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• ICGC Oesophageal adenocarcinoma - 100 tumour samples

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

  Study EGAS00001000724

• Transdisciplinary Research Into Cancer of the Lung (TRICL) - Exome Plus Targeted Sequencing

  The study was conducted under the auspices of the Transdisciplinary Research In Cancer of the Lung (TRICL) Research Team, which is a part of the Genetic Associations and MEchanisms in ONcology (GAME-ON) consortium, and associated with the International Lung Cancer Consortium (ILCCO). Ethics All participants provided written informed consent. All studies were reviewed and approved by institutional ethics review committees at the involved institutions. Sequencing data are derived from four sub-studies. The sub-studies that contributed include Harvard, Liverpool, Toronto, and IARC. The IARC and Toronto studies are described above. A description of the Harvard and Liverpool studies is provided below. Liverpool Lung Project: The Liverpool Lung Project (LLP)1 is a case control and cohort study, which has over 11,500 individuals, with detailed epidemiological, clinical and outcome data with associated specimens (i.e. tumour tissue, blood, plasma, sputum, bronchial lavage, EBUS and oral brushings). The participants have completed a detailed lifestyle questionnaire and updated data on clinical outcome and hospital events are collected through the Office of National Statistics, Cancer Registry and from Health Episode Statistics. The project is registered on the UK National Institute for Health Research (NIHR) lung cancer portfolio and has all the required ethical approvals and sponsorship arrangements in place. The LLP has detailed standard operating procedures (SOP) for all aspects of the recruitment, data, specimen collection as well as the data storage. The LLP Cohort study has 8,224 participants with blood and 7,761 with plasma samples. The LLP case-control samples have been incorporated into in a large number of international GWAS and molecular studies 2,3, methylation 4-7, microRNA 8and next generation studies 9-11, resulting in high ranking publications, as well as forming the basis for the LLP risk prediction model 12-14 which has been utilised in the UK lung cancer screening trial (UKLS) 15-17 Patient and control DNAs were derived from EDTA-venous blood samples. Harvard Samples. David Christiani at the Harvard University School of Public Health has been directing research studies to investigate etiological factors influencing lung cancer development since 1983 and has amassed a collection of 2000 controls and 5055 lung cancer cases. He has been actively collecting and storing snap frozen tumor samples since 1992. Around 1500 tumor samples have been collected and the average wet tumor yield is about 30 grams of tumor, of which 631 cases have completely annotated clinical and survival information. Pathology confirmation is provided by two pathologists. At the time of surgery, a minimum of 30 grams of wet lung tumor tissue and 30 grams of non-involved tissue from the same lobe is sectioned, flash frozen and sent to Dr. Christiani's lab for logging and storage. A blood sample for DNA and serum is collected. A structured interview by trained research staff is conducted on each case, and clinical outcomes and treatments is extracted and entered into the molecular epidemiology data base at Harvard. Fresh frozen samples have been collected from 1451 lung cancer and are available for study. Samples from this collaborative study have played key roles in major studies, including the initial finding describing EGFR mutations in lung cancer 22. Participants in this study are patients, > 18 years of age, with newly diagnosed histologically confirmed lung cancer. Samples that are included in the analysis have the following histologies: Adenocarcinoma: 8140/3, 8250/3, 8260/3, 8310/3, 8480/3 8560/3; LCC: 8012/3, 8031/3; squamous carcinoma: 8070/3, 8071/3, 8072/3, 8074/3; and other NSCLC: 8010/3, 8020/3, 8021/3, 8032/3, 8230/3. The Toronto Study: The Toronto study was conducted in the Great Toronto Area between 1997 and 2014. Cases were recruited at the hospitals in the network of University of Toronto and Lunenfeld- Tanenbaum Research Institute. At the time of recruitment in the clinical setting, provisional diagnoses of lung carcinoma were first assigned based on clinical criteria. Diagnoses for all cases included were histologically confirmed by the reference pathologist who is a specialist in pulmonary pathology, based on review of pathology reports from surgery, biopsy or cytology samples in 100% of cases. Diagnostic classification was done initially according to ICD-9, ICD-10, and ICD for oncology-2, and subsequently converted to ICD-O-3. Tumors were grouped into the major categories included in this analysis according to primary cancer type based on the ICD-3 definitions. Controls were randomly selected from individual visiting family medicine clinics and Ministry of Finance Municipal Tax Tapes. All subjects were interviewed using a standard questionnaire and information on lifestyle risk factors, occupational history, medical and family history was collected. Blood samples were collected from more than 85% of the subjects. IARC: The IARC data are derived from case-control studies conducted in Russia and include samples that have available tissue samples. Patient and control DNAs were derived from EDTA-venous blood samples. The lung cancer patients were classified according to ICD-O-3; SQ: 8070/3, 8071/3, 8072/3, 8074/3; AD: 8140/3, 8250/3, 8260/3, 8310/3, 8480/3, 8560/3, 8251/3, 8490/3, 8570/3, 8574/3; with tumous with overlapping histologies classified as mixed. The Lung Cancer Transdisciplinary Research Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" section of this top-level study page phs000876 Lung Cancer Transdisciplinary Research Cohort. phs000877 Meta Analysis phs000878 CIDR Lung Cancer phs001681 Affy Axiom Array

  Study phs000876

• Genomic determinants of response and resistance to inotuzumab in B-ALL

  Inotuzumab Ozogamicin (InO) is an antibody-drug conjugate which delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO treated B-cell acute lymphoblastic leukemia (B-ALL) patients, we sought to understand the genomic determinants of response to InO. Acquired CD22 mutations were observed in 11% (3/27) of post-InO relapsed samples. CD22 mutation types were diverse (frameshift, nonsense, missense and stoploss) and we identified multiple mechanisms of mutation induced CD22 escape, including protein truncation, protein destabilization, and epitope alteration. Accelerated acquisition of mutations by error-prone DNA damage repair could drive CD22 mutation and escape. Acquired loss-of-function mutations in TP53, ATM and CDKN2A were observed, suggesting compromise of the G1/S DNA damage checkpoint as a mechanism of evading InO-induced apoptosis. In conclusion, genetic alterations modulating CD22 expression and DNA damage response influence InO efficacy. The diverse mechanisms of CD22 escape advocates for a refined approach for monitoring CD22-targeted therapy.

  Study EGAS50000000067

• Blood Group Genotypes and Phenotypes in Omani Blood Donors and Its Links With Susceptibility to Malaria

  The Omani population experienced endemic malaria prior to eradication in the late 1990's. Since malaria is known to be a strong selective pressure on the human genome, particularly at blood group associated loci, we aimed to understand how selective pressures from malaria may be affecting genetic variation at blood group loci. Blood samples were collected from 100 healthy, Omani blood donors. Serology testing for 10 clinically relevant blood groups and whole genome sequencing (WGS) to an average coverage of 16X were performed on all samples. Additionally, using the WGS data, genetic variants (SNPs and INDELs) were called for chromosomes 1 - 22 using GRCh38. We find signals of selection at the Plasmodium vivax associated locus, ACKR1 (the Duffy blood group), but not at any Plasmodium falciparum associated loci. We also characterized several previously undescribed blood group alleles in the Omani population affecting antigenic expression, mostly at the RHD, RHCE, and GYPB loci. The data available from this project include BAM files from 100 Omani samples aligned to GRCh38, per chromosome VCF files, and results from the serology tests for all 10 blood groups.

  Study phs003694

• 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

• Transcription Factor Analysis of SLE

  Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with protean manifestations. This study identifies two histone marks of activation and the binding of p300 genome-wide in three cell types and three clinical subsets to better understand cell-specific effects and differences across clinical subsets. Results: We examined 20 patients with SLE and 8 controls and found the TNF, IL-2/STAT5, and KRAS pathways were identified across multiple cell types and ChIP data sets. Patients with cutaneous lupus and lupus nephritis generally had less dramatically altered chromatin than the general SLE group. Conclusions: NFkB and classical inflammatory pathways were strongly associated with increased peak heights across all cell types but were the highest-ranking pathway for all three antibodies in monocytes according to fgsea analysis. IL-6 Jak/STAT3 signaling was the most significant pathway association in T cells marked by H3K27ac change. Therefore, each cell type experiences the disease process distinctly although in all cases there was a strong theme of classical inflammatory pathways. These studies define important cell type differences and emphasize the breadth of the inflammatory effects in SLE.

  Study phs003713

• Characterisation of the genomic landscape of CRLF2-d ALL

  To determine the clinical and genetic landscape of CRLF2 deregulated acute lymphoblastic leukaemia (CRLF2-d ALL). We identified 172 patients with a CRLF2 rearrangement treated on either the UKALL2003 trial for children and adolescents (1-24 years) or the UKALLXII trial for adolescents and adults (15-59 years). Genomic technologies from conventional karyotyping, and FISH through to whole genome and exome sequencing were used to characterise the genomes of patients with CRLF2-d ALL. This is the largest study to date to investigate the genomic landscape of CRLF2-d ALL and define CRLF2-d as a unique subgroup of B-other ALL. We have confirmed the high incidence of CRLF2-d in Down syndrome-ALL and demonstrated the co-existence of CRLF2-d with other primary chromosomal rearrangements, suggesting that in these patients CRLF2-d can be a secondary genetic abnormality. Other defining features included enrichment of IKZF1, BTG1 and ADD3 deletions in IGH-CRLF2 patients and specific chromosomal gains seen at much higher frequencies than B-other ALL . We report recurrent established and new co-operating abnormalities and the novel involvement of USP9X and DDX3X in CRLF2-d ALL. It is clear from these data that CRLF2-d ALL is heterogenoeus, requiring a combination of genetic abnormalities in functionally relevent genes, to work alongside the deregulated expression of CRLF2 in order to initiate and drive leukaemogenesis in this subtype. Although the functional relevance of many of the abnormalities presented here are currently unknown, many are likely to activate alternate pathways or sensitize patients to current therapies.

  Dataset EGAD00001002008

• Characterisation of the genomic landscape of CRLF2-d ALL

  To determine the clinical and genetic landscape of CRLF2 deregulated acute lymphoblastic leukaemia (CRLF2-d ALL). We identified 172 patients with a CRLF2 rearrangement treated on either the UKALL2003 trial for children and adolescents (1-24 years) or the UKALLXII trial for adolescents and adults (15-59 years). Genomic technologies from conventional karyotyping, and FISH through to whole genome and exome sequencing were used to characterise the genomes of patients with CRLF2-d ALL. This is the largest study to date to investigate the genomic landscape of CRLF2-d ALL and define CRLF2-d as a unique subgroup of B-other ALL. We have confirmed the high incidence of CRLF2-d in Down syndrome-ALL and demonstrated the co-existence of CRLF2-d with other primary chromosomal rearrangements, suggesting that in these patients CRLF2-d can be a secondary genetic abnormality. Other defining features included enrichment of IKZF1, BTG1 and ADD3 deletions in IGH-CRLF2 patients and specific chromosomal gains seen at much higher frequencies than B-other ALL . We report recurrent established and new co-operating abnormalities and the novel involvement of USP9X and DDX3X in CRLF2-d ALL. It is clear from these data that CRLF2-d ALL is heterogenoeus, requiring a combination of genetic abnormalities in functionally relevent genes, to work alongside the deregulated expression of CRLF2 in order to initiate and drive leukaemogenesis in this subtype. Although the functional relevance of many of the abnormalities presented here are currently unknown, many are likely to activate alternate pathways or sensitize patients to current therapies.

  Dataset EGAD00001002007

• Foundation Medicine Adult Cancer Clinical Dataset (FM-AD)

  The Foundation Medicine adult cancer clinical dataset consists of 18,004 unique solid tumor samples that underwent genomic profiling on a single uniform platform as part of standard clinical care. The dataset is derived from the FoundationOne® genomic profiling assay version 2 that interrogates exonic regions of 287 cancer-related genes and selected introns from 19 genes known to undergo rearrangements in human cancer. Genomic DNA samples were sequenced to over 500x median coverage, and custom computational analyses identified all classes of genomic alterations (base substitutions, insertions and deletions, copy number alterations, and rearrangements). Since matched normal tissue was unavailable for analysis, these data underwent additional filtering to enrich for cancer-related events. The reported data includes genomic alterations that are known and suspected tumor drivers, as well as variants of unknown significance. To preserve patient anonymity, all known or suspected germline variants were removed from the data unless known to be associated with cancer development. The dataset contains genomic alteration profiles generated by FoundationOne version 2 testing for adult cancer patients (over 18 y.o.), and represents a vast diversity of tumor subtypes, including many rare diseases not profiled as part of large-scale profiling efforts. Cases are grouped into 16 broad disease categories containing tumors from 162 unique disease subtypes. Since specimens were profiled as part of clinical care, limited clinical parameters were available, including age, gender, tissue of origin, % of tumor nuclei, and diagnosis. Publication of this dataset is intended to allow the broad scientific community access to this unique cohort for use in scientific research projects of common and rare types of cancer, both for generating leads regarding causal mechanisms as well as cross-testing and confirming existing hypotheses. A pediatric cancer clinical dataset consisting of data from 1,215 patients under 18 y.o. is available separately at: FOUNDATION MEDICINE

  Study phs001179

• NHLBI TOPMed: Genetics of Cardiometabolic Health in the Amish

  The Amish Complex Disease Research Program includes a set of large community-based studies focused largely on cardiometabolic health carried out in the Old Order Amish (OOA) community of Lancaster, Pennsylvania (http://medschool.umaryland.edu/endocrinology/amish/research-program.asp). The OOA population of Lancaster County, PA immigrated to the Colonies from Western Europe in the early 1700's. There are now over 30,000 OOA individuals in the Lancaster area, nearly all of whom can trace their ancestry back 12-14 generations to approximately 700 founders. Investigators at the University of Maryland School of Medicine have been studying the genetic determinants of cardiometabolic health in this population since 1993. To date, over 7,000 Amish adults have participated in one or more of our studies. Due to their ancestral history, the OOA may be enriched for rare variants that arose in the population from a single founder (or small number of founders) and propagated through genetic drift. Many of these variants have large effect sizes and identifying them can lead to new biological insights about health and disease. The parent study for this WGS project provides one (of multiple) examples. In our parent study, we identified through a genome-wide association analysis a haplotype that was highly enriched in the OOA that is associated with very high LDL-cholesterol levels. At the present time, the identity of the causative SNP - and even the implicated gene - is not known because the associated haplotype contains numerous genes, none of which are obvious lipid candidate genes. A major goal of the WGS that will be obtained through the NHLBI TOPMed Consortium will be to identify functional variants that underlie some of the large effect associations observed in this unique population.

  Study phs000956

• Analysis of Somatic Mutations in Pediatric AML FAB-M7 Subtype by Whole Transcriptome Sequencing

  High resolution analysis of DNA copy number abnormalities and loss-of-heterozygosity on acute myeloblastic leukemia samples utilizing SNP arrays has demonstrated that in contrast to pediatric ALL, de novo AML is characterized by a very low burden of genomic alterations (Radtke, et al., PNAS, 2009). Samples for this study represented a cross-section of the different subtypes of pediatric AML. The only AML subtype that was an outlier from the above observations was acute megakaryocytic leukemia (AML FAB-M7), with the majority of these cases being characterized by complex chromosomal rearrangements and a high number of copy number alterations. To more fully define the genomic landscape of this subtype, we performed transcriptome sequence analysis on 14 pediatric FAB-M7 cases and mutation recurrence screening in a panel of 62 adult and pediatric AML FAB-M7 samples using the Illumina platform. Our results identified chromosomal rearrangements resulting in the expression of novel fusion transcripts in 11/14 cases. Remarkably, in 7/14 cases we detected an inversion on chromosome 16 that results in the juxtaposition of the CBFA2T3 gene next to the GLIS2 gene resulting in a CBFA2T3-GLIS2 chimeric gene that encoded an in frame fusion protein. This fusion led to the acquisition or preservation of self-renewal in colony forming assays, providing functional evidence for a role in leukemogenesis. In addition to novel chimeric transcripts, we found mutations in genes previously identified to play a role in megakaryoblastic leukemia that carry a proliferative advantage to the cell, such as JAK2 and MPL. These data demonstrate that AML FAB-M7 is characterized by cooperating Class I and Class II mutations leading to leukemogenesis.

  Study phs000413

• Glioblastoma stem cell lines RNA-seq (Guilhamon et al.)

  RNA was extracted from GSCs using the Qiagen RNeasy Plus kit. RNA sample quality was measured by Qubit (Life Technologies) for concentration and by Agilent Bioanalyzer for RNA integrity. All samples had RIN above 9. Libraries were prepared using the TruSeq Stranded mRNA kit (Illumina). Two hundred nanograms from each sample were purified for polyA tail containing mRNA molecules using poly-T oligo attached magnetic beads, then fragmented post-purification. The cleaved RNA fragments were copied into first strand cDNA using reverse transcriptase and random primers. This is followed by second strand cDNA synthesis using RNase H and DNA Polymerase I. A single “A” base was added and adapter ligated followed by purification and enrichment with PCR to create cDNA libraries. Final cDNA libraries were verified by the Agilent Bioanalyzer for size and concentration quantified by qPCR. All libraries were pooled to a final concentration of 1.8nM, clustered and sequenced on the Illumina NextSeq500 as a pair-end 75 cycle sequencing run using v2 reagents to achieve a minimum of ~40 million reads per sample.

  Dataset EGAD00001006813

• Quantification of chromosomal copy number aberrations by shallow whole-genome sequencing

  Detection of DNA copy number aberrations by shallow whole-genome sequencing (WGS) faces many challenges including lack of completion and errors in the human reference genome, repetitive sequences, polymorphisms, variable sample quality, and biases in the sequencing procedures.Formalin-fixed paraffin-embedded (FFPE) archival material, the analysis of which is important for studies of cancer, presents particular analytical difficulties due to degradation of the DNA and frequent lack of matched reference samples. We present a robust, cost-effective WGS method for DNA copy number analysis that addresses these challenges more successfully than currently available procedures. In practice very useful profiles can be obtained with 0.1 fold genome coverage. We improve on previous methods by; first, implementing a combined correction for sequence mappability and GC content, and second, applying this procedure to sequence data from the 1000 Genomes Project in order to develop a blacklist of problematic genome regions. A small subset of these blacklisted regions were previously identified by ENCODE, but the vast majority are novel unappreciated problematic regions. Our procedures are implemented in a pipeline called QDNAseq. We have analyzed over 1,000 samples, most of which were obtained from the fixed tissue archives of over 25 institutions.We demonstrate that for most samples our sequencing and analysis procedures yield genome profiles with noise levels near the statistical limit imposed by read counting. The described procedures also provide better correction of artifacts introduced by low DNA quality than prior approaches, and better copy number data than high-resolution microarrays at substantially lower cost.

  Study EGAS00001000642

• Whole Exome Sequencing of Calcitonin Producing Pancreatic Neuroendocrine Neoplasms (CT-pNENs) Indicates a Unique Molecular Signature

  Calcitonin-producing pancreatic neuroendocrine neoplasms (CT-pNENs), which can mimic clinical and laboratory features of medullary thyroid carcinoma, are an extremely rare clinical entity with approximately 60 cases reported worldwide. The molecular profile of CT-pNENs is not yet known. Whole-exome sequencing (WES) was performed on tumor and corresponding serum samples of five patients with increased calcitonin serum levels and histologically proven calcitonin-positive CT-pNENs. cBioPortal analysis and gene enrichment analysis with DAVID were performed to validate candidate genes. Immunohistochemistry was used to detect protein expression of MUC4 and MUC16 in CT-pNEN specimens. Common somatic mutations of pNENs like MEN1, ATRX and PIK3CA were identified in cases of CT-pNENs. New somatic SNVs in ATP4A, HES4, and CAV3 have not yet been described in CT-pNENs. Pathogenic germline mutations in FGFR4 and DPYD were found in three of five cases. Mutations of CALCA (calcitonin) and the corresponding receptor CALCAR were found in all five tumor samples, but none of them resulted in clinical or protein sequelae. All five tumor cases showed single nucleotide variations (SNVs) in MUC4, and four cases showed SNVs in MUC16, both of which were membrane-bound mucins. Immunohistochemistry showed protein expression of MUC4 and MUC16 in one case each, and the liver metastasis of a third case was double positive for MUC4 and MUC16. The homologous recombination deficiency (HRD) score of all tumors was low.CT-pNENs have a unique molecular signature compared to other pNEN subtypes, specifically involving the FGFR4, DPYD, MUC4, MUC16 and the KRT family genes. However, these WES data from only five cases must be interpreted with caution because causal interpretation of the mutational landscape in CT-pNENs is difficult. Further research is needed to explain differences in pathogenesis compared with other pNENs. In particular, multi-omics data such as RNASeq, methylation, and whole genome sequencing could be informative.

  Study phs003060

• Resource for Genetic Epidemiology Research on Adult Health and Aging (GERA)

  The Resource for Genetic Epidemiology Research on Aging (GERA) Cohort was created by a RC2 "Grand Opportunity" grant that was awarded to the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) and the UCSF Institute for Human Genetics (AG036607; Schaefer/Risch, PIs). The RC2 project enabled genome-wide SNP genotyping (GWAS) to be conducted on a cohort of over 100,000 adults who are members of the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC), and participating in its RPGEH. The purpose of the RPGEH is to facilitate research on the genetic and environmental factors that affect health and disease by linking together clinical data from electronic health records, survey data on demographic and behavioral factors, and environmental data from various sources, with genetic data derived from biospecimens collected from participants. At the time of the award of the RC2 project in late 2009, the RPGEH had established a cohort of about 140,000 individuals who had answered a detailed survey, provided saliva samples for extraction of DNA, and given broad consent for the use of their data in studies of health and disease. To maximize the diversity of the resulting sample, the GERA cohort was formed by including all racial and ethnic minority participants with saliva samples (N = 20,925; 19%); the remaining participants were drawn sequentially and randomly from white non-Hispanic participants (89,341; 81%). A total of 110,266 participant samples were included to ensure that at least 100,000 were successfully assayed. The resulting GERA cohort is 42% male, 58% female, and ranges in age from 18 to over 100 years old with an average age of 63 years at the time of the RPGEH survey (2007). The sample is ethnically diverse, generally well-educated with above average income. Approximately 69% of the participants are married or living with a partner. Length of membership in KPNC averages 23.5 years. UCSF and RPGEH investigators worked with the genomics company Affymetrix to design four custom microarrays for genotyping each of the four major race-ethnicity groups included in the GERA Cohort, described in detail in Hoffmann et al., 2011a and 2011b. Following genotyping and quality control procedures, and after removal of invalid, discordant, or withdrawn samples, about 103,000 participants were successfully genotyped. The resulting genotypic data were linked to survey data and data abstracted from the electronic medical records. As described below, all RPGEH participants were mailed new consent forms with explicit discussion of the placement of data in the NIH-maintained dbGaP. About 77% of participants returned completed consent forms, resulting in a final sample size of 78,486 participants in the GERA Cohort with data for deposit into dbGaP. Origins of the RPGEH GERA Cohort The goal in creating the RPGEH GERA cohort was to create a large, multiethnic, and comprehensive population-based resource for research into the genetic and environmental basis of common age-related diseases and their treatment, and factors influencing healthy aging and longevity. The GERA Cohort consists of a diverse cohort of more than 100,000 adults who are members of the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC), and participating in its Research Program on Genes, Environment and Health (RPGEH). KPNC is an integrated health care delivery system with a population of about 3.3 million people in northern California. The membership of KPNC is representative of the general population in the 14 county area in which facilities are located, although the membership is underrepresented for the extremes of income at both ends of the spectrum. The RPGEH utilizes the longitudinal electronic health records (EHR) of KPNC to obtain clinical, laboratory, imaging and pharmacy information on all cohort members, to which personal demographic, behavioral and health characteristics have been added through member surveys. The GERA Cohort comprises a subsample of the RPGEH participant cohort, and was created through the RC2 award from the NIA, NIMH, and NIH Common Fund as described above. GERA Study Design The GERA Cohort is a subsample, as described above, of the longitudinal cohort enrolled in the Kaiser Permanente RPGEH. The RPGEH cohort includes about 400,000 survey participants of whom about 200,000 have provided broad consent and a sample of saliva or blood for use in studies of genetic and environmental factors in health and disease. The GERA Cohort was developed from a mailed survey sent to all adult members of KPNC who had been members for two years or more in 2007. All survey respondents were contacted and asked to complete a consent form; those who completed consent forms were asked to provide a saliva sample. Additional male participants were added to the RPGEH through inclusion of the Northern California sample of the California Men's Health Study (CMHS) cohort of about 40,000 men from KPNC, ages 45-69 years old at the time of the CMHS survey in 2002-2003. The CMHS participants contributed about 15,400 saliva samples to the RPGEH and were eligible for inclusion in the GERA Cohort. CMHS participants were included according to the same sampling design as for the RPGEH cohort as a whole. Specifically, all minority participants were selected for inclusion in order to maximize representation of minorities in the GERA Cohort, and Non-Hispanic White participants were selected at random to complete the sample of 110,266 GERA Cohort participants. GERA Genotypic Data High-density genotyping was conducted at UCSF using custom designed Affymetrix Axiom arrays, as described in Hoffmann et al. (2011a; 2011b). To maximize genome-wide coverage of common and less common variants, four specific arrays were designed for individuals of Non-Hispanic White (EUR), East Asian (EAS), African-American (AFR), and Latino (LAT) race/ethnicity. There was broad overlap among the SNPs on the arrays, which were designed using a hybrid greedy imputation algorithm (Hoffmann et al., 2011b) applied to genotype information validated by Affymetrix from the 1000 Genomes Project. However, in order to capture low frequency variants specific to particular race-ethnicity groups, SNP content varies between arrays. A more detailed description of the process of genotyping and results is included in Genotyping of DNA Samples. Description of the analyses of population structure and development of principal components for adjustment of population structure is included in Population Structure Analysis. GERA Phenotypic Data RPGEH and CMHS Survey Data. The sources of data on demographic and behavioral factors deposited in dbGaP for the GERA Cohort are the RPGEH and CMHS surveys. Data on common demographic factors such as gender, race/ethnicity, marital status, and education and on behavioral factors such as smoking, alcohol consumption, and body mass index, have been cleaned, edited, reconciled between the two surveys, and compiled into summary indices, where appropriate, for deposition into dbGaP. A more complete description of the survey variables is included in Survey Variables Documentation. Please note that the terms of use of the GERA Cohort Data, as specified in the Data Use Certification (DUC), prohibit the use of survey variables as outcomes in analyses. For example, a genome-wide association study (GWAS) of education or smoking is not permitted as specified by the DUC. Only health conditions can be used as outcome variables in analyses. Health Conditions derived from Kaiser Permanente Electronic Medical Records. Data on the occurrence of health conditions in participants in the GERA Cohort have been derived from summarizing ICD-9 coded diagnoses in Kaiser Permanente's electronic medical records. An algorithm that aggregates specific ICD-9 codes into appropriate diagnostic groups for selected conditions is applied to outpatient and inpatient databases; see Disease and Conditions Definitions Documentation for details. The criterion for including a condition as "present" for a participant is the occurrence of two or more diagnoses within a diagnostic category occurring on separate days. Two or more is used as the criterion in order to reduce false positives due to mistakes or rule-out diagnoses. When compared with validated disease registries, the criterion of 2+ diagnoses yields high specificity and good sensitivity. ICD-9 codes in the electronic records are specified in several ways. For outpatient visits occurring during the period 1995 to 2006, diagnoses were assigned by the treating physician who endorsed specific diagnoses on an optically scanned list that varied by specialty. Beginning in 2006 with the advent of an integrated, fully electronic medical record, outpatient diagnoses are made by physicians/ providers using a pull down menu. Discharge diagnoses from inpatient stays are specified by physicians and coded by specially trained coders. Databases of ICD-9 codes for diagnoses assigned at outpatient visits, or as one of the discharge diagnoses following inpatient stays, are complete and available for all KPNC members dating back to 1995. Although the average length of KPNC membership among GERA cohort members is 23.5 years in 2007, not all have been members since 1995, so the history for some conditions, such as those that are not chronic or recurrent, may not be complete for all cohort members. The year of first membership in KPNC is included as a variable in the list of survey variables, enabling investigators to estimate the number of years of observation of each Cohort member. RPGEH Access and Collaborations Website and Procedures The RPGEH maintains a web portal for inquiries and applications for collaboration and access to data. The url is: https://rpgehportal.kaiser.org/. RPGEH has an application process and an Access Review Committee that reviews applications for collaboration and use. For more details, please contact RPGEH through the website.

  Study phs000674

• RNA-Seq of human longitudinal whole blood samples from PCR-positive and PCR-negative recent household contacts of COVID-19 index cases.

  Little is known about the transcriptomic profile of individuals who are exposed to SARS-CoV-2 yet resist becoming PCR positive. To investigate this, longitudinal whole-blood samples were taken (0, 7, 14, and 28 days after enrolment) from PCR positive and PCR negative SARS-CoV-2-naïve household contacts who were recently exposed to a COVID-19 index. Samples were also taken from pre- and post-pandemic unexposed controls. Total RNA was extracted from PAXgene tubes before undergoing poly(A) selection followed by globin and rRNA depletion. DNA libraries were constructed using the NEBNext® Ultra™ II Directional RNA Library Prep Kit for Illumina. All samples were then sequenced across 2 flowcells of an Illumina HiSeq 4000.

  Study EGAS50000000473

• Rare Disease Susceptibility Alleles in Children with Crohn Disease

  The overall goal of this proposed project is to identify rare genetic variants contributing to childhood onset-Crohn disease. Crohn disease is a chronic inflammatory disorder of the gastrointestinal tract of unclear etiology and no known cure. Affected children suffer from diarrhea, abdominal pain, growth disturbances, and an impaired quality of life. The identified Crohn disease susceptibility alleles have improved our understanding of Crohn disease pathogenesis. However, the identified susceptibility alleles do not account for the observed heritability, nor have disease-causing alleles in many genomic regions been identified. For the proposed studies, we will use 1) existing DNA samples collected from high-risk Crohn kindreds identified using the extensive genealogical records available only in Utah, 2) existing DNA samples obtained from very young children with Crohn disease and their parents, and 3) existing DNA samples obtained from healthy controls that are free of a personal or family history of autoimmune disorders.

  Study phs000926

• Single-cell transcriptome of T-ALL P1

  In this study, we profiled single-cell transcriptome (10X genomics) of Patient-derived xenografts (PDX) T-ALL replase samples from P1 patient. Primary human T-ALL cells were recovered from cryopreserved bone marrow aspirates of patients enrolled in the ALL-BFM 2009 study. Patient-derived xenografts (PDX) were generated as previously described by intrafemoral injection of 1 Million viable primary ALL cells in NSG mice110 PDX-derived (P1)28 cells were frozen until processing. For scRNA-seq library preparation, cryopreserved cells were thawed rapidly at 37 ℃ and resuspended in 10 ml warm Roswell Park Memorial Institute (RPMI) medium with 100 μg/ml Dnase I. Cells were centrifuged for 5 mins at 300 g, and resuspended in ice-cold phosphate buffered saline (PBS) with 2% foetal bovine serum (FBS) and 5mM EDTA. Cells were stained on ice with anti-murine-CD45-PE (mCD45)(clone 30-F11; BioLegend; 1:20) in the dark for 30 mins. 1:100 DAPI was added and incubated in the dark for 5 mins before sorting. Triple negative cells (DAPI-mCD45-GFP-) were sorted (Fig. S27) using a BD FACSAria™ Fusion Cell Sorter into ice cold 0.03% bovine serum albumin (BSA) in PBS. All isolated cells were immediately used for scRNA-seq libraries, which were generated as per the standard 10x Genomics Chromium 3′ (v.3.1 Chemistry) protocol. Completed libraries were sequenced on a NextSeq5000 sequencer (HIGH-mode, 75 bp paired-end).

  Dataset EGAD00001008325

• Type 1 Diabetes Genetics Consortium (T1DGC): Copy Number Variant (CNV) Study

  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 parent-offspring trios as well as cases and controls were ascertained from existing and de novo collections. For T1D, the genome-wide association study (GWAS) design has been successful at detecting ~50 loci that contribute disease risk. However, in the case of T1D as well as almost all other traits, the sum of these loci does not fully explain the heritability estimated from familial studies. One possibility for the undiscovered contribution to familial aggregation is that additional variants exist but have not yet been found because they have not effectively been targeted by the GWAS design. In this study, we focus on a specific class of large deletions/duplications -- copy number variants (CNVs) - and particularly to the subset of these loci that mutate rapidly, are not tagged by SNPs, and are highly polymorphic. The T1DGC assembled 2,601 T1D ASP families and 69 Parent-T1D offspring trios, that were eligible for this study. 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. Importantly, the source of DNA for CNV evaluation was uniform within a family (either all from PBMC or from EBV-transformed cell lines). We use a family based design that was optimized to capture these previously untested variants. We then perform a genome-wide scan to assess their contribution to T1D.

  Study phs000910

• Personalized peptide vaccination among 173 patients with IDH wildtype glioblastoma: a retrospective analysis

  Tumors from 173 GBM patients were analysed for somatic mutations to generate a personalized peptide vaccine targeting tumor-specific neoantigens. Exome libraries for 173 glioblastoma tumors and matched normal DNA were sequenced on Illumina platform, alongside whole transcriptomes from the tumor samples. Paper Abstract: Current treatment outcome of patients with glioblastoma (GBM) remains poor. Following standard therapy, recurrence is universal with limited survival. GBM tumors from 173 patients were analysed for somatic mutations to generate a personalized peptide vaccine targeting tumor-specific neoantigens. Among all patients, including 70 treated prior to progression (primary) and 103 treated after progression (recurrent), the median overall survival from first diagnosis was 31.9 months (95% CI: 25.0-36.5). Side effects were infrequent and were predominantly grade 1 or 2. A vaccine-induced immune response to at least one of the vaccinated peptides was detected in blood samples of 87 of 99 (88%) monitored patients. T-cell responses to vaccinated neoepitope peptides were durable in most patients. Significantly prolonged survival was observed for patients with multiple vaccine-induced immune responses (53 months) compared to those with no/low induced responses (27 months; P=0.03). Altogether, our results highlight that the application of personalized neoantigen-targeting peptide vaccine is feasible and represents a promising potential treatment option for GBM patients.

  Study EGAS50000000449

• Whole genome sequencing data of paediatric T cell acute lymphoblastic leukemia (T-ALL)

  T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy accounting for approximately 15–25% of pediatric and adult ALL cases. Despite significant therapeutic improvements over the last decade, the prognosis of T-ALL remains less favorable than that of B-ALL, with 5-year EFS and OS of around 76–82% and 80–88%, respectively, depending on the treatment protocol used. T-ALL patients often suffer from failure of induction therapy or early relapse, which is associated with a dismal prognosis. Approximately 10–15% of T-ALL patients experience relapse, and survival after relapse is poor.

  Study EGAS50000001387

• Genome-wide characterization of Kuwaiti Arab Population

  All the 620 individuals were genotyped using Illumina HumanOmniExpress arrays for 730,525 SNPs.

  Study EGAS00001005034

• The ICGC-TCGA DREAM Somatic Mutation Calling - Tumour Heterogeneity Challenge

  Tumors are composed of many different cell types, ranging from the normal tissue micro-environment, infiltrating immune cells and tumour cells. This group of tumour cells is itself intrinsically highly heterogeneous, driven by the rapid mutation rate of cancer cells to become a mixture of different sub-populations. These different types of cells, called subclones, have different sets of mutations in their DNA. Because some subclones evolve from others, many subclones share mutations. While it is increasingly easy to determine what mutations are present in the tumor, it remains very difficult to determine which subclones have which mutations. The task of assigning mutations to subclones is called subclonal reconstruction.The ICGC-TCGA DREAM Somatic Mutation Calling - Tumour Heterogeneity Challenge (SMC-Het) is an international effort to improve standard methods for subclonal reconstruction: to quantify and genotype each individual cell population present within a tumor. The goal of this challenge is to identify the best subclonal reconstruction algorithms and to identify the conditions that affect their performance.

  Study EGAS00001002092

• Genetic Analysis of Normal Human Facial Variation

  The purpose of this project is to identify genes associated with normal human quantitative facial variation. The motivation for this project stems from the fact that very little is known about how variation in specific genes relates to the diversity of facial forms commonly observed in humans. Viable candidates for these morphogenes originate from a number of sources: tissue expression studies, animal models with targeted or spontaneous mutations, and genetic syndromes with craniofacial manifestations. Importantly, understanding the genetic basis for normal facial variation also has important implications for health-related research. For example, this work has the potential to shed light on the factors influencing liability to common craniofacial anomalies such as orofacial clefts. There is now ample evidence that certain facial features (e.g., increased midfacial retrusion) characterize individuals genetically at-risk for orofacial clefts (e.g., biological relatives of affected cases). While these predisposing facial features are statistically over-represented in at-risk groups, they are also common in the general population. Since many of the current candidate genes for clefting are thought to play a critical role in facial morphogenesis, variation in these genes may also underlie normal variation in these facial features. These candidate genes, however, probably represent only a small fraction of the total number of loci influencing normal human facial variation. Phenotypes for this project were obtained from over 3000 healthy Caucasian subjects recruited through three separate studies. The majority of the subjects were recruited as part of the 3D Facial Norms Project, which is described in extensive detail here: (https://www.facebase.org/facial_norms/notes). The provided dbGaP phenotypes include a series of anthropometric craniofacial measurements (linear distances) primarily derived from 3D photographic facial surface scans (see previous hyperlink). The specific genotyping requested is described elsewhere in this document. Our analysis team is pursuing a variety of different analytic approaches to derive genetically informative phenotypes, including various shape-based morphometric methods. For those interested in pursuing more advanced phenotypic approaches, the original 3D surface scans and additional phenotypic traits are available to researchers through the FaceBase Consortium. This dataset has the potential to facilitate the discovery of new genetic loci with an important role in both normal and abnormal facial development. It may also serve as a dataset to test hypotheses regarding specific SNP associations (e.g. as a replication dataset) or as part of a larger meta-analysis.

  Study phs000949

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

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

  Study phs003190