and CRIM-negative Pompe disease patients with and without immune modulation To investigate the role of immune response to treatment

  Study phs001555

• Shedding light over COVID-19 susceptibility and severity

  “One of the most remarkable features of SARS-CoV-2 infection is the variation in consequence ranging from asymptomatic to life-threatening” state the authors of the majestic Nature paper released in accelerated pre-view on July 2021. This variation in consequences represent not only an issue of burning medical relevance, but also a scientific and intellectual challenge for scientists around the globe. Researchers are known to be easily triggered by a challenge, and they recently demonstrated to be even better at double their efforts to focus on an urgent societal need. In this work led and coordinated by the COVID-19 Host Genetics Initiative (COVID-19 HGI), researchers gathered data from 49,562 cases and two million controls from 46 studies performed worldwide. The majority of the data has been deposited at the EGA, where 29 datasets have been collected under the study number EGAS00001005304. Data gathered from diverse sources conferred a huge robustness to the results. Genetic data from different ancestry origin were included in the analyses, even though data from patients with European origin was highly predominant (approx. 75%). Separated analysis of the different ancestries gave rise to relevant differences in the results, highlighting how important it is to take this aspect in consideration for future studies. Data from the individual studies was compiled into three categories according to COVID-19 severity for a meta-analysis: (a) critically ill cases (b) moderate or severe cases (c) all cases. They were paired with non-COVID-19-reported controls. All three analysis resulted in a total of 13 genetic loci associated with COVID-19 severity. Out of those, 9 loci associated specifically with critical illness, while 6 (a few overlapped) associated with moderated illness. Some genomic position matched previous findings. Interestingly, working with such an enormous amount of data allowed the depth to discriminate association with disease susceptibility vs severity, an issue of large medical relevance. Several loci mapped into biological relevant genes, like TYK2, PPP1R15A and FOXP4, previously implicated in immune response and/or lung functions. Researchers participating in the COVID-19 Host Genetics Initiative have worked in an unprecedented time-tight collaboration, prioritizing data sharing and collective results to tackle the pandemic affecting the world. The scientific community won’t miss any of the lessons to learn from this, and the EGA is ready to keep working to enable safe data sharing and fruitful collaborations.

  Blog covid-19-susceptibility-and-severity

• Characterization of mutational signatures in human cancer cell lines reveals episodic APOBEC mutagenesis

  Multiple signatures of somatic mutations have been identified in human cancer genomes. To investigate whether mutational signatures continue to be generated, and if so their temporal patterns of activity, subsets of cell lines were cultured in vitro for extended periods and subjected to single cell cloning and whole genome or exome sequencing or directly to single cell whole genome sequencing. As expected, signatures of past exogenous exposures, such as tobacco smoke and ultraviolet light, were not generated in vitro. In contrast, signatures of normal and defective DNA repair and replication continued to be generated at essentially constant mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing activity exhibited a distinctive pattern with substantial fluctuations in mutation rate over time and episodic bursts of mutations. The initiating factors for these bursts are unclear although retrotransposon mobilisation may play a role. This cell line set now constitutes a comprehensive resource of live experimental models of mutational processes of both known and unknown aetiologies potentially retaining the patterns of activity and regulatory influences operative in human cells in vivo.

  Dataset EGAD00001004202

• Mult-omics Palbociclib Resistance Study in HR+/HER2– Metastatic Breast Cancer

  This study is multi-omics study of a Asian longitudinal metastatic breast cancer (MBC) cohort treated with palbociclib plus endocrine therapy. It contains NGS of baseline (BL) and progressive disease (PD) from 70 patients, consisting of 79 tumor/normal matched whole exome sequencing (WES) from 62 patients and 90 tumor whole transcriptome sequecing samples (WTS) from 70 patients. There were 56 BL biopsies profiled by WES and 64 by WTS; 23 PD biopsies were profiled by WES and 26 by WTS. Twenty and 23 patients had paired BL and PD biopsies profiled by WES and WTS, respectively.

  Dataset EGAD00001008314

• MassArray1-80

  234 samples genotyped at 40 loci using the MassArrayiPLEX genotyping assay using the iPLEX Gold genotyping kit (Agena Biosciences, cat. 10148-2) Gabriel et al. (2009) [Gabriel, S. , Ziaugra, L. and Tabbaa, D. (2009), SNP Genotyping Using the Sequenom MassARRAY iPLEX Platform. Current Protocols in Human Genetics, 60: 2.12.1-2.12.18. doi:10.1002/0471142905.hg0212s60]). Products were detected on a MassArray mass spectrophotometer and data were acquired in real time with MassArray RT software 4.0.0.2 (Agena Biosciences). SNP clustering and validation was carried out with Typer 4.0.26.75 software (Agena Biosciences).

  Dataset EGAD00010001906

• ETMR_Nanostring

  Total RNA (100ng) from 21 ETMRs with C19MC structural alterations and 28 other PBTs was prepared with nCounter miRNA Sample Prep Kit according to standard protocol. miRNA expression profiling was conducted with human v1, v2, or v3 miRNA panel on nCounter miRNA expression platform (NanoString Technologies, Seattle, WA) according to manufacturer’s protocol. Signal normalization was done using nSolver Analysis and batch corrected using ComBat (Johnson et al. Biostatistics. 2007). 565 miRNAs overlapped between all three versions and was used for further analyses. Fold change and supervised t-test with FDR correction was calculated between the ETMRs and other PBTs.

  Dataset EGAD00010001701

• The Longevity Genes Project

  Aging is a complex, universal condition leading to the functional decline of all cells and organisms, and to major national and global public health problems. Although aging is the major risk factor for developing most adult-onset diseases, systematic investigations into the fundamental physiology, biology and genetics of aging are only just beginning. In the Longevity Genes Project at Albert Einstein College of Medicine, Dr. Nir Barzilai and his team conducted genetic research on more than 500 healthy elderly people between the ages of 95 and 112, and on their children. The identification of longevity genes by Einstein researchers could lead to new drug therapies that might help people live longer, healthier lives and avoid or significantly delay age-related diseases such as Alzheimer's disease, type 2 diabetes and cardiovascular disease.

  Study phs000584

• NIDDK⁄CIDR Inflammatory Bowel Disease Genetics Consortium (IBDGC) Genome Wide Association Study in Familial Crohn's Disease

  The National Institute of Diabetes and Digestive and Kidney Diseases Inflammatory Bowel Disease Genetics Consortium (NIDDK - IBDGC) conducted a genome wide association study (GWAS) using the Human Omni2.5-Quad beadchip from Illumina to identify disease variants associated with familial Crohn's disease. This study includes a subset of individuals from an original cohort of affected subjects and affected/unaffected relatives from a previous linkage scan which showed increased linkage evidence at three novel risk loci. A total of 708 samples were selected based on various criteria for inclusion from the 6 Genetic Research Centers (GRC) in North America that participate in the IBDGC. This project was supported by an ancillary R01 grant from the NIDDK with resources made available through the IBDGC.

  Study phs000367

• Health Professionals Follow-Up Study

  Health Professionals Follow-up Study (HPFS) is a prospective cohort study of men designed to evaluate hypotheses about men’s health related to diet and lifestyle to the incidence of serious illnesses, such as cancer, heart disease, and other vascular diseases. It consisted of 51,529 U.S. male health professionals who were 40-75 years old at baseline in 1986 and completed a mailed six-page baseline questionnaire. Information on age, height and weight, ancestry, medications, disease history, physical activity, lifestyle factors, and diet were gathered, with follow-up questionnaires sent biennially to update information and record health outcomes with every four years to update their diet. This datafile includes responses to the 2016 questionnaire, which is available at: https://cdn1.sph.harvard.edu/wp-content/uploads/sites/2471/2017/09/16L.pdf

  Study phs002460

• International Genetics of Parkinson Disease Progression (IGPP) Consortium: EPIPARK and HBS2 Cohorts

  EPIPARK and HBS2 cohorts were analyzed as part of the International Genetics of Parkinson Disease Progression (IGPP) Consortium. EPIPARK is a population-based cohort to study non-motor symptoms in parkinsonism in the city of Lübeck, Germany led by Drs. Meike Kasten and Christine Klein. HBS2 is a recently enrolled subset of participants in the Harvard Biomarkers Study led by Dr. Clemens Scherzer (www.bwhparkinsoncenter.org/biobank) of 89 participants with a diagnosis of Parkinson Disease (PD). Genotyping with Illumina Infinium Multi-Ethnic Genotyping Arrays (MEGA chip) was performed by Dr. Scherzer, Harvard Medical School and Brigham and Women’s Hospital. 179 participants with a diagnosis of PD from EPIPARK and 89 participants with a diagnosis of PD from HBS2 met Q/C criteria were analyzed.

  Study phs002328

• Single cell multi-omics analysis of chromothriptic medulloblastoma highlights genomic and transcriptomic consequences of genome instability

  Chromothripsis is a form of genome instability, whereby a presumably single catastrophic event generates extensive genomic rearrangements of one or few chromosome(s). However, little is known about the heterogeneity of chromothripsis across different clones from the same tumor, as well as changes in response to treatment. We analyzed single-cell genomic and transcriptomic alterations linked with chromothripsis in human p53-deficient medulloblastoma (n=7). We reconstructed the order of somatic events, identified early alterations likely linked to chromothripsis and depicted the contribution of chromothripsis to malignancy. We characterized subclonal variation of chromothripsis and its effects on double-minute chromosomes, cancer drivers and putatively druggable targets. Furthermore, we highlighted the causative role and the fitness consequences of specific rearrangements in neural progenitors.

  Study EGAS00001005410

• Low mutation burden and frequent loss of CDKN2A/B and SMARCA2, but not PRC2, define pre-malignant neurofibromatosis type 1-associated atypical neurofibromas

  Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder caused by germline mutations in NF1. NF1 patients have an 8-16% lifetime risk of developing a malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft-tissue sarcoma, often arising from pre-existing benign plexiform neurofibromas (PN) and atypical neurofibromas (ANF). ANF are distinct from both PN and MPNST, representing an intermediate step in malignant transformation. In the first comprehensive genomic analysis of ANF, we performed tumor/normal exome sequencing (ES) of 16 ANFs. In addition, we conducted ES of three MPNSTs, copy-number meta-analysis of 26 ANF and 28 MPNST, and whole transcriptome RNA-seq analysis of five ANF and five MPNST. We identified low mutation burden (median 1, range 0-5) in the exomes of ANF (only NF1 somatic mutations were recurrent), and frequent deletions of CDKN2A/CDKN2B (69%) and SMARCA2(42%) loci. We determined that polycomb repressor complex 2 (PRC2) genes EED or SUZ12 were frequently mutated, deleted or downregulated in MPNST but not in ANF. Our gene expression study revealed upregulated NRAS, MDM2, CCND1/CCND2/CCND3 and CDK4/CDK6 in both ANF and MPNST, and overexpression of EZH2 in MPNST only. We conclude that the PN-ANF transition is primarily driven by the deletion of CDKN2A/CDKN2B in addition to already present inactivated NF1. Further progression from ANF to MPNST likely involves broad chromosomal rearrangements and frequent inactivation of the PRC2 genes, loss of the DNA repair genes, and copy-number increase of signal transduction, cell cycle and pluripotency self-renewal genes.

  Study phs001993

• Study of Controlled Human Malaria Infections to Evaluate Protection After Intravenous or Intramuscular Administration of PfSPZ Vaccine in Malaria-Naive Adults

  The study was performed to evaluate whole-blood transcriptomic profiles via RNA-seq before, during, and after immunization with the PfSPZ Vaccine in malaria-naïve, health adults enrolled in VRC 314 (NCT02015091). VRC 314 was designed as an open-label evaluation of the safety, tolerability, immunogenicity, and protective efficacy of the PfSPZ Vaccine. This study was designed to substantiate the initial results with the IV vaccination route for protection against CHMI that was observed in VRC 312 (NCT01441167). Based on the potential importance of dose and schedule in optimizing sustained immunity with this vaccine, an increase in PfSPZ IV dosage on schedules of 3 to 5 vaccinations was evaluated for protection against CHMI conducted early (about 3 weeks) and late (about 24 weeks) after completion of vaccinations. To assess if a higher dose given by another route confers protection, one group received PfSPZ IM, with half of the amount administered in each arm on a schedule with 4 vaccination. The primary objectives of the study were related to the safety and tolerability of vaccinations by the IV and IM routes of administration and protection against Plasmodium falciparum (Pf) challenge performed via a well-established CHMI procedure early (2-4 weeks) after completing schedules of 3 to 5 vaccinations. The secondary objective was related to the durability of protection at 20-26 weeks after the last vaccination, and exploratory objectives were related to the immunogenicity of the PfSPZ Vaccine and identifying potential immune correlates of protection. To further determine potential molecular correlates of immunogenicity and/or protection, RNA-seq was performed on whole blood collected from subjects in all dose groups at time points before, during, and after immunization.

  Study phs002423

• Genetic Aberrations and Subclonal Structure Impact Chronic Lymphocytic Leukemia

  Large-scale whole-exome sequencing (WES) of primary tumor samples enables the unbiased discovery of recurrent putative driver events and patterns of clonal evolution. We report the identification of 44 recurrently mutated genes and 11 recurrent CNVs through the WES of 538 chronic lymphocytic leukemia (CLL) and matched germline DNAs. These include previously unrecognized cancer drivers (e.g., RPS15, IKZF3), and collectively identify nuclear export, MYC activity and MAPK signaling as central pathways affected by somatic mutation in CLL. A clonality analysis of this large dataset further enabled the reconstruction of temporal relationships between these driver events. Several drivers were associated with shorter progression-free survival (PFS) in 280 samples that were collected prior to uniform treatment with front line chemo-immunotherapy, with mature follow up of greater than 10 years. Direct comparison between matched pretreatment and relapse CLL from 59 samples demonstrated marked clonal evolution occurring in more than 95% of these patients. Distinct patterns of clonal evolution in relationship to specific gene alteration were observed, suggesting a hierarchy of fitness amongst mutations. Thus, large WES datasets of clinically informative samples enable the discovery of novel driver genes as well as the network of relationships between the drivers and their impact on disease relapse and clinical outcome.Additionally, we performed RNA-seq for 268 CLL samples (including 26 follow-up samples) and used them to identify expression subtypes of CLL. RRBS for 30 of these samples was also generated. In an integrative analysis of genetic, transcriptomic, and epigenetic data, incorporating known and newly identified subtypes of CLL, we built new models to improve patient prognostication.

  Study phs000922

• Genomic platform specific polygenic risk scores impact breast cancer risk stratification

  Background: At present, there is no consensus on which genotyping platform should serve as the standard for clinical polygenic risk score (PRS) implementation. Previous studies have compared the overall performance and concordance of different genotyping and sequencing technologies; however, these analyses have generally averaged the results over the whole genome. We evaluated differences in a 313-variant breast cancer PRS (PRS313) across genomic platforms and their impact on risk stratification. Methods: We compare PRS313 derived from genotyping arrays (Global Screening Array [GSA], OncoArray-500K [OncoArray], Global Diversity Array [GDA], custom Axiom_PrecipV1 array [ThermoFisher]) and low-coverage genome sequencing (lc-WGS) in 2 cell lines and 92 individuals. Probes are designed for all variants on ThermoFisher (success rate: 259/313). Sanger sequencing profiles indels. Concordance of high-risk classification (PRS313scoresum > 0.6) across platforms is assessed using Kappa statistics. Results: In saliva samples, indel concordance with Sanger sequencing varies widely (Kappa: 0.007-1.000). PRS313-ThermoFisher is predictable from other platforms using linear models, despite systematic differences. Greater agreement is observed between arrays with high imputation overlap (e.g., GDA ~ GSA slope=0.986). Agreement in high-risk classification before mean correction is moderate (Fleiss's Kappa=0.552) and improves after mean correction (Kappa=0.650). Arrays with similar designs show higher agreement before mean correction (Kappa=0.745). Mean correction narrows high-risk proportions from 4-45% to 15-21%. Overall, 26 of 92 samples are classified as high risk on at least one platform, but only 7 are high risk across all. When restricting to identical variants across all platforms for PRS313 calculation, the corresponding number of high-risk individuals are 24 and 11. Conclusion: Our findings demonstrate that platform-specific variability can influence PRS313 estimates to potentially reclassify individuals around clinically relevant thresholds.

  Study EGAS00001008439

• Recurrent somatic DICER1 mutations in non-epithelial ovarian tumors

  Background: Germline truncating mutations in DICER1, an RNase III-type endoribonuclease essential for processing of microRNAs, are seen in families with the pleuropulmonary blastoma-family tumor and dysplasia syndrome; these individuals have a propensity to develop non-epithelial ovarian tumors (i.e. sex-cord stromal and germ cell tumors). Methods: We sequenced the whole transcriptomes or exomes of 14 non-epithelial ovarian tumors and noted closely clustered mutations in the RNase IIIb domain of DICER1 in four cases. Using Sanger sequencing, we then analyzed additional ovarian tumors for mutations in this region. The impact of the mutations on the enzymatic activity of Dicer1 was determined using in vitro RNA cleavage assays. Results: RNase IIIb domain DICER1 mutations were found in 30/102 non-epithelial ovarian tumors (29%), predominantly Sertoli-Leydig cell tumors (26/43, 60%), including 4/4 from individuals with germline DICER1 mutations. The mutations were restricted to metal binding sites within the RNase IIIb catalytic centres critical for miRNA interaction and cleavage, and were somatic in all 14 cases where germline DNA was available for testing. Of 266 epithelial ovarian and endometrial cancers tested, one case, an ovarian carcinosarcoma, had a hotspot mutation. In vitro, the mutant DICER proteins showed reduced RNase IIIb activity but retained RNase IIIa activity. Conclusions: Somatic missense mutations of the RNase IIIb domain of DICER1 are common in non-epithelial ovarian tumors. Genetic, pathologic, and functional evidence suggest that these mutations do not obliterate DICER1 function, rather, they alter it in specific cell types, a novel mechanism through which perturbed microRNA expression is oncogenic.

  Study EGAS00001000135

• Genetic characterization of B-cell prolymphocytic leukemia: a hierarchical prognostic model involving MYC and TP53 abnormalities - WXS

  B-PLL is a rare disease, whose molecular pathology is largely unknown. We report here the cytogenetic and molecular findings in a large series of 34 B-PLL. Karyotype (K) was complex (≥3 abnormalities) in 73%, and highly complex (HCK≥5) in 45%. The most frequent chromosomal aberrations were: translocation targeting the MYC gene [t(MYC)] (62%), 17p deletion including TP53 gene (38%), trisomy 18/18q (30%), 13q14 deletion (29%), trisomy 3 (24%), trisomy 12 (24%) and 8p deletion (23%). Whole-Exome Sequencing performed in 16 patients revealed recurrent mutations in TP53 (6/16, 38%), MYD88 (n=4), BCOR (n=4), MYC (n=3), SF3B1 (n=3), FAT1 (n=3), SETD2 (n=2), CHD2 (n=2), CXCR4 (n=2) and BCLAF1 (n=2). The main group of patients (21/34, 62%) had a t(MYC) associated with a higher percentage of prolymphocytes (p=0.03), CD38 expression (p<0.001), lower K complexity (p=0.0004), mutations in MYC and in genes involved in RNA metabolism and chromatin remodeling. Principal component analysis of gene expression data showed that patients with t(MYC) clustered together. A second group with MYC gain (5/34, 15%), was associated with HCK≥5 (p=0,01) and trisomy 3 (p=0,008). Altogether, 26/34 patients (76%) had a MYC activation, translocation or gain, that were mutually exclusive. We identified 3 distinct cytogenetic prognostic groups (p=0.0006): lower risk: absence of MYC activation (median not reached); intermediate risk: MYC activation without del17p (125 months); high risk: MYC activation + del17p (11 months). Our results show that cytogenetic analysis is a useful diagnostic tool in B-PLL that improves prognostic stratification.

  Study EGAS00001003275

• PCGP Ph-like ALL

  Background: BCR-ABL1-like, or Ph-like acute lymphoblastic leukemia is characterized by a gene expression profile similar to BCR-ABL1 positive ALL, genetic alterations of lymphoid transcription factor genes, and poor outcome. Sequencing of small numbers of Ph-like ALL cases has identified genetic alterations activating kinase signaling suggesting Ph-like ALL may be amenable to treatment with tyrosine kinase inhibitors. However, the spectrum of genetic alterations in childhood and adult Ph-like ALL is incompletely understood. Methods: We performed genomic profiling of 1736 B-ALL cases and next-generation sequencing for 160 Ph-like cases. We examined the functional effects of chimeric fusion proteins in mouse cell lines. Results: The frequency of Ph-like ALL rose from 11% in children to 26% in young adults, and was associated with very poor outcome. Kinase-activating alterations were identified in 90% of Ph-like cases, most commonly fusions involving 10 kinase or cytokine receptor genes (ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B and TYK2), and mutations involving FLT3, IL7R and SH2B3. Expression of ABL1, ABL2, CSF1R and JAK2 fusions resulted in cytokine-independent proliferation of cell lines and activation of pSTAT5. Cells expressing ABL1, ABL2, CSF1R and PDGFRB fusions were sensitive to dasatinib, and JAK2 fusions to ruxolitinib. Conclusions: Ph-like ALL is characterized by a diverse range of genomic alterations that converge on a limited number of kinase signaling pathways amenable to inhibition with currently available tyrosine kinase inhibitors. Trials identifying Ph-like ALL and testing the efficacy of tyrosine kinase inhibitor therapy are warranted

  Study EGAS00001000654

• Genetic characterization of B-cell prolymphocytic leukemia: a hierarchical prognostic model involving MYC and TP53 abnormalities - RNA-seq

  B-cell prolymphocytic leukemia (B-PLL) is a rare disease, whose molecular pathology is largely unknown. We report here the cytogenetic and molecular findings in a large series of 34 B-PLL. Karyotype (K) was complex (≥3 abnormalities) in 73%, and highly complex (HCK≥5) in 45%. The most frequent chromosomal aberrations were: translocation targeting the MYC gene [t(MYC)] (62%), 17p deletion including TP53 gene (38%), trisomy 18/18q (30%), 13q14 deletion (29%), trisomy 3 (24%), trisomy 12 (24%) and 8p deletion (23%). Whole-Exome Sequencing performed in 16 patients revealed recurrent mutations in TP53 (6/16, 38%), MYD88 (n=4), BCOR (n=4), MYC (n=3), SF3B1 (n=3), FAT1 (n=3), SETD2 (n=2), CHD2 (n=2), CXCR4 (n=2) and BCLAF1 (n=2). The main group of patients (21/34, 62%) had a t(MYC) associated with a higher percentage of prolymphocytes (p=0.03), CD38 expression (p<0.001), lower K complexity (p=0.0004), mutations in MYC and in genes involved in RNA metabolism and chromatin remodeling. Principal component analysis of gene expression data showed that patients with t(MYC) clustered together. A second group with MYC gain (5/34, 15%), was associated with HCK≥5 (p=0,01) and trisomy 3 (p=0,008). Altogether, 26/34 patients (76%) had a MYC activation, translocation or gain, that were mutually exclusive. We identified 3 distinct cytogenetic prognostic groups (p=0.0006): lower risk: absence of MYC activation (median not reached); intermediate risk: MYC activation without del17p (125 months); high risk: MYC activation + del17p (11 months). Our results show that cytogenetic analysis is a useful diagnostic tool in B-PLL that improves prognostic stratification.

  Study EGAS00001003274

• National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) Consortium Glaucoma Genome-Wide Association Study: Whole Exome Resequencing in Glaucoma

  This is a study of primary open angle glaucoma (POAG) conducted through exome sequencing of cases and comparison of variant frequencies with general population frequencies available in dbGAP and controlled for sequencing platform artifact to minimize false positives. POAG is an intraocular pressure (IOP) related progressive optic neuropathy that ultimately leads to blindness. This study builds upon the efforts of an on-going collaborative consortium that studied 2,170 POAG cases and 2,347 controls with a unified definition of POAG (the NEIGHBOR consortium: NEI Glaucoma Human genetic collaBORation). The case definition for NEIGHBOR was harmonized with an additional 976 cases and 1140 controls from the NHGRI supported GENEVA (gene-environment) study of glaucoma (GLAUGEN) (NIH/NHGRI U01HG004728, Pasquale PI). In NEIGHBOR, cases and controls were recruited from ophthalmology clinics and were examined by ophthalmologists. For cases, the clinical exam included intraocular pressure measurements, optic nerve assessment and visual field evaluation. Controls had no family history of glaucoma, normal intraocular pressure and normal optic nerves. Cases and controls were also drawn from two clinical trial populations: Advanced Glaucoma Intervention Study (AGIS, NEI U10EY006827, D. Gaasterland PI) and Collaborative Initial Glaucoma Treatment Study (CIGTS, NEI U10 EY009149, P. Lichter PI). The Glaucoma Exome Sequencing study has one Principal Investigator: Theresa Gaasterland (UCSD) and two Co-Investigators: Robert Weinreb, MD, and Kang Zhang, MD, PhD, all of whom are part of the NEIGHBOR, subsequently NEIGHBORHOOD, consortium, which in turn has two Co-Principal Investigators: J. Wiggs (Harvard, MEEI), and M. Hauser (Duke). NEIGHBOR collaborators who contributed samples and/or expertise to the Glaucoma Exome Sequencing study included the following: Harvard Medical School (Massachusetts Eye and Ear Infirmary) (J. Wiggs, L. Pasquale); Duke University Medical Center (M. Hauser, E. Hauser, R. Allingham, S. Schmidt); University of Michigan (J. Richards, S. Moroi, P. Lichter); University of Miami (M. Pericak-Vance, R. Lee, D. Budenz); Vanderbilt University (J. Haines); University of California San Diego (K. Zhang, R. Weinreb; T. Gaasterland); University of Pittsburgh (J. Schuman, G. Wollenstein); University of West Virginia (A. Realini, J. Charlton, S. Zareparsi); Johns Hopkins University (D. Friedman); Stanford University (D. Vollrath, K. Singh), Eye Doctors of Washington (D. Gaasterland), Marshfield Clinic (Cathy McCarty). Hemin Chin serves as the NEI Staff Collaborator. This national collaborative study is supported by multiple NIH grants: NEI R01 EY015543 (Allingham); NEI U10 EY006827 (D. Gaasterland); NHLBI R01 HL073389 (E. Hauser); NEI R01 EY13315 (M. Hauser); NEI U10 EY009149 (Lichter); NEI R01 EY015473 (Pasquale); NEI U10 EY012118 (Pericak-Vance); NEI R03 EY015682 (Realini); NEI R01 EY011671 (Richards); NEI R01 EY09580 (Richards); NEI R01 EY013178 (Schuman); NEI R01 EY015872 (Wiggs); NEI R01 EY009847 (Wiggs); NEI R01 EY010886 (Wiggs); NEI R01 EY144428 (Zhang); NEI R01 EY144448 (Zhang); NEI R01 EY18660 (Zhang). Funding support for genotyping through exome sequencing, which was performed at the University of California, San Diego, was provided by the National Eye Institute (RC2 EY020678-01).

  Study phs000558

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

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

  Study phs000264

• Shanghai Breast Cancer Genetics Study (SBCGS)

  The Shanghai Breast Cancer Genetics Study (SBCGS) includes data from four population-based studies conducted among Chinese women in urban Shanghai: the Shanghai Breast Cancer Study (SBCS), the Shanghai Breast Cancer Survival Study (SBCSS), the Shanghai Women's Health Study (SWHS), and the Shanghai Endometrial Cancer Study (SECS, contributing controls only). Shanghai Breast Cancer Study (SBCS): The SBCS is a population-based, case-control study conducted in urban Shanghai. Subject recruitment in the initial phase of the SBCS (SBCS-I) was conducted between August 1996 and March 1998. The second phase (SBCS-II) of recruitment occurred between April 2002 and February 2005. Breast cancer cases were identified through the population-based Shanghai Cancer Registry and supplemented by a rapid case-ascertainment system. Controls were randomly selected using the Shanghai Resident Registry. Approximately 3500 cases and 3500 controls were recruited in the study. Shanghai Breast Cancer Survival Study (SBCSS) and Shanghai Endometrial Cancer Study (SECS): The SBCSS also used the population-based Shanghai Cancer Registry to identify newly diagnosed breast cancer cases. A total of 5,046 breast cancer patients were recruited. In-person interviews were conducted to collect information on known breast cancer risk factors and anthropometrics by using protocols and questionnaires similar to those used in the SBCS. For genetic studies, controls for the SBCSS cases came from the SECS, which recruited healthy women between January 1997 and December 2003. With the exception of a few questions related specifically to breast or endometrial cancer risk, the questionnaires used in the SECS and the SBCS were very similar. Shanghai Women's Health Study (SWHS): The SWHS is a population-based prospective cohort study of approximately 75,000 adult women who were recruited between 1997 and 2000. The cohort has been followed by a combination of record linkage and active follow-ups. Breast cancer patients identified in the SWHS and non-cases were included in the current study.

  Study phs001088

• Elucidating Transcription Regulation by Epigenetics in Neuroblastoma

  PURPOSE Whole-genome profiles of the epigenetic modification 5-hydroxymethylcytosine (5-hmC) are robust diagnostic biomarkers in adult patients with cancer. We investigated if 5-hmC profiles would serve as novel prognostic markers in neuroblastoma, a clinically heterogeneous pediatric cancer. Because this DNA modification facilitates active gene expression, we hypothesized that 5-hmC profiles would identify transcriptomic networks driving the clinical behavior of neuroblastoma. PATIENTS AND METHODS Nano-hmC-Seal sequencing was performed on DNA from Discovery (n = 51), Validation (n = 38), and Children's Oncology Group (n = 20) cohorts of neuroblastoma tumors. RNA was isolated from 48 tumors for RNA sequencing. Genes with differential 5-hmC or expression between clusters were identified using DESeq2. A 5-hmC model predicting outcome in high-risk patients was established using linear discriminant analysis. RESULTS Comparison of low- versus high-risk tumors in the Discovery cohort revealed 577 genes with differential 5-hmC. Hierarchical clustering of tumors from the Discovery and Validation cohorts using these genes identified two main clusters highly associated with established prognostic markers, clinical risk group, and outcome. Genes with increased 5-hmC and expression in the favorable cluster were enriched for pathways of neuronal differentiation and KRAS activation, whereas genes involved in inflammation and the PRC2 complex were identified in the unfavorable cluster. The linear discriminant analysis model trained on high-risk Discovery cohort tumors was prognostic of outcome when applied to high-risk tumors from the Validation and Children's Oncology Group cohorts (hazard ratio, 3.8). CONCLUSION 5-hmC profiles may be optimal DNA-based biomarkers in neuroblastoma. Analysis of transcriptional networks regulated by these epigenomic modifications may lead to a deeper understanding of drivers of neuroblastoma phenotype. "Reprinted from Applebaum et. JCO Precision Oncology, 2019, with permission from creative commons license."

  Study phs001831

• Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) - Genome-Wide Association Study Meta-Analysis

  Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) was one of five projects funded in 2010 as part of the NCI's Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative (http://epi.grants.cancer.gov/gameon/). GAME-ON's overall goal was to foster an intra-disciplinary and collaborative approach to the translation of promising research leads deriving from the initial wave of cancer GWAS. Specific goals included replication of previous GWAS findings and identification of new susceptibility loci through meta analyses of existing GWAS data and fine mapping of identified loci to better pinpoint causal variants; and identify germline variants that are associated with risk of multiple cancers. The other four funded GAME-ON projects were: the ColoRectal TransdisciplinaryStudy (CORECT), Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE), Follow-up of Ovarian Cancer Genetic Association and Interaction Study (FOCI), and Transdisciplinary Research in Cancer of the Lung (TRICL). To identify additional cancer risk loci, improve the precision of fine-mapping, and facilitate cross-cancer analyses, DRIVE investigators performed a meta-analysis of eleven genome-wide association studies of breast cancer: The Australian Breast Cancer Family Study (ABCFS), the British Breast Cancer Study (BBCS), the Breast and Prostate Cancer Cohort Consortium (BPC3), the Breast Cancer Family Registries (BCFR), the Dutch Familial Bilateral Breast Cancer Study (DFBBCS), German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), the Helsinki breast cancer family Study (HEBCS), the Mammary Carcinoma Risk factor Investigation (MARIE), the Singapore and Sweden Breast Cancer Study (SASBAC), the Triple Negative Breast Cancer Study (TNBC), and the UK2 GWAS. These studies comprised a total of 16,062 cases and 46,157 controls. Imputation to the 1,000 Genomes Project Phase 1 v3 ALL reference panel was performed by study, and summary statistics from each study were combined using fixed-effect meta analysis.

  Study phs001263

• Shanghai Breast Cancer Genetics Study (SBCGS)

  The Shanghai Breast Cancer Genetics Study (SBCGS) includes data from four population-based studies conducted among Chinese women in urban Shanghai: the Shanghai Breast Cancer Study (SBCS), the Shanghai Breast Cancer Survival Study (SBCSS), the Shanghai Women's Health Study (SWHS), and the Shanghai Endometrial Cancer Study (SECS, contributing controls only). Shanghai Breast Cancer Study (SBCS): The SBCS is a population-based, case-control study conducted in urban Shanghai. Subject recruitment in the initial phase of the SBCS (SBCS-I) was conducted between August 1996 and March 1998. The second phase (SBCS-II) of recruitment occurred between April 2002 and February 2005. Breast cancer cases were identified through the population-based Shanghai Cancer Registry and supplemented by a rapid case-ascertainment system. Controls were randomly selected using the Shanghai Resident Registry. Approximately 3500 cases and 3500 controls were recruited in the study. Shanghai Breast Cancer Survival Study (SBCSS) and Shanghai Endometrial Cancer Study (SECS): The SBCSS also used the population-based Shanghai Cancer Registry to identify newly diagnosed breast cancer cases. A total of 5,046 breast cancer patients were recruited. In-person interviews were conducted to collect information on known breast cancer risk factors and anthropometrics by using a protocol and questionnaire similar to those used in the SBCS. For genetic studies, controls for the SBCSS cases came from the SECS, which recruited healthy women between January 1997 and December 2003. With the exception of a few questions related specifically to breast or endometrial cancer risk, the questionnaires used in the SECS and the SBCS were very similar. Shanghai Women's Health Study (SWHS): The SWHS is a population-based prospective cohort study of approximately 75,000 adult women who were recruited between 1997 and 2000. The cohort has been followed by a combination of record linkage and active follow-ups. Breast cancer patients identified in the SWHS and non-cases were included in the current study.

  Study phs000799

• Genetic Epidemiology Network of Arteriopathy (GENOA)

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

  Study phs000379

• Characterizing the Neurobehavioral Phenotype(s) in MPS III (Pilot Study)

  Mucopolysaccharidosis III (MPSIII) syndrome is characterized by a severe cognitive decline ending in dementia and death. MPSIII is also associated with a range of abnormal and disruptive behaviors that can include, but go well beyond, childhood noncompliance and oppositionality. The purpose of this study is to conduct a cross-sectional investigation to identify the behavioral phenotype and its neural basis in MPSIII. An overall goal of this research is to develop easily administered, sensitive and specific neurobehavioral markers to characterize the behavioral phenotype(s) of MPSIII, track their progression, and to delineate their possible neural substrates. The study looks to develop develop a sensitive and specific behavioral rating of disease progression in MPS III which can be used for clinical outcome studies. The research objectives are: Develop a measure for the use of health professionals to use in tracking MPSIII phenotypes and disease progression. Test our model of MPSIII with objectively recorded behaviors in a well-defined experimental setting. Elucidate the neural bases of MPSIII by correlating behavioral profiles with changes in brain structures through quantitative neuroimaging. Determine the relationship between the loss of cognitive functions and development of behavioral abnormalities in MPSIII. This is an observational pilot study that will enroll 45 individuals with MPS III Type A or B. Those participating in the study will be evaluated during a one-day assessment and chart review.

  Study phs001330

• BAM file s of WGS data of Progressive supranuclear palsy patients

  BAM files of healthy controls (3) and Progressive supranuclear palsy (PSP) patients (4). Genomic DNA from donors was fragmented, end-polished, A-tailed, and ligated with Illumina adapters, followed by size selection. Libraries were PCR-amplified (unless PCR-free), purified with AMPure XP, assessed on the Agilent Fragment Analyzer, and quantified using Qubit and qPCR. Qualified libraries were pooled and sequenced on Illumina platforms, and low-quality reads or adapter-contaminated reads were removed. Clean data were then mapped to the hg38 reference genome using BWA.

  Dataset EGAD50000001758

• CASCADE low-pass whole genome sequencing data

  Low-pass whole genome sequencing data (median coverage: 0.37X, range: 0.07X-5.8X) from diagnostic formalin-fixed paraffin-embedded tissue and fresh frozen postmortem tissues from ten organs and postmortem blood from patients who participated in the CASCADE rapid autopsy program and died of metastatic castration resistant prostate cancer. For samples CA27_11, CA34_10, CA35_5, CA35_6, CA36_3, CA36_11, CA63_13, CA63_34, CA76_4, CA76_11, CA79_4, CA83_14 and CA83_26, we subsampled (using `samtools view -s 0.01` after mapping) from respective high coverage data from "CASCADE tumour high-coverage whole genome sequencing data" dataset.

  Dataset EGAD00001009494

• Female Infertility: Primary Ovarian Insufficiency

  Premature ovarian failure, or primary ovarian insufficiency (POI) is a phenotype of diminished or absent ovarian function occurring in 1-2% of reproductive aged women. Most cases occur spontaneously. Evaluation of the gametes in women with POI is difficult and invasive. Practitioners must often rely on indirect biomarkers of ovarian function and oocyte health, making it difficult to identify patients who may benefit from therapies allowing them to achieve pregnancy utilizing their own oocytes. This study will generate exome sequences from POI patients in an effort to elucidate the causes of unexplained POI and to better understand the normal processes of ovarian aging. A better understanding of the genetics of ovarian function may lead to new non-invasive tools for managing women's reproductive health, and direct better use of existing biomarkers in diagnosis, screening and predicting clinical outcomes.

  Study phs001174

• Massachusetts General Hospital (MGH) Atrial Fibrillation Study

  The Massachusetts General Hospital (MGH) Atrial Fibrillation Study was initiated in 2001. The study has enrolled serial probands, unaffected and affected family members with atrial fibrillation. At enrollment participants undergo a structured interview to systematically capture their past medical history, AF treatments, and family history. An electrocardiogram is performed; the results of an echocardiogram are obtained; and blood samples are obtained. The Massachusetts General Hospital (MGH) Atrial Fibrillation Study is utilized in the following dbGaP substudies. To view genotypes, analysis, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" box located on the right hand side of this top-level study page phs001001 Massachusetts General Hospital (MGH) Atrial Fibrillation Study. phs001116 MGH AF CHARGE-S phs001117 MGH AF Exome Sequencing phs001118 MGH AF Medical Resequencing

  Study phs001001

• National Heart, Lung, and Blood Institute SNP Health Association Asthma Resource Project (SHARP)

  SNP Health Association Resource (SHARe) Asthma Resource project (SHARP) is conducting a genome-wide analysis in adults and children who have participated in National Heart, Lung, and Blood Institute's clinical research trials on asthma. This includes 1041 children with asthma who participated in the Childhood Asthma Management Program (CAMP), 994 children who participated in one or five clinical trials conducted by the Childhood Asthma Research and Education (CARE) network, and 701 adults who participated in one of six clinical trials conducted by the Asthma Clinical Research Network (ACRN). There are three study types. The longitudinal clinical trials can be subsetted for population-based and/or case-control analyses. Each of the childhood asthma studies has a majority of children participating as part of a parent-child trio. The ACRN (adult) studies are probands alone. Control genotypes will be provided for case-control analyses.

  Study phs000166

• Characterization of X Chromosome Inactivation Using Integrated Analysis of Whole-Exome and mRNA Sequencing

  This study of DNA and RNA sequencing of 5 parent-offspring trios is a single center study. The goal of this study is to characterize X chromosome inactivation (XCI) ratio in females using phased genomic variations obtained through whole genome or exome sequencing in trios, followed by allele-specific expression analysis of the phased, heterozygous alleles in the mRNA of the female offspring, and to apply this method to clinical diagnosis. The distribution of allele ratios across X obtained from mRNA sequencing allows for the estimation of X inactivation status of inherited X chromosomes, and the parameters of each parental allele distributions in the offspring's mRNA data can be used as determinants for XCI ratio. This approach was used to evaluate the contribution of skewed XCI ratio to phenotypic heterogeneity in an undiagnosed, mild neurological condition.

  Study phs000816

• University of Texas at Austin (UTA) Histone Modification and Gene Expression Profiling in 9 Primary Glioblastoma Multiforme, 2 Anaplastic Astrocytomas and Two Meningiomas

  The primary goal of this study was to collect and analyze genomic data from primary glioblastoma multiforme tumors. Our collaborators at St David's Medical Center (SDMC) obtained informed consent from patients undergoing surgery to remove a tumor in the brain. After consent was obtained, specimens were removed from the operating suite and flash frozen in liquid nitrogen. Tumors were analyzed if they were a grade III (anaplastic astrocytoma) or grade IV glioma (glioblastoma multiforme). Tumors were transported from SDMC to UT Austin, then weighed and homogenized. Chromatin immunoprecipitation was performed for 7 proteins in each tumor (histone modifications H3K4me3, H3K4me1, H3K9ac, H3K9me3, H3K27ac, H3K27me3, and the multifunctional insulator binding protein CTCF) and no-antibody input was also sequenced. An aliquot of tumor material was set aside for isolation of total RNA.

  Study phs001389

• Rapid Acceleration of Diagnostics - Digital Health Technologies (RADx-DHT): Digital Health Solutions for COVID-19: COVID Community Action and Research Engagement (COVID-CARE)

  Vibrent Health will expand the Vibrent Digital Health Solutions Platform (DHSP) implementation to additional populations among diverse user groups for additional validation of the technology's performance, usability, and reliability in refinement of analytics generating predictive algorithms for infection and that support individual, organizational, community and societal-level decision-making in the COVID-19 pandemic response. This includes the aims to innovate a technology that can differentiate between COVID-19 and flu (or other respiratory illness); develop and test a novel WIFI-based contact tracing tool using a University’s enterprise WIFI system and software release of augmented contact tracing capabilities in Vibrent's DHSP; and develop a full technical integration approach and strategy to support data exchange between this solution and the NCI data hub.DOI: https://rapids.ll.mit.edu/10.57895/ravs-1b57

  Study phs002533

• Glioma International Case Control Study (GICC)

  The main goals of the GICC Study were: 1) to identify novel genetic risk variants for glioma, as well as validate variants implicated by previous genome-wide association studies of glioma; and 2) to explore biologically relevant gene-gene and gene-environment interactions in glioma susceptibility. The GICC Study includes participants from the following centers: Brigham and Women's Hospital (Boston, Massachusetts), Case Western Reserve University (Cleveland, Ohio), Columbia University (New York, New York), the Danish Cancer Society Research Centre (Copenhagen, Denmark), Duke University (Durham, North Carolina), the University of Texas MD Anderson Cancer Center (Houston, Texas), Memorial Sloan Kettering Cancer Center (New York, New York), the Mayo Clinic (Rochester, Minnesota), NorthShore HealthSystem (Chicago, Illinois), Umea University (Umea, Sweden), the University of California, San Francisco (San Francisco, California), the University of Southern California (Los Angeles, California), and the Institute of Cancer Research (London, United Kingdom).

  Study phs001319

• Admixture Mapping of Staphylococcus aureus Bacteremia

  In this study, we used admixture mapping to test the hypothesis that genomic variations with different frequencies in European and African ancestral genomes influence susceptibility to Staphylococcus aureus bacteremia (SAB) in a sample of African Americans. A total of 565 adult African Americans were genotyped for admixture mapping. Cases were unique African American adult inpatients with monomicrobial SAB (N=390) and controls are age-matched adult African American inpatients with no current or past S. aureus infection (N=175). After empirical multiplicity adjustment, one region on chromosome 6 (52 SNPs, P = 4.56e-05) in the HLA class II region was found to exhibit a genome-wide statistically significant increase in European ancestry. This region encodes genes involved in HLA-mediated immune response and these results provide additional evidence for genetic variation influencing HLA-mediated immunity, modulating susceptibility to SAB.

  Study phs001441

• The Ultrasound Study of Tamoxifen

  The Ultrasound Study of Tamoxifen is a 12-month longitudinal study to describe volumetric breast density change over time among women with and without tamoxifen exposure. Women were enrolled at the Karmanos Cancer Institute and Henry Ford Health Systems in Detroit, Michigan between 2011-2014. Enrollment included women prescribed tamoxifen for clinical indication (n=82) and a comparison group of women frequency matched on age, race, and menopausal status (n=165). Whole breast ultrasound tomography (UST) scans were used to measure volume averaged sound speed (m/s) as a surrogate of volumetric breast density. Ultrasound tomography (UST) scans were completed at baseline prior to tamoxifen initiation and were repeated at 1-3 months, 4-6 months, and 12 months after tamoxifen initiation. For the comparison group, UST scans were completed at baseline and 12 months. Questionnaires were completed at each scan.

  Study phs003183

• Genome-wide Association Study and Meta-Analysis of Ewing Sarcoma

  We combined a set of 122 French Ewing sarcoma (EWS) cases from the Institut Curie, 19 EWS cases from the National Cancer Institute (NCI) Center for Cancer Research (CCR), and 29 EWS cases from the NCI Bone Disease and Injury Study. All EWS cases were confirmed by medical record review and the presence of a specific EWSR1-ETS translocation were noted when data was available. Each participant provided informed consent and each participating study was approved by the Institutional Review Boards of their study center. DNA was extracted using standard methods from blood, saliva (Oragene), or buccal cells. All de novo genotyping of EWS cases was performed at the NCI CGR on the Illumina OmniExpress-24 v1.1 array. Genotyping was performed according to manufacturer's guidelines using the Infinium HD Assay automated protocol.

  Study phs001549

• Women's Interagency HIV Study (WIHS)

  The Women's Interagency HIV Study (WIHS), a multicenter, prospective study, was established in August 1993 to carry out comprehensive investigations of the impact of HIV infection and its clinical, laboratory, and psychosocial effects in women. The purpose of this study is to collect and evaluate these data from HIV infected and at-risk women to better understand and provide support for women whom are currently HIV infected or who are at risk for HIV infection. Participants will have study visits every 6 months. Questionnaires regarding sexual behavior, health care utilization, medical and obstetric/gynecological history, psychosocial factors, and sociodemographics will be completed by participants. Physical, gynecological, and lipodystrophy examinations will also be conducted at each visit, and current medication regimen will be noted. Blood and other bodily fluid samples will be collected and registered in both local and national repositories of the WIHS in conjunction with NIAID.

  Study phs001503

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): REasons for Geographic and Racial Differences in Stroke (REGARDS)

  Cohort DescriptionThe REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort is one of the nation's largest, most comprehensive population-based cohorts, and it uses innovative home- and telephone-based data collection. REGARDS centrally recruited and initially examined 30,239 Black and White men and women aged ≥45 years in 2003-7 to understand why Southerners and Black Americans have a higher incidence of stroke and related diseases that affect brain health.Data Being Submitted Wave 1 questionnaire data includes 397 variables for 8109 REGARDS participants in C4R. Wave 2 questionnaire data includes 448 variables for 6421 REGARDS participants in C4R. Dried Blood Spot/Serosurvey data includes 7 variables for 4058 REGARDS participants in C4R. Derived data includes 43 variables for 8606 REGARDS participants in C4R. Phenotype data includes 113 variables for 7880 REGARDS participants in C4R.

  Study phs002919

• Next Generation Sequencing to Predict Risk of Events from Coronary Artery Disease

  Coronary artery disease (CAD) and myocardial infarction (MI) remain the leading cause of death worldwide and in the US. In recent years, clinical studies that considered intermediate phenotypes (phenotypic or genomic data isolated between DNA and the main disease phenotype) have greatly enhanced our understanding of complex traits like CAD by enabling inference of biological networks from the combination of genetic and genomic datasets isolated from disease-relevant tissue(s). The NGS-PREDICT study used whole transcriptome sequence data generated from primary macrophages derived in vitro from venous blood that was obtained from CAD cases and non-CAD controls. This study provided a valuable resource for the validation of biomarkers identified in STARNET NGS data from macrophages obtained from patients with and without CAD. It also can be used as a reference dataset for the study of metabolic syndrome as well as other systemic inflammatory diseases.

  Study phs003883

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

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

  Study EGAS50000000391

• Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia

  The mutational and transcriptional landscape of P2RY8-CRLF2-positive ALL was defined in 41 major clone fusion-positive cases including 19 matched diagnosis and relapse pairs by an integrated analysis of whole-exome and RNA sequencing. We detected a variety of frequently subclonal and highly unstable JAK/STAT but also RTK/Ras pathway activating mutations in 76% of cases at diagnosis and virtually all relapses. Unlike P2RAY8-CRLF2 that was lost in 32% of relapses, all other genomic deletions affecting lymphoid development and cell cycle remained stable. Only IKZF1 alterations predominated in relapsing cases and increased from initially 36 to 58% in matched cases. IKZF1¹s transcriptional signature revealed compromised stem cell features with signs of impaired lymphoid differentiation, enhanced focal adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug resistance.

  Study EGAS00001001847

• DNA methylation and somatic mutations converge on cell cycle and define similar evolutionary histories in brain tumors

  The evolutionary history of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast to the stability of genetic events, epigenetic states are reversible and sensitive to the microenvironment, prompting the question whether epigenetics can be similarly used to discover tumor phylogeny. We examined the spatial and temporal dynamics of DNA methylation in a cohort of low-grade gliomas and their patient-matched recurrences. Genes upregulated through promoter hypomethylation during malignant progression to high-grade glioblastoma were enriched in cell cycle function, evolving in parallel with genetic alterations that deregulate the G1/S cell cycle checkpoint. Moreover, phyloepigenetic relationships robustly recapitulated phylogenetic patterns inferred from somatic mutations. These findings highlight widespread co-dependency of genetic and epigenetic events throughout brain tumor evolution.

  Study EGAS00001001255

• NHLBI TOPMed: The Jackson Heart Study (JHS)

  Since there is a greater prevalence of cardiovascular disease among African Americans, the purpose of the Jackson Heart Study (JHS) is to explore the reasons for this disparity and to uncover new approaches to reduce it. The JHS is a large, community-based, observational study whose 5306 participants were recruited from among the non-institutionalized African-American adults from urban and rural areas of the three counties (Hinds, Madison, and Rankin) that make up the Jackson, MS, metropolitan statistical area (MSA). Jackson is the capital of Mississippi, the state with the largest percentage (36.3%) of African Americans in the United States. The JHS design included participants from the Jackson ARIC study who had originally been recruited through random selection from a drivers' license registry. Approximately six months before the JHS was to begin, an amendment to the federal Driver's Privacy Protection Act was passed that changed the level of consent for public release of personal information from driver's license lists from an "opt out" to an "opt in" basis. The Mississippi Highway Patrol was no longer able to release a complete listing of all persons with driver's licenses or state identification cards, which prevented its use in the JHS. New JHS participants were chosen randomly from the Accudata America commercial listing, which provides householder name, address, zip code, phone number (if available), age group in decades, and family components. The Accudata list was deemed to provide the most complete count of households for individuals aged 55 years and older in the Jackson MSA. A structured volunteer sample was also included in which demographic cells for recruitment were designed to mirror the eligible population. Enrollment was opened to volunteers who met census-derived age, sex, and socioeconomic status (SES) eligibility criteria for the Jackson MSA. In addition, a family component was included in the JHS. The sampling frame for the family study was a participant in any one of the ARlC, random, or volunteer samples whose family size met eligibility requirements. Eligibility included having at least two full siblings and four first degree relatives (parents, siblings, children over the age of 21) who lived in the Jackson MSA and who were willing to participate in the study. No upper age limit was placed on the family sample. Known contact information was obtained during the baseline clinic examination from the index family member with a verbal pedigree format to identify name(s), age(s), address (es), and telephone number(s). Recruitment was limited to persons 35-84 years old except in the family cohort, where those 21 years old and above were eligible. Only persons who otherwise met study criteria but were deemed to be physically or mentally incompetent by trained recruiters were excluded from study eligibility.1 1 Wyatt SB, Diekelmann N, Henderson F, Andrew ME, Billingsley G, Felder SH et al. A community-driven model of research participation: the Jackson Heart Study Participant Recruitment and Retention Study. Ethn Dis 2003; 13(4):438-455 (PMID: 14632263).

  Study phs000964

• Varieties of Impulsivity in Opiate and Stimulant Users

  The study was conducted in Bulgaria as a collaboration between Virginia Commonwealth University (Richmond, VA, USA), the Bulgarian Addictions Institute (Sofia, Bulgaria), the Molecular Medicine Center/Medical University (Sofia, Bulgaria), and Indiana University (Bloomington, IN, USA). The overall aim of this study is to investigate the role of impulsivity as an endophenotype for drug addiction. Although impulsivity is considered one of the strongest candidate endophenotypes for addiction, progress in the field is hampered by the heterogeneity of impulsivity, characterized by multiple personality, psychiatric, and neurocognitive dimensions, rarely examined concurrently in the same population; and the heterogeneity of addiction phenotypes, due in part to the high rates of polysubstance dependence among substance users. To address these challenges, we have developed a program of addiction research in Bulgaria, a key transit country for heroin trafficking due to its strategic geographical location on the "Balkan Drug Route" and a major European center for production of synthetic amphetamine-type stimulants. This has allowed us to access rare populations of predominantly mono-substance dependent heroin and amphetamine users, many in protracted abstinence. Our preliminary results reveal a complex relationship between trait and neurocognitive (state) dimensions of impulsivity, often manifested in opposite directions in heroin and amphetamine dependent individuals. Pilot computational modeling analyses of decision-making, a central neurocognitive aspect of impulsivity, have proved particularly informative by indicating that different mechanisms may underlie the impaired decision-making of opiate and stimulant users. A different modeling approach, i.e. phenotypic modeling, holds significant promise to address the pervasive "missing heritability" problem in genetic studies. While genetic heterogeneity is often invoked as an explanation, the manner in which complex phenotypic traits are measured and modeled is equally important contributor to the missing heritability problem but has received much less attention in the literature. Despite the multidimensionality of traits measured by psychometric, diagnostic, and neurocognitive instruments, most GWAS studies typically use aggregate sum scores that do not reflect the underlying phenotypic multidimensionality. Therefore, at least part of the missing heritability problem may originate in misspecification of the phenotypic models. Consequently, sample sizes requirements may increase from ~800 subjects in correctly specified models to 6,000-16,000 subjects in incorrectly specified models. The current study aims to increase our understanding of the complex relationship between multiple putative impulsivity endophenotypes to help redefine endophenotypes as multi-level combination of measures that could inform multivariate multilevel models of complex phenotypes. The specific aims of the study are to: (1) Assess the utility of various personality, psychiatric, and neurocognitive indices of impulsivity (either individually or in combination) as candidate endophenotype(s) for drug addiction in general and for opiate and stimulant addictions in particular; (2) Evaluate the viability of computational model parameters modeling various neurocognitive dimensions of impulsivity as novel endophenotype(s) for addiction; and (3) Test the external validity of the optimal endophenotype(s) by evaluating their associations with HIV and other risk behaviors in opiate and stimulant users in protracted abstinence, a question of critical importance for prevention and intervention efforts in this much less-well understood stage of the addiction cycle.

  Study phs001647

• eMERGE Network Phase III Clinical Sequencing: eMERGEseq Panel

  The Electronic Medical Records and Genomics (eMERGE) Network is a National Institutes of Health (NIH)-organized and funded consortium of U.S. medical research institutions. The primary goal of the eMERGE Network is to develop, disseminate, and apply approaches to research that combine biorepositories with electronic medical record (EMR) systems for genomic discovery and genomic medicine implementation research. eMERGE was announced in September 2007 and began its third phase in September 2015. eMERGE III consists of nine study sites, two central sequencing and genotyping facilities, and a coordinating center. eMERGE Phase III aims to: 1) sequence and assess the phenotypic implication of rare variants in a custom designed eMERGEseq panel consisting of 109 genes (including 56 ACMG actionable finding list genes and the top 6 genes from each site relevant to their specific aims), as well as approximately 1400 SNPs; 2) assess the phenotypic implications of these variants by developing, validating and implementing new phenotype algorithms, 3) integrate genetic variants into EMRs to inform clinical care; and 4) create community resources. Included in this study are: ~24,000 eMERGE participants from 10 eMERGE III study sites. Corresponding demographics, body mass index measurements. Top PheWAS codes generated from a collated list of ICD codes from all study sites. Study sites and participants include: Cincinnati Children's Hospital Medical Center (CCHMC): Cincinnati Children's Hospital Medical Center (CCHMC) is a not-for-profit hospital and research center pioneering breakthrough treatments, providing outstanding family-centered patient care and training healthcare professionals for the future, and dedicated to improving health and welfare of children and to the shared purpose of discovery and practical application of new genomic information to the ordinary care of children. We bring a comprehensive electronic health record (EPIC), a deidentified i2b2 data warehouse of 680K patient records, a biobank with >261,000 consents that allow return of results to >84,000 patients and guardians who have provided DNA samples, and hundreds of faculty and senior staff who make genomics or informatics an active focus of their research. CCHMC will help the eMERGE III Steering Committee identify genes for the eMERGE III targeted sequencing panel, provide 3,000 DNA samples from CCHMC patients to be sequenced, review targeted gene panels from clinical care at CCHMC for somatic mosaicism and reinterpretation, and further develop and disseminate a software workflow suite for sequence analysis. We will also extend our work generating phenotype algorithms using heuristic and machine learning methods to many new childhood diseases. We will develop tools to evaluate adolescent return of results preferences, examine the ethical and legal obligations and potential to reanalyze results, and develop clinical decision support for phenotyping, test ordering, and returning sequencing results. Children's Hospital of Philadelphia (CHOP): The Center for Applied Genomics (CAG) is a specialized Center of Emphasis at the Children's Hospital of Philadelphia (CHOP), and one of the world's largest genetics research programs, with to state-of-the-art high-throughput sequencing and genotyping technology. Our primary goal is to translate basic research findings to medical innovations. We aim to develop new and better ways to diagnose and treat children affected by rare and complex medical disorders, including asthma, autism, epilepsy, pediatric cancer, learning disabilities, and a range of rare diseases. Ultimately, our objective is to generate new diagnostic tests and to guide physicians to the most appropriate therapies. Participants were recruited from the CAG biorepository (n>450,000), specifically from >100,000 CHOP pediatric patients and family members, which is enriched for rare-diseases (n>12,000). Center for Applied Genomics, The Children's Hospital of Philadelphia We gratefully thank all the children and their families who enrolled in this study, and all individuals who donated blood samples for research purposes. Genotyping for this project was performed at the Center for Applied Genomics and supported by an Institutional Development Award from The Children's Hospital of Philadelphia. Sequencing was supported by the National Institutes of Health through an award from the National Human Genome Research Institute's Electronic Medical Records and Genomics (eMERGE) program (U01HG008684). Columbia University: The goal of the Columbia eMERGE III project is to develop methods for integrating genomic data in EHRs and to study the impact of such genomic informatics interventions on the health of a diverse, underserved urban adult English- and Spanish-speaking patient population in Northern Manhattan served by Columbia University Medical Center/New York-Presbyterian Hospital system. The study group is 2500 patients recruited from diverse clinics and community outreach centers of self-reported White (~61%), Asian (~11%), African-American (~11%), American Indian/Alaska Native (<1%) racial and Hispanic (~33%) ethnic backgrounds. There are two subgroups in the study cohort - a retrospective group (N=1052) that includes patients from oncology and nephrology clinics, and a prospective one (N=1448) that includes healthy individuals as well as participants with diverse medical conditions. Confirmed pathogenic variants in 70 selected genes will be returned to participants and their healthcare providers through the EHR integration. Participants are able to choose the results they receive and will have the freedom to meet with a genetic counselor and a geneticist to review results. The impact of genetic testing on clinical care is determined by periodic monitoring of EHRs. Geisinger: Samples and phenotype data in this study were provided by the Geisinger MyCode® Community Health Initiative. Participants are recruited across the Geisinger System via online consents or in-person consents at a hospital or clinic visit. Enrollment is ongoing with over 100,000 individuals currently consented. Partners Healthcare (Harvard University): The Partners HealthCare Biobank is a large research program designed to help researchers understand how people's health is affected by their genes, lifestyle, and environment. This large research data and sample repository provides access to high-quality, consented blood samples to help foster research, advance our understanding of the causes of common diseases, and advance the practice of medicine. For the Partners research community (Massachusetts General Hospital and Brigham and Women's Hospital), the Biobank provides: Banked samples (plasma, serum, and DNA) collected from consented patients Blood samples that were discarded after clinical testing in the Crimson Cores maintained in the Brigham and Women's Hospital and Massachusetts General Hospital Pathology Departments Sample handling and preparation services Link to the biobank data to the Partners Research Patient Data Registry (RPDR) a research instance of our electronic clinical chart Data access through our research portal. To date, over 70,000 Partners patients have given their consent to enroll, give a blood sample, receive research results and agreed to be re-contacted for additional research studies. The Biobank has enabled Partners investigators to compete for nationally recognized grants in personalized medicine such as a clinical electronic Medical Records and Genomics network (eMERGE) site and the national All of US program. The Biobank currently supports over 120 Partners investigators and over 130 million dollars in NIH research. Kaiser Permanente Washington/ (KPWA) / University of Washington (UW): KPWA participants were enrolled in the eMERGE Network through the Northwest Institute of Genetic Medicine (NWIGM) biorepository, and provided the appropriate consent to receive clinically relevant genetic results (N=2,500.) NWIGM is based at the University of Washington and co-managed by the University of Washington and KPWA. The purpose of the NWIGM biorepository is to build infrastructure and resources to carry out a broad range of future genetic research. KPWA members enrolled in the biorepository are asked to provide informed consent to providing a DNA sample for storage in the NWIGM biorepository. The consent is purposefully broad to serve the dual purpose of reducing the burden on researchers who wish to use this biorepository and the IRB committees who will be responsible for reviewing these requests in the future. Participants were eligible if aged 50 - 65 years old at the time of their enrollment into the NWIGM repository, living, enrolled in KPWA's integrated group practice, and had completed an online Health Risk Appraisal. The selection algorithm was based on several data sources from the EHR at KPWA. 1) Demographics - participants with self-reported race as Asian ancestry were prioritized and selected to enrich for non-European ancestry. The KPWA eMERGE cohort includes N=1,245 members of Asian ancestry. 2) Participants were also selected for a history of colorectal cancer (N=1,255), in order to allow us to enrich germline pathogenic variants. Mayo Clinic: The Return of Actionable Variants Empirical (RAVE) Study was approved by the Mayo Clinic IRB. We recruited 2537 participants from Mayo Clinic biobanks in Rochester, MN, who had hypercholesterolemia or colon polyps, thereby enriching for Familial hypercholesterolemia (FH) and monogenic causes of colorectal cancer (CRC). Additional eligibility criteria were: 1) residents of Southeast MN who were alive and aged 18-70 years; 2) LDL-C level >155 or >120 mg/dl while on lipid-lowering therapy; 3) no known cause of secondary hyperlipidemia; and 4) no cognitive impairment or dementia that would compromise their ability to give written informed consent. Based on these criteria, we identified 5270 eligible patients and obtained informed consent from 3030 participants. Recruitment was conducted in waves and utilized mailed recruitment packets consisting of a study brochure, a written informed consent form, a baseline psychosocial questionnaire, and a return postage-paid envelope. DNA of 2537 participants was sent for CLIA-certified targeted sequencing of 109 genes including genes associated with FH and CRC. Targeted sequencing and genotyping was performed in a Central Laboratory Improvement Amendment (CLIA)-certified laboratory. Northwestern University: Samples and data used in this study were obtained from patients from Northwestern Medicine, an integrated healthcare system, formed through a partnership of Northwestern Memorial HealthCare and Northwestern University Feinberg School of Medicine. Participants include a retrospective cohort from the Northwestern Pharmacogenomics Study, funded through the eMERGE II project, NHGRI (3U01HG006388-02S1) and a prospective cohort from the Genetic Testing and Your Health Study, funded through the eMERGE III project, NHGRI (U01HG008673). Patients were eligible to participate if they were18 years or older and see a physician at Northwestern Medicine. Patients consented to genetic testing and to allow their results to be placed in their electronic medical record. Vanderbilt University Medical Center: Vanderbilt University Medical Center (VUMC) participants were enrolled in the eMERGE Network through the Vanderbilt Genome-Electronic Records (VGER) project. Patients were provided the appropriate consent to receive clinically relevant genetic results (N=2,700). Participants were eligible if aged 21 or over, had a healthcare provider at VUMC, and visited the provider at least 3 times in the past 3 years. Meharry Medical College: Inclusion of ethnic groups in genomic research is critical to identify possible reasons for health disparities. African-Americans are being enrolled in various outpatient clinics of Nashville General Hospital at Meharry, an inner city hospital primary serving a poorer patient group. A total of 500 African Americans with four cancer types demonstrating health disparities in this population - prostate, colon, breast, lung are identified and approached by clinical research coordinators. The purpose of the study is to determine if any genetic information can be identified from these patients who have or are at high risk of one of these disparate cancers. All participants provide written informed consent and HIPAA authorization to provide blood samples for broad research use and permission to access data in their hospital electronic medical record for research now and in the future. An extensive demographic profile is obtained and entered into a REDCap database. Blood samples are obtained for a panel of alleles from extracted DNA at Baylor. In addition, de-identified coded samples are processed and stored in a central biorepository for further DNA, RNA and proteomic analyses. The survey and phlebotomy are performed at the time of the initial contact and agreement to participate. Nearly all patients approached willingly agree to participate for potential benefit to themselves, family members, or humankind. Little concern is voiced of providing samples for genetic analysis. Study investigators will share results with the participants and providers if testing does not indicate high risk. Results indicating increased risk or actionable alleles for the patient and/or family will be returned by a genetic counselor. Monitoring of the patients' health in this cohort will continue to be followed in the EMR to identify any future associations that might explain health disparities in African Americans. Proposals will be reviewed from investigators to study the genetic or proteomic samples as well as the clinical and demographic information in the repository. Please note that this version of the dataset has a handful of mismatches between genotyped and provided sex. Data with the following IDs should be removed prior to analysis: 420252874213744142412243424569384245694642672223

  Study phs001616

• High-depth whole genome sequencing of 26 premalignant breast lesions

  Ductal carcinoma in situ (DCIS) is a non-obligate precursor lesion of breast cancer, representing 20-25% of newly diagnosed breast cancer lesions. It is currently not possible to predict which DCIS patients will progress to invasive breast cancer. The samples deposited here are part of a larger study using high-depth whole-genome sequencing (WGS) to investigate the somatic mutation genomic landscape of DCIS. Comprehensive evaluation of DCIS genomes aims to uncover biological insights into breast cancer progression and potential opportunities to stratify DCIS patients for personalised treatment options or active surveillance. Due to specific restrictions imposed by the ethical approval at sample collection, the use of the germline data is restricted to filtering of somatic mutation calls only and cannot be used outside this purpose.

  Study EGAS50000001559

• Smoking-dependent expression alterations in nasal epithelium reveal immune impairment linked to germline variation and lung cancer risk.

  Lung cancer is the leading cause of cancer-related death in the world. In contrast to many other cancers, a direct connection to lifestyle risk in the form of cigarette smoke has long been established. More than 50% of all smoking-related lung cancers occur in former smokers, often many years after smoking cessation. Despite extensive research, the molecular processes for persistent lung cancer risk are unclear. CT screening of current and former smokers has been shown to reduce lung cancer mortality by up to 26%. To examine whether clinical risk stratification can be improved upon by the addition of genetic data, and to explore the mechanisms of the persisting risk in former smokers, we have analyzed transcriptomic data from accessible airway tissues of 487 subjects. We developed a model to assess smoking associated gene expression changes and their reversibility after smoking is stopped, in both healthy subjects and clinic patients. We find persistent smoking associated immune alterations to be a hallmark of the clinic patients. Integrating previous GWAS data using a transcriptional network approach, we demonstrate that the same immune and interferon related pathways are strongly enriched for genes linked to known genetic risk factors, demonstrating a causal relationship between immune alteration and lung cancer risk. Finally, we used accessible airway transcriptomic data to derive a non-invasive lung cancer risk classifier. Our results provide initial evidence for germline-mediated personalised smoke injury response and risk in the general population, with potential implications for managing long-term lung cancer incidence and mortality.

  Dac EGAC50000000169

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

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

  Dataset EGAD00001010025

• Influence of the Microbiome on Epigenetic Mechanisms in IBD

  Live CD4 T cells were sorted from inflamed and non-inflamed tissue samples of IBD patients or from healthy and IBD blood samples. ATAC-Seq libraries were generated from live CD4 T cells sorted from i) inflamed and non-inflamed tissue samples, ii) healthy and IBD blood samples, or from iii) CD4 T cell subsets polarised from healthy blood samples. After isolating crude nuclei, live CD4+ T cells were treated with Tagment DNA buffer and Tagment DNA Enzyme (Nextera DNA Library Prep Kit, Illumina), and then the DNA was purified by MinElute PCR Purification Kit (Qiagen). Transposed DNA fragments were amplified using specific adapters followed by purification with MinElute PCR Purification Kit (Qiagen). Fragments from 240-360pb were selected in the PippinHT system (Sage Science). The quality of the library and its DNA concentration were assessed by Bioanalyzer instruments (Agilent Technologies) and ultimately submitted for sequencing using Illumina HiSeq 2500 sequencer, V4 chemistry. On the other hand, single cell RNA-Seq libraries were generated exclusively from inflamed and non-inflamed tissue samples of Crohn’s disease patients. Briefly, live CD4 T cells were captured and encapsulated before cDNA amplification using the 10X Genomics Chromium Platform. Samples were prepared as outlined by 10x genomics Single Cell 3’ Reagent Kits v2 user guide. Samples were sequenced on a HiSeq 2500 with the following run parameters: Read 1 – 26 cycles, read 2 – 98 cycles, index 1 – 8 cycles.

  Dataset EGAD00001011066

• GeneSTAR (Genetic Study of Atherosclerosis Risk) NextGen Consortium: Functional Genomics of Platelet Aggregation Using iPS and Derived Megakaryocytes

  The causal mechanisms of common diseases and their therapies have been only marginally illuminated by genetic variants identified in genome wide association studies (GWAS) utilizing single nucleotide polymorphism (SNPs). Platelet activation pathways reflecting hemostasis and thrombosis are the underlying substrate for many cardiovascular diseases and related acute events. To overcome GWAS limitations, genomic studies are needed that integrate molecular surrogates for platelet-related phenotypes assayed in cell-based models derived from individuals of known genotypes and phenotypes. In our GWAS study of native platelet aggregation phenotypes and aggregation in response to low dose aspirin in 2200 subjects (GeneSTAR, Genetic Study of Aspirin Responsiveness), important genome wide "signals" (p<5x10-8) associated with native platelet aggregation and important "signals" associated with platelet responsiveness to aspirin were identified and replicated. Although we are currently performing functional genomics studies to elucidate our most promising findings in known genes (PEAR1, MET, PIKC3G), most "signals" occurred in intergenic regions or in introns. Mechanistic interpretation is limited by uncertainty as to which gene(s) are up- or down-regulated in the presence of most SNP modifications. In this 3 phase proposal, we will (1) create pluripotent stem cells (iPS) from peripheral blood mononuclear cells, and then differentiate these stem cells into megakaryocytes (2) develop an efficient strategy to produce iPS and megakaryocytes using a novel pooling method, and (3) produce iPS and megakaryocytes from 250 subjects in GeneSTAR (European Americans and African Americans), selected based on specific hypotheses derived from GWAS signals in native and post aspirin platelet function; characterize genetic mRNA transcripts using a comprehensive Affymetrix array; measure protein expression for transcripts of interest using mass spectrometry; examine mRNA and protein expression patterns for each GWAS signal to determine the functional pathway(s) involved in native platelet phenotypes; and examine the functional genomics of variations in responsiveness to aspirin using our prior genotyped and phenotyped population. Precise information about the exact functional processes in megakaryocytes and platelets may lead to innovative and tailored approaches to risk assessment and novel therapeutic targets to prevent first and recurrent cardiovascular and related thrombotic events.

  Study phs001074

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

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

  Study phs000279

• NIDDK IBD Genetics Consortium Crohn's Disease Genome-Wide Association Study

  This dataset contains data from a genome-wide association study performed with 968 Inflammatory Bowel Disease (IBD) affected cases and 995 unrelated controls using the Illumina HumanHap300 Genotyping BeadChip. Cases were selected to have Crohn's disease with ileal involvement, and controls were matched to cases based on sex and year of birth. Subjects were drawn from two cohorts: (1) persons with non-Jewish, European ancestry (561 cases and 563 controls), and (2) persons with Jewish ancestry (407 cases and 432 controls). Genotyping was performed at the Feinstein Institute for Medical Research. Seven-hundred fifty-four of the samples (468 cases and 286 controls) were taken from the NIDDK IBD Genetics Consortium cell line repository. These samples are identified in the IBD_Sample file. The subject IDs for these individuals may be used to request corresponding samples for follow-up research through the repository. In addition, complete phenotype data for these individuals are available, together with the Consortium's phenotyping manual and the forms used to collect the data. The remaining 1,209 samples were obtained from pre-existing collections ascertained through Cedars-Sinai Medical Center, Johns Hopkins University, University of Chicago, University of Montreal, University of Pittsburgh, University of Toronto, and the New York Health project (controls only). For these samples, only sex, cohort (Jewish vs. non-Jewish), and age at diagnosis (cases only) are available. Two-hundred three individuals from among the pre-existing samples did not provide consent to release their genotype data (designated as consent group 2 in the file IBD_Subject). Thus, individual genotype data are only provided for 1,760 samples. To compensate for this, we have provided summary results for each SNP. These are based on a stratified analysis testing case/control association. Fifty-one samples had a call rate less than 93% and were therefore excluded from this analysis, leaving an overall sample size of 1,963 - 51 = 1,912. X Chromosome Heterozygosity Nine samples have X chromosome heterozygosity that is neither consistent nor inconsistent with their phenotypic sex. One of these samples was found to have Turner Syndrome. The remaining 8 samples have heterozygosity ranging from 35-76%.

  Study phs000130

• NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (Ischemic Stroke Genetic Study, ISGS)

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. The Ischemic Stroke Genetics Study (ISGS) is a study of newly onset cases (~600) with ischemic stroke (a stroke due to sudden interruption of blood flow to a part of the brain) compared with sex- and age-matched non-stroke participants. The study was conducted to determine the genes and their variants that contribute to an individual's risk of developing an ischemic stroke. The coordination of the recruitment and flow of the samples occurred at the Mayo Clinic, Jacksonville, FL, under the direction of James F. Meschia, MD. The University of Virginia (Stephen S. Rich, PhD) served as the analytic site for the genetic data. All GWAS data on ISGS participants have been deposited into dbGaP. As part of the NHLBI Exome Sequencing Project, DNA from a subset of ISGS participants will undergo exome sequencing. For the NHLBI ESP, a subset of 92 individuals with lacunar (small vessel) or atherosclerotic (large vessel) TOAST subtypes were selected from among all ISGS participants, excluding those individuals with TOAST subtypes of stroke of other etiology or of stroke with undetermined etiology. All 92 samples pass initial quality control metrics and 89 samples completed exome sequencing. A total of 75 participants with appropriate consent and variant calls had their genetic and phenotypic data deposited into dbGaP.

  Study phs000546

• Type 1 Diabetes Genetics Consortium (T1DGC): ImmunoChip Study

  The Type 1 Diabetes Genetics Consortium (T1DGC) was formed to address issues of limited sample size and consistency of phenotyping that had limited genetic investigations on risk of type 1 diabetes (T1D). The T1DGC first collected affected sib pair (ASP) families from four geographic networks (Asia-Pacific, Europe, North America, United Kingdom). In addition, T1D cases and controls were ascertained from existing and de novo collections. The T1DGC assembled 2,601 T1D ASP families and 69 Parent-T1D offspring trios, T1D cases from the UK Genetic Resource Investigating Diabetes (UKGRID, N=6,670), and controls from the British 1958 Birth Cohort (B58BC, N=6,523), the UK National Blood Services collection (NBS, N=2,893) and the NIHR Cambridge Biomedical Research Centre BioResource (CBR, N=2,846). All samples included in this series have reported or self-declared European ancestry. All DNA samples were collected after approval from relevant institutional research ethics committees. Genotyping was performed using a custom Illumina Infinium high-density genotyping array, ImmunoChip (Illumina, Inc; CA) according to manufacturer's protocols. The ImmunoChip was designed to densely genotype, using 1000 Genomes and any other available disease specific resequencing data, immune-mediated disease loci identified by common variant GWAS. The ImmunoChip Consortium selected 186 distinct loci containing markers meeting genome wide significance criteria (P<5x10-8) from twelve such diseases (autoimmune thyroid disease, ankylosing spondylitis, Crohn's disease, celiac disease, IgA deficiency, multiple sclerosis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, T1D and ulcerative colitis). All 1000 Genomes Project pilot phase CEU population variants (Sept 2009 release) within 0.1cM (HapMap3 CEU) recombination blocks around each GWAS region lead marker were submitted for array design. No filtering on correlated variants (linkage disequilibrium) was applied. Additional content included regional resequencing data (submitted by several groups) as well as a small proportion of investigator-specific undisclosed content including intermediate GWAS results. After data cleaning and quality control, a total of 154,939 single nucleotide polymorphisms (SNPs) from 186 loci on ImmunoChip were scored. Case-control and family data were analyzed independently and combined by meta-analysis.

  Study phs000911

• Weighing Risks and Benefits of Laparoscopic Anti-Reflux Surgery in Patients With Idiopathic Pulmonary Fibrosis (WRAP-IPF-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: To determine if the reduction of abnormal gastro-esophageal reflux (GER) with laparoscopic anti-reflux surgery will slow the progression of idiopathic pulmonary fibrosis (IPF) as measured by forced vital capacity (FVC).Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease of unknown cause and increasing prevalence in the United States. Aside from lung transplantation, which approximately only 1% of participants will receive, there is no FDA-approved therapy. Abnormal acid gastro-esophageal reflux (GER) has been well described in participants with IPF and is thought to play a role in the progression of the disease. The several retrospective cohort studies that have assessed the association of anti-acid therapies for GER with clinical outcomes in IPF have had inconsistent results.Participants: A total of 58 participants were enrolled.Design: The WRAP-IPF trial was a multicenter, unblinded randomized clinical trial with participants randomized to either laparoscopic anti-reflux surgery or no surgery. Participants in the no-surgery group had the option of receiving laparoscopic anti-reflux surgery from 24 weeks after randomization if their clinician deemed it medically necessary. Medications for acid GER were allowed in both groups if the clinician felt it was necessary.Participants were followed up from time of randomization to 52 weeks. All participants had study visits at baseline, 12, 24, 36, and 48 weeks, during which spirometry, 6-min walk testing, and participant-related outcome assessments were done. Participants in the surgery group had clinical visits for preoperative evaluation, laparoscopic anti-reflux surgery, and postoperative management as clinically indicated. Surgery participants additionally underwent repeat 24-hour pH testing at 24 weeks to assess the efficacy of the surgery. All participants were contacted by telephone for safety assessments at weeks 4, 8, 16, 20, 28, 32, 40, 44, and 52. All participants completed an exploratory questionnaire on reflux symptoms at baseline and 48 weeks. The primary endpoint was change in FVC from randomization (baseline) to 48 weeks. Secondary endpoints included acute exacerbation, non-elective hospitalization (both all-cause and respiratory-related), death, change in cough severity, change in dyspnea severity, change in health-related quality of life, change in 6-min walk distance, and time to selected event-driven composite endpoints of disease progression. Conclusions: In participants with IPF and abnormal acid GER, laparoscopic anti-reflux surgery is safe and well tolerated but did not significantly slow the rate of FVC decline. Further research is needed, particularly with a larger study in order to achieve sufficient statistical power, regarding the possible benefits of anti-reflux surgery in this population.Raghu G, Pellegrini CA, Yow E, et al. Laparoscopic anti-reflux surgery for the treatment of idiopathic pulmonary fibrosis (WRAP-IPF): a multicentre, randomised, controlled phase 2 trial. Reference: Raghu, et al., 2018; PMID: 30100404.

  Study phs003968

• Whole Genome Sequencing of a Triple Negative Breast Cancer Patient: Matched Primary Tumor, Normal, Metastasis and Xenograft samples

  Breast Cancer Subject Participant ID 700064 (Source Sample names: 6888 and 206). We used massively parallel DNA sequencing technologies to screen entire genomes, in an unbiased manner, for genetic changes associated with tumor growth and metastasis. We describe the complete genome sequence analysis of four DNA samples from a 44-year old African-American patient with basal-like breast cancer: peripheral blood, the primary tumor, a brain metastasis that developed within a year of initial therapy, and a first-passage xenograft derived from the primary tumor. A total of 50 validated mutations were discovered within coding, RNA, or splice site sequences. Of these, 20 mutations were abundantly present in all three tumors, including mutations in CSMD1 and JAK2. These two genes subsequently were found to be mutated in other breast tumors. The metastasis contained two de novo mutations not present in the primary tumor, and was significantly enriched for 20 shared mutations, suggesting that they may be involved in the metastatic process. The xenograft contained no unique coding, RNA, or splice site mutations and retained all primary tumor mutations, albeit at different frequencies. However, a significant increase in copy number alterations was observed in the xenograft as compared to the primary tumor. We validated 28 large deletions and six inversions, as well as seven translocations in at least one of the three tumor samples. Among them, a 26 kb deletion in MECR was solely identified, assembled, and validated in the brain metastasis and two overlapping large deletions on chromosome 5 encompassing CTNNA1, a potential tumor suppressor gene, were identified in all three tumors. The differential mutation frequencies and structural variation patterns between primary and metastatic tumors suggest that metastatic tumors may arise from minor subpopulations of cells within the primary. Namely, the metastatic and xenografting processes apparently select for cells harboring a distinct subset of the primary tumor mutation repertoire.

  Study phs000245

• Genetic analysis of HLA and immune escape genes in Diffuse Large B-cell Lymphoma

  Fifty percent of diffuse large B-cell lymphoma (DLBCL) cases lack cell-surface expression of the class-I major histocompatibility complex (MHC-I), thereby escaping immune recognition by cytotoxic T cells. In order to comprehensively identify the mechanisms involved in MHC-I loss, we first performed immunophenotypic analysis of both MHC class-I and -II in 657 cases across the spectrum of B-NHL, revealing that loss of MHC-I, but not MHC-II, is preferentially restricted to DLBCL. We then used whole exome and targeted deep-sequencing to examine genes involved in MHC-I expression in 74 DLBCL samples representative of MHC-I positive and negative cases. We show here that somatic biallelic or monoallelic inactivation of B2M and/or HLA-I is present in 80.9% (34/42) of MHC-I negative tumors. Furthermore, 68.8% (22/32) of MHC-I positive DLBCLs also harbored monoallelic HLA-I genetic alterations (MHC-I positivemono) that lead to allelic imbalance, suggesting allele-specific inactivation. Both MHC-I negative and MHC-I positivemono cases showed a significantly higher mutational burden as well as a higher number of inferred neo-antigens, suggesting co-selection of HLA-I loss and sustained neo-antigen production. Interestingly, the analysis of > 500.000 individuals in two databases revealed homozygosity of germline HLA-I genes in 26-38% of DLBCL patients, a frequency significantly higher than that observed in any other cancer type. In mice, germinal-center B cells lacking HLA-I expression did not progress to lymphoma and were counterselected in the context of oncogene-driven lymphomagenesis, suggesting that additional events are needed to license immune evasion. These results suggest a multi-step process of HLA-I loss including both germ-line and somatic events in DLBCL development, and have direct implications for the pathogenesis and immunotherapeutic targeting of this disease.

  Study EGAS00001005054

• Targeted sequencing of healthy individuals, aged individuals and AML patients

  Targeted sequencing using BD Rhapsody with 462 mRNA and 97 antibodies of healthy young and aged adult as well as AML bone marrow mononuclear cells from iliac crest aspirations. Please note raw and integrated gene expression data, cell type annotation, metadata and dimensionality reduction are available as Seurat v3 objects through figshare. Access link is https://figshare.com/s/0fda29b169c719223ee3.

  Dataset EGAD00001008188

• University of Miami Udall Center of Excellence Identification of Rare Variants in PD through Whole Exome Sequencing

  The focus of this study is to identify a new level of genetic variation, i.e. rare genetic variants with a population frequency less than 5%, usually less than 1%, which are believed to provide a stronger risk per variant than those studied to date in the large genome wide association studies (GWAS). To do this we are generating whole exome sequencing data on the Illumina HiSeq. Each HiSeq produces at least 600 billion base pairs of DNA sequence in one run. Whole exome sequencing sequence data, about 50 million base pairs, or about 1.5% of the total DNA of each person's genome, is generated. We are using this data to look for new DNA variations that give risk for Parkinson disease, as well as "modifiers", that may lead to having more severe or milder disease or later or earlier ages of onset.

  Study phs000908

• Vanderbilt Genome-Electronic Records (VGER) Project: QRS Duration

  An important potential enabling resource for Personalized Medicine is the combination of a DNA repository with Electronic Medical Record (EMR) systems sufficiently robust to provide excellence in clinical care and to serve as resources for analysis of disease susceptibility and therapeutic outcomes across patient populations. The Vanderbilt EMR is a state of the art clinical and research tool (that includes >1.7 million records), and is associated with a DNA repository which has been in development for over 3 years; these are the key components of VGER, the Vanderbilt Genome-Electronic Records project, a part of NHGRI's eMERGE network. The VGER model acquires DNA from discarded blood samples collected from routine patient care, and can link these to de-identified data extracted and readily updated from the EMR. The phenotype we analyze here is the QRS duration on the electrocardiogram, since slow conduction (indicated by longer QRS duration) is a marker of arrhythmia susceptibility.

  Study phs000188

• Total exRNA Profiles from Plasma, Saliva, and Urine of Healthy Subjects

  We sequenced small RNAs from 183 plasma samples, 204 urine samples and 46 saliva samples from 55 college athletes ages 18-25 years. Many of the participants provided more than one sample, weeks or months apart, allowing us to assess variability in an individual's exRNA expression levels over time. Several individuals provided all three biofluid types at one time, producing data on individual expression levels across several biofluid types. Here we provide a systematic analysis of small exRNAs present in each biofluid, as well as an analysis of exogenous RNAs. We find that a large number of RNA fragments in plasma (63%) and urine (54%) have sequences that are assigned to YRNA and tRNA fragments respectively. Surprisingly, while many miRNAs can be detected, there are few miRNAs that are consistently detected in all samples from a single biofluid. Additionally, we performed whole transcriptome sequencing on 134 plasma and 115 urine samples and identified circRNA.

  Study phs001258

• Genome-Wide Association Study of Parkinson Disease: Genes and Environment

  This is a gene-environment study of Parkinson's disease. PD is a common, progressive, age-related, movement disorder that affects 1-2% of the people over the age of 65. The NeuroGenetics Research Consortium (NGRC) is the infrastructure of the study. Protocols and methods are standardized across NGRC clinics and labs as much as possible. The 2000 patients and 2000 control subjects selected for this GWAS were recruited at the NGRC-affiliated movement disorder clinics in Oregon, Washington, Georgia and New York. All 4000 subjects were white and all DNA samples were extracted from whole blood and unamplified. Seventy-five percent of subjects have data on cigarette smoking and caffeinated coffee consumption, which are inversely associated with PD risk. This study population represents the norm for clinical genetic studies of PD; i.e., NGRC estimates of risk to relatives, heritability, genotype frequencies, and exposure frequencies (see references) are very close to estimates from meta-analyses.

  Study phs000196