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• Single-cell genome-wide concurrent haplotyping and copy-number profiling through genotyping-by-sequencing

  scGBS is a single-cell sequencing-based methodology to haplotype and copy-number profile single cells. Genomic size and complexity is reduced through restriction enzyme digestion and DNA is genotyped through sequencing of the restriction fragments. scGBS data serves as the input for haplarithmisis, an algorithm we previously developed for SNP array-based single-cell haplotyping (Zamani Esteki et al., 2015). We established technical parameters and developed an analysis pipeline enabling accurate concurrent haplotyping and copy-number profiling of single cells with the use of a HapMap cell line pedigree (7 single cells). A clinical validation of the methodology with a total of 14 single blastomeres and 3 trophectoderm samples biopsies from human preimplantation embryos for 6 PGT-M families were processed with scGBS and were previously haploptyped via SNP array.

  Dataset EGAD00001007794

• 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

• A next-generation dual guide CRISPR system for genetic interaction library screening

  Raw sgRNA sequencing data from a pilot CRISPR screening library to test the dual guide vector system (8,914 guide pairs), and from a large scale genetic interaction screen (~100,136 guide pairs) in HT-29 cells. This data refers to Burgold et al. Nature Communications 2025.

  Dataset EGAD00001015754

• Genomic evolution and natural history of myeloproliferative neoplasms on therapy - SCC_CALRmutated ET

  Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts but disease can progress to myelofibrosis or acute myeloid leukaemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukaemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukaemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of haematopoietic colonies revealed age-appropriate polyclonal haematopoiesis in triple-negative essential thrombocythaemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C>G mutations following azacitidine and characteristic T>A/T>G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis.

  Dataset EGAD00001016068

• WTS and WES of Renal Cell Carcinoma Tumors From a Phase III Anti-Angiogenic Adjuvant Therapy Trial

  Archival de-identified formalin-fixed paraffin-embedded RCC tumor tissue blocks from nephrectomy or tumor biopsy were processed as per below and the same sections were used for both DNA and RNA extractions. For WES (ACE version 3; Illumina NovaSeq), samples were profiled using Personalis ACE Cancer Exome (Personalis, Inc, Menlo Park, CA) Whole-transcriptome profiles were generated by RNA-seq (Accuracy and Content Enhanced (ACE) version 3; Illumina NovaSeq) using Personalis ACE Cancer Transcriptome (Personalis, Inc, Menlo Park, CA ) Of the 615 patients in the intent-to-treat population in S-TRAC trial, 193 individual specimens were available for molecular profiling, of which 171 (27.8%) (sunitinib, n = 91; placebo, n = 80) returned results for the WES analysis, and 133 (21.6%) (sunitinib, n = 72; placebo, n = 61) returned results for the GES analysis. Of the 138 WTS samples with data, replicates for two patients were summarized by median expression, and three samples were excluded from the final analysis due to low counts.

  Dataset EGAD00001009294

• RNA Expression in Diverse Donor Derived Dermal Fibroblasts Correlates with Reprogramming to Pluripotency

  The cohort used in this study includes 36 African American (17 female, 19 male) and 36 White American (19 female, 17 male) individuals. The total cohort has a median age of 32 years, with a range of 20-64 years. The African American cohort has a median age of 34, with a range of 21-52 years. The White American cohort has a median age of 31, with a range of 20-64 years. Primary dermal fibroblast lines were derived from skin biopsies obtained from adult individuals at the NIEHS under institutional review board approved protocol human subjects 10-E-0063, "Sample Collection Registry for Quality Control of Biological and Environmental Specimens and Assay Development and Testing protocol" (ClinicalTrials.gov #NCT01087307). All participants gave written informed consent for tissue donation. Donor sex, age, and ancestry were voluntarily self-reported. Fibroblast cells were reprogrammed via lentiviral transduction using six transcription factors contained in three plasmids (ADDGENE/PSIN4-EF2-N2L, ADDGENE/PSIN4-EF2-O2S and ADDGENE/PSIN4-CMV-K2M). Reprogramming efficiency was determined by alkaline phosphatase staining of triplicate 10cm reprogrammed dishes containing colonies, which were then scanned. The saved images were analyzed with ImageJ 1.51h (Wayne Rasband, National Institutes of Health, USA) to count colonies, using color threshold adjusted and binary converted images of each dish. Triplicate plates were averaged and reported as colony counts or percent reprogramming efficiency ((# of colonies/250,000) x100). The African American cohort had reprogramming efficiencies ranging from 0.06-1.37%, with a median of 0.655%. The White American cohort had reprogramming efficiencies ranging from 0.02-1.13%, with a median of 0.455%. Our goal was to define transcriptomic heterogeneity that could be contributing to differences in reprogramming efficiency between individuals and between groups. Total RNA was obtained from dermal fibroblasts and matched iPSCs. For each sample, 500 ng total RNA was used as input for preparation of whole transcriptome rRNA depleted libraries. An adapter-ligated library was prepared with the KAPA HyperPrep Kit (KAPA Biosystems, Wilmington, MA) using Bioo Scientific NEXTflex™ DNA Barcoded Adapters (Bioo Scientific, Austin, TX, USA) according to KAPA-provided protocol. Sequencing was performed using an Illumina HiSeq 2500 following Illumina-provided protocols for 2x150 bp paired-end sequencing. Each transcriptome was sequenced to a target depth of 125 million reads. The following mean raw reads were obtained: African American dermal fibroblasts= 129,571,450; White American dermal fibroblasts= 131,939,505; African American iPSCs= 132,501,335; White American iPSCs= 134,394,164. Raw reads were aligned to hg19 using the STAR alignment tool (https://github.com/alexdobin/STAR). The following mean aligned reads were obtained: African American dermal fibroblasts= 123,315,343; White American dermal fibroblasts= 125,178,035; African American iPSCs= 123,148,312; White American iPSCs= 123,886,992. Reprinted from L. C. Mackey et al., Epigenetic Enzymes, Age, and Ancestry Regulate the Efficiency of Human iPSC Reprogramming. Stem Cells 36, 1697-1708 (2018), with permission from Wiley. Reprinted from L. S. Bisogno et al., Ancestry-dependent gene expression correlates with reprogramming to pluripotency and multiple dynamic biological processes. Science Advances 6 (47) (2020) (PMID: 33219026), with permission from AAAS.

  Study phs002341

• The Role of E2F4 in Controlling Resistance to Irinotecan (CPT-11) in Human Colon Cancer

  This study reports the results of RNA sequencing (RNA-seq) experiments performed on three isogenic clones of the human HT29 colon cancer cell line, genetically engineered to achieve the selective inactivation of the adenovirus early 2 (E2) gene transcription factor 4 (E2F4) protein, a key functional component of the multimeric transcriptional repression complex known as the dimerization partner (DP), retinoblastoma-like (RB-like), E2F and multi-vulva class B (MuvB) complex (DREAM). In previous studies, we identified E2F4 as a key regulator of colorectal cancer (CRC) resistance to irinotecan (CPT-11), a cytotoxic agent that stands at the backbone of multiple chemotherapy regimens for the treatment of metastatic CRCs. The molecular mechanisms linking E2F4 to irinotecan resistance, however, remain poorly understood. The present study was designed to identify which genes are under the transcriptional control of E2F4, either at baseline or following exposure to SN38 (i.e., the active metabolite of irinotecan, generated in vivo by biotransformation in the liver) in order to clarify the role played by E2F4 in shaping colon cancer resistance to chemotherapy. The cell line used for this study (HT29) is aneuploid and contains three copies of the E2F4 gene, because of a trisomy of chromosome 16, where the E2F4 gene is located (Kawai et al., Genes, Chromosomes & Cancer, 34:1-8, 2002; PMID: 11921276). HT29 cells were infected with lentivirus vectors encoding for CRISPR/Cas9 constructs designed to selectively inactivate the E2F4 gene, using three distinct guide-RNAs (gRNAs), each targeting a different sequence within the proximal exons of the E2F4 gene (exon 1, exon 2). Lentivirus-infected cells were sub-cloned by single-cell fluorescence-activated cell sorting (FACS), based on the differential expression of a fluorescent reporter (EGFP) expressed in tandem with the gRNAs. Isogenic clones (EGFP+) were then screened to identify those with a tri-allelic knock-out, as revealed by both genetic sequencing of the E2F4 gene (revealing the presence of three distinct frameshift mutations) and Western blot (revealing complete loss of E2F4 protein expression). The study includes twelve (n=12) RNA-seq experiments, representative of 3 experimental replicates (i.e., three distinct isogenic clones of the HT29 cell line, each displaying complete loss of E2F4 expression) and 3 negative controls (i.e., three independent preparations of the parent HT29 cell line, infected with a lentivirus vector encoding for a non-targeting gRNA) exposed to 2 distinct in vitro cell culture conditions: a) treatment with SN38 resuspended in dimethyl sulfoxide (DMSO); or b) treatment with DMSO alone (negative control). The in vitro treatment regimen used for SN38 (32 nM, 24 hours) was designed so that the exposure to SN38 experienced in vitro by HT29 cells would mirror the exposure to SN38 experienced in vivo by malignant tissues, as measured, for example, in metastatic CRC patients receiving a standard dose of irinotecan (180 mg/m2) administered by intravenous infusion over 90 minutes (Deyme et al., Cancer Chemotherapy and Pharmacology, 88:247-258, 2021; PMID: 33912999).

  Study phs003560

• 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

• Multi-Site Collaborative Study for Genotype-Phenotype Associations in Alzheimer's disease and Longitudinal follow-up of Genotype-Phenotype Associations in Alzheimer's disease and Neuroimaging component of Genotype-Phenotype Associations in Alzheimer's disease

  GenADA is a multi-site collaborative study, involving GlaxoSmithKline Inc and nine medical centres in Canada, to develop a dataset containing 1000 Alzheimer's disease patients and 1000 ethnically-matched controls in order to associate DNA sequence (allelic) variations in candidate genes with Alzheimer's disease phenotypes. The study consists of both retrospective and prospective components, that is, patients with an existing diagnosis of Alzheimer's disease as well as newly diagnosed patients were enrolled in the study. Thus, clinical data was retrospectively or prospectively obtained on Day 1 of entry into GenADA. Where possible, biological relatives with Alzheimer's (up to third degree relationship such as cousins) and unaffected siblings of AD cases were also recruited. Note that recruitment numbers for biological relatives were lower than expected and genotypic data has not been submitted to dbGap for these subjects. The purpose of this study is: To identify DNA sequence variations (genotype) in candidate genes that are associated with the clinical symptoms and behavioural features of Alzheimer's disease (phenotype), which differ between study participants with and without the disease. To identify other genotype-phenotype associations in cognitively impaired study participants such as age of onset, family history, rate of cognitive decline, patterns of behavioural/psychiatric non-cognitive symptoms factors, response to treatment co-morbid conditions, and risks/exposure. The final subject recruitment for this study included 875 Alzheimer's disease patients, 850 ethnically-matched controls, and 37 family members. GenADA LONG is a longitudinal assessment to the original GenADA study. Eligible subjects were recruited from five of the nine memory clinics that participated in the GenADA study. Mild to moderate AD participants, a matched subset of controls, and biological related siblings (both affected and unaffected) or other blood relatives affected with AD, were initially examined a minimum of 12 months from recruitment into the original GenADA study, then at two further intervals of 12 and 18 months after time of entry into GenADA LONG. This enables an evaluation of the disease progression in AD patients and a determination of whether controls show evidence of cognitive decline. The overall goal of this extension study is to identify genetic differences and environmental influences that modulate the age of onset of the disease, the course of the disease, and/or biomarkers for neurodegenerative processes. Three of the five memory clinics that participated in the GenADA LONG study recruited eligible patients into GenADA Imaging. A concurrent neuroimaging sub-study was conducted at three of the five memory clinics participating in GenADA LONG. Eligible AD cases with mild to moderate AD, who were recruited into the original GenADA study and participated in the GenADA LONG extension study, were enrolled. Additionally, controls that showed signs of cognitive decline, as part of the assessment in GenADA LONG, were imaged at baseline, 12 and 18 month scanning intervals. The objective of this study is to find genes that: affect changes in AD brain volume measure by magnetic resonance in order to investigate how well change in brain volume predicts other key clinical measures in AD, such as neurodegenerative scales; that correlate changes in brain volume for other genotype-phenotype associations in cognitively impaired study participants; and that correlate with other clinically applicable magnetic resonance measures of pathology that can be conducted at the same time as structural volume measures, and are complementary to the volume measures. The ultimate aim of this research is to obtain a better understanding and definition of Alzheimer's Disease in order to develop new improved medicines.

  Study phs000219

• Rapid Whole Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care Units

  Monogenic diseases are frequent causes of neonatal morbidity and mortality, and disease presentations are often undifferentiated at birth. More than 3,500 monogenic diseases have been characterized, but clinical testing is available for only some of them and many feature clinical and genetic heterogeneity. As such, an immense unmet need exists for improved molecular diagnosis in infants. Because disease progression is extremely rapid, albeit heterogeneous, in newborns, molecular diagnoses must occur quickly to be relevant for clinical decision-making. We describe 50-hour differential diagnosis of genetic disorders by whole-genome sequencing (WGS) that features automated bioinformatic analysis and is intended to be a prototype for use in neonatal intensive care units. Retrospective 50-hour WGS identified known molecular diagnoses in two children. Prospective WGS disclosed potential molecular diagnosis of a severe GJB2-related skin disease in one neonate; BRAT1-related lethal neonatal rigidity and multifocal seizure syndrome in another infant, identified BCL9L as a novel, recessive visceral heterotaxy gene (HTX6) in a pedigree, and ruled out known candidate genes in one infants. Sequencing of parents or affected siblings expedited the identification of disease gene in prospective cases. Thus, rapid WGS can potentially broaden and foreshorten differential diagnosis, resulting in fewer empirical treatments and faster progression to genetic and prognostic counseling. Reprinted from Saunders et. al, Rapid Whole-Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care Units. Sci. Transl. Med. 4, 154ra135 (2012; PMID: 23035047) with permission from AAAS.

  Study phs000564

• Biomarkers in Transplant Recipients

  Biliary atresia causes jaundice and liver failure in newborn children. In this study, single nucleotide polymorphisms were characterized in children with biliary atresia and identified ARF6 as a susceptibility gene for this disease. Knockdown of this gene in zebrafish embryos impaired formation of bile ducts and excretion of bile from the zebrafish liver. Subject enrollment: Children with biliary atresia were enrolled at Children's Hospital of Pittsburgh (CHP) after obtaining written consent from parents for the University of Pittsburgh IRB approved protocol number 0405628. At the Center for Applied Genomics (CAG), all subjects were enrolled after obtaining written consent from parents per Children's Hospital of Philadelphia IRB approval number 06-004886 Genotyping array: Genotyping of DNA obtained from blood was performed with the Infinium HumanHap550K BeadChip (Illumina, San Diego, CA). Statistical methods and software: SNP genotype frequencies were compared between cases and controls with a chi-square test statistic applied in Plink [Purcell et al, 2007] for SNPs with at least 90% call rate and 1% minor allele frequency (MAF). Cases and controls: All DNA samples had excellent data quality with call rates > 98%. A total of 63 Caucasian BA cases and 1907 controls were compared at > 550000 SNPs, and demonstrated a very low genomic inflation factor of 1.00627. Description of Cases: Biliary atresia patients had received a Kasai procedure and demonstrated histopathological features of biliary obstruction, and were recruited at evaluation for transplantation or after liver transplantation.

  Study phs000960

• Indexing Genes Impacted by Copy Number Variation in Developmental Disorders

  A challenge in clinical genomics is to predict whether copy number variation (CNV) affecting a gene or multiple genes will manifest as disease. Increasing recognition of gene dosage effects in neurodevelopmental disorders prompted us to develop a computational approach based on critical-exon (highly expressed in brain, highly conserved) examination for potential etiologic effects. Using a large CNV dataset, our updated analyses revealed significant (P < 1.64 x 10-15) enrichment of critical-exons within rare CNVs in cases compared to controls. Separately, we used a weighted gene co-expression network analysis (WGCNA) to construct an unbiased protein module from prenatal and adult tissues and found it significantly enriched for critical exons in prenatal (P < 1.15 x 10-50, OR = 2.11) and adult (P < 6.03 x 10-18, OR = 1.55) development. WGCNA yielded 1,206 proteins for which we prioritized the corresponding genes as likely to have a role in neurodevelopmental disorders. We compared the gene lists obtained from critical-exon and WGCNA analysis and found 438 candidate genes associated with CNVs annotated as pathogenic, or variants of uncertain significance (VOUS), from among 10,619 developmental delay cases. We identified genes containing CNVs previously considered to be VOUS, to be new candidate genes for neurodevelopmental disorders (GIT1, MVB12B and PPP1R9A) demonstrating the utility of this strategy to index the clinical effects of CNVs. Reprinted from Uddin et al, 2016, with permission from Scientific Reports.

  Study phs001154

• Genome Wide Association for Asthma and Lung Function

  The SNP Typing for Association with Multiple Phenotypes from Existing Epidemiologic (STAMPEED) asthma project includes subjects with asthma and controls from the Chicago Asthma Genetics Study (CAG), NHLBI multicenter Severe Asthma Research Program (SARP) and NHLBI Collaborative Studies on the Genetics of Asthma CSGA (Wake Forest). All studies included European American and African American children and adults with asthma ranging from mild to severe and adult controls. CAG participants were collected at the University of Chicago. SARP participants were recruited at the NHLBI SARP sites with an emphasis on recruiting severe asthmatics (Moore et al, Am J Respir Crit Care Med, 2010, PMID: 19892860). CSGA cases and controls collected by the Wake Forest investigators were also included. Asthma status was based on both a physician's diagnosis and either bronchodilator reversibility or hyper-responsiveness to methacholine as well as less than 5 pack years of smoking. Genotyping was performed on the Illumina 1Mv1 platform, with individual genotypes called using clustering algorithms as implemented in the BeadStudio software by Illumina. The total number of markers following standard QC was 1,025,129. Imputation was performed using the HapMap phase 2, release 21 SNPs using MACH with the phased HapMap CEU and YRI haplotypes as a reference. Case/control association tests for asthma status were performed using logistic regression in R (http://CRAN.R-project.org/) on genotype dosages, and adjusting for the first principal component from EIGENSTRAT.

  Study phs000355

• Whole Exome Sequencing of DNA from Pre-and Post-Chemotherapy Needle Biopsies of Triple Negative and Inflammatory Breast Cancers Enrolled in the S0800 Trial

  Purpose: The purpose of this study was to assess the somatic mutation landscape of breast tumors before and after neoadjuvant chemotherapy. The data includes whole exome sequencing of pre- and post- tissues that were collected in the context of an already published clinical trial SWOG S0800 (ZA Nahleh et al. Breast Cancer Research and Treatment. 158:485-495, 2016). The trial compared the efficacy of sequential nab-paclitaxel followed or preceded by doxorubicin/cyclophosphamide anthracycline chemotherapy with or without bevacizumab as preoperative therapy for stage II-III breast cancer. Experimental Design: 29 pre-treatment biopsies and 9 matching post-treatment surgically resected cancer tissues were available for analysis and were subjected to whole exome sequencing to identify mutational patterns associated with response to neoadjuvant chemotherapy. The 9 paired samples with residual invasive cancer after therapy were also analyzed to assess changes in mutational patterns in response to therapy. No matching normal tissues were available for germline sequencing and therefore we used n=7 post-treatment breast tissues without residual cancer (i.e. complete eradication of cancer by therapy) as a normal cohort to facilitate somatic variant calling.Conclusion: These results suggest that genomic disturbances in BRCA-related DNA repair mechanisms, reflected by a dominant mutational signature 3, confer increased chemotherapy sensitivity. Cancers that survive neoadjuvant chemotherapy, frequently have alterations in cell cycle regulating genes but different genes are affected in different patients.

  Study phs001883

• Transdisciplinary Studies of Genetic Variation in Colorectal Cancer(CORECT): Meta-analysis

  This study is part 2 of 2 for Schumacher et al, Nat Communication. 2015 Jul 7;6:7138. Part 2 is the pooled meta-analysis of 29 different studies of 37,955 European (18,299 Cases/19,656 Controls) participants using eight different genotyping platforms/variations. table, th, td { border: 1px solid black; border-collapse: collapse; } Study Name Participants Platform CFR-1 2976 Illumina 1M, 1M Duo, Omni1 CFR-2 3053 Affymetrix Axiom MECC 1 982 Illumina Omni 2.5 MECC2 1940 Affymetrix Axiom Kentucky 2172 Affymetrix Axiom ACS/CAPII 1086 Affymetrix Axiom Melbourne 1008 Affymetrix Axiom Newfoundland 672 Affymetrix Axiom ASTERKSI 1895 Illumina 300K COLO23 212 Illumina 300K DACHS1 3417 Illumina 300K DACHS2 1173 Illumina OmniExpress DALS1 1416 Illumina 550k/610K DALS2 874 Illumina 300K HPFS1 457 Illumina OmniExpress HPFS2 348 Illumina OmniExpress HPFS AA 658 Illumina OmniExpress MEC 674 Illumina 300K NHS1 1168 Illumina OmniExpress NHS2 340 Illumina OmniExpress NHSAA 1091 Illumina OmniExpress OFCCR 1172 Affymetrix 100k/500K PHS 771 Illumina OmniExpress PMH 402 Illumina 300K PLCO1 2509 Illumina 550k/610K PLCO2 901 Illumina 300K VITAL 573 Illumina 300K WHI1 1999 Illumina 550k/610K WHI2 573 Illumina 300K Since this study is a meta-analysis no corresponding phenotype, pedigree, sample, subjects, or primary molecular data are available. Each contributing study/platform will have fulfilled its own DBGAP submission commitment. This DBGAP entry is for European participants in the the pooled meta-analysis exclusively.

  Study phs001499

• The Genetics of Type 2 Diabetes Consortium (GoT2D): Low-Pass Sequencing and High-Density SNP Genotyping for Type 2 Diabetes

  The Genetics of Type 2 Diabetes Consortium (GoT2D) is a collaboration between the University of Michigan, the Broad Institute and the Wellcome Trust Centre for Human Genetics. The overall aim is to extend upon recent efforts, such as genome-wide association studies (GWAS) and large scale meta-analyses. While they have proved successful at mapping genomic loci that influence human diseases, like type 2 diabetes, much of the heritability remains unexplained. In this study, we use next generation sequencing and genotyping technologies to query for lower frequency variants in the human genome. Thereby, allowing a deeper characterization of the spectrum of alleles associated with type 2 diabetes risk, and a better assessment of the genes that play a role in the etiology of type 2 diabetes development. We studied 1,326 T2D cases and 1,331 normoglycemic controls from Northern and Central Europe (Sweden, Finland, UK, and Germany). To efficiently characterize the entire genome sequence of each individual, we performed low-coverage (~5x) whole-genome sequencing, augmented by deep coverage (~100x) sequencing of the exome (Fuchsberger et al, 2016), and dense (2.5M) single nucleotide polymorphism (SNP) genotyping using the HumanOmni2.5 array. The data deposited in dbGaP will include all the Swedish, Finnish, and UK samples, but the German data will be deposited in the European Genome-phenome Archive (EGA), by virtue of the project specific funding requirements.

  Study phs000840

• Trisomy 21 Dosage Compensation Map (T21DoCoMap)

  Excess gene dosage from human chromosome 21 (HSA21), due to trisomy or translocation of HSA21 material, causes Down syndrome (DS). We derived trisomy 21 (T21) induced pluripotent stem cells (iPSCs) alongside otherwise isogenic euploid controls from mosaic DS fibroblasts (GM00260, first described in Lubiniecki et al., PMID: 225951) of the NIGMS genetic cell repository, to enable analysis of whole-chromosomal and individual gene dosage imbalance in the context of in vitro models of DS development. Virtual karyotyping (by Infinium CytoSNP-850k), and phased genotyping (by linked-read whole-genome sequencing) of the resulting iPSC lines provide a deeply-characterized genomic platform for dissection of HSA21 gene dosage. We apply this highly unique resource to allelic analysis of mRNA sequencing of iPSCs and differentiated neural lineages, and demonstrate its utility in the context of inducible HSA21 dosage compensation. To this end, we equipped one distinct HSA21 copy with a doxycycline-inducible XIST transgene, which endogenously silences one X in 46,XX females. Standard and allele-specific RNA-seq analysis confirms mono-allelic T21 silencing to be virtually complete and irreversible, further supported by DNA methylation data (Infinium methylEPIC). This full-length HSA21 map of phased single-nucleotide and insertion/deletion variants enables allele-specific applications for gene-level dissection T21 dosage effects. Because our XIST remains inducible in post-mitotic T21 neurons and astrocytes, we perform single-nuclei RNA-seq to demonstrate XIST efficiently represses genes even after terminal differentiation.

  Study phs002397

• The Genomic and Transcriptomic Landscape of a HeLa Cell Line

  HeLa is the most widely used model cell line for studying human cellular and molecular biology. To date, no genomic reference for this cell line has been released, and experiments have relied on the human reference genome. Effective design and interpretation of molecular genetic studies performed using HeLa cells require accurate genomic information. Here we present a detailed genomic and transcriptomic characterization of a HeLa cell line. We performed DNA and RNA sequencing of a HeLa Kyoto cell line and analyzed its mutational portfolio and gene expression profile. Segmentation of the genome according to copy number revealed a remarkably high level of aneuploidy and numerous large structural variants at unprecedented resolution. Some of the extensive genomic rearrangements are indicative of catastrophic chromosome shattering, known as chromothripsis. Our analysis of the HeLa gene expression profile revealed that several pathways, including cell cycle and DNA repair, exhibit significantly different expression patterns from those in normal human tissues. Our results provide the first detailed account of genomic variants in the HeLa genome, yielding insight into their impact on gene expression and cellular function as well as their origins. This study underscores the importance of accounting for the strikingly aberrant characteristics of HeLa cells when designing and interpreting experiments, and has implications for the use of HeLa as a model of human biology. Copyright Landry et al., "The Genomic and Transcriptomic Landscape of a HeLa Cell Line," G3: Genes | Genomes | Genetics (2013).

  Study phs000643

• Field studies of Cryptosporidiosis and Enteropathogens in Bangladesh

  Cryptosporidiosis causes severe diarrhea in infants in the developing world. There is no vaccine to prevent it, and little in the way of treatment. This study on Bangladeshi urban slum children aims to support the design of a vaccine, both by determining how the immune system protects from infection and by identifying the genotypes of the parasite that should be included in a vaccine, as well as aid in development of therapies by identifying human genes that control infection. The primary objective of the study was to determine the incidence and contribution to disease of the different species and genotypes of cryptosporidia. Secondary objectives were designed to determine acquired immune response to cryptosporidiosis and identify human genes that influence susceptibility to cryptosporidiosis. This is an observational study. Children were recruited from Mirpur Dhaka slum (Cohort 1) and rural Mirzapur (Cohort 2) and followed for cryptosporidium infection longitudinally from birth through age 4 years in Cohort 1 and birth through age 2 years in Cohort 2. Biweekly household visits for diarrheal surveillance were made in addition to anthropometric measurements of mother and child, blood samples collected two times each year from the child, a work-up of diarrheal stools and non-diarrheal surveillance stools for cryptosporidium and other enteropathogens, and blood and breast milk samples from the mother. A detailed description of the study design and procedures can be obtained from publication: Kevin L Steiner, et al., 2018, PMID: 29897482.

  Study phs001665

• NIPT samples for systematic evaluation of BinDel, a software tool for detecting clinically significant microdeletions in low-coverage WGS-based NIPT samples

  This dataset contains three sets of samples. The first sample set contains euploid fetus pregnancies reported by NIPTIFY screening test and postnatal evaluation. Dataset was processed similarly to previously published guidelines from KU Leuven, with modifications [1]. Briefly, peripheral blood samples were collected in cell-free DNA BCT tubes (Streck, USA), and plasma was separated with standard dual centrifugation. Cell-free DNA was extracted from 3 ml plasma using MagMAX Cell-Free DNA Isolation Kit (ThermoFisher Scientific). Whole-genome libraries were prepared using the FOCUS (Fragmented DNA Compact Sequencing Assay, Competence Centre on Health Technologies, Estonia) NIPT method protocol with 12 cycles for the final PCR enrichment step. In the following quantification, equal amounts of 36 samples were pooled, and the quality and quantity of the pool were assessed on Agilent 2200 TapeStation (Agilent Technologies, USA). Whole genome sequencing was performed on the NextSeq 550 instrument (Illumina Inc.) with an average coverage of 0.32× (minimum 0.08 and maximum 0.42) and producing 85 bp single-end reads. The second sample set contains a single NIPT sample postnatally diagnosed with Prader-Willi syndrome. The sample was sequenced with Illumina NextSeq 500 platform, producing 85 bp single-end reads with an average per-sample coverage of 0.32× at the University of Tartu, Institute of Genomics Core Facility, according to the manufacturer’s standard protocols, as described previously [2]. The third sample set contains samples SC005 (SeraCare Life Sciences Inc lot #10446565), SC0042 (#10571706), and SC016 (#10560229). These are SeraCare Life Sciences Inc circulating cell-free DNA (ccfDNA) like mixture of human genomic DNA that consists of matched maternal and fetus. SC005 and SC0042 consist of matched DNA of maternal and fetus with DiGeorge Syndrome. SC016 is a custom-ordered DNA Mix with fetus DNA having a pathogenic loss of the terminal region of 20p13 and a pathogenic 3q29 duplication. SC016 was processed as the first sample set was processed, and SC0042 was processed as the second sample set was processed. Sample SC005 was processed once as was sample set 1 and once as was sample set 2 processed. This study was performed with the approval of the Research Ethics Committee of the University of Tartu (#352/M-12). 1. Bayindir B, Dehaspe L, Brison N, Brady P, Ardui S, Kammoun M, et al. Noninvasive prenatal testing using a novel analysis pipeline to screen for all autosomal fetal aneuploidies improves pregnancy management. Eur J Hum Genet. 2015;23: 1286– 1293. doi:10.1038/ejhg.2014.282 2. Žilina O, Rekker K, Kaplinski L, Sauk M, Paluoja P, Teder H, et al. Creating basis for introducing noninvasive prenatal testing in the Estonian public health setting. Prenat Diagn. 2019;39: 1262–1268. doi:10.1002/pd.5578

  Dataset EGAD00001009512

• GWAS Results from Danjou et al, Nature Genetics 2015

  We report genome-wide association study results for the levels of A1, A2 and fetal hemoglobins, analyzed for the first time concurrently. Integrating high-density array genotyping and whole-genome sequencing in a large general population cohort from Sardinia, we detected 23 associations at 10 loci. Five signals are due to variants at previously undetected loci: MPHOSPH9, PLTP-PCIF1, ZFPM1 (FOG1), NFIX and CCND3. Among the signals at known loci, ten are new lead variants and four are new independent signals. Half of all variants also showed pleiotropic associations with different hemoglobins, which further corroborated some of the detected associations and identified features of coordinated hemoglobin species production.

  Study EGAS00001003645

• TRACERx100 metastatic samples

  Whole exome sequencing of 10 metastatic biopsies from four TRACERx100 patients (see EGA dataset EGAS00001002247), collected either after relapse or death. The data from these samples are initially published with Abbosh, C. et al. Phylogenetic ctDNA analysis depicts early stage lung cancer evolution. Nature, http://dx.doi.org/10.1038/nature22364 (2017). Abstract: Earlier detection of relapse following primary surgery for non-small cell lung cancer and the characterization of emerging subclones seeding metastatic sites might offer new therapeutic approaches to limit tumor recurrence. The potential to non-invasively track tumor evolutionary dynamics in ctDNA of early-stage lung cancer is not established. Here we conduct a patient-specific approach to ctDNA profiling in the first 100 lung TRACERx (TRAcking Cancer Evolution through therapy (Rx)) study participants, including one patient co-recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release in early-stage non-small cell lung cancer and perform tumor volume limit of detection analyses. Through blinded profiling of post-operative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients destined to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastases, providing a new approach for ctDNA driven therapeutic studies.

  Dataset EGAD00001003301

• Mechanisms of patient response to Dabrafenib in Melanoma

  Samples will be from the BRF113683 (BREAK-3) study which is a Phase III Randomized, Open-label Study Comparing GSK2118436 to Dacarbazine (DTIC) in Previously Untreated Subjects With BRAF Mutation Positive Advanced (Stage III) or Metastatic (Stage IV) Melanoma (n=250 enrolled)*NGS [Agilent capture (Sanger V2 panel): 360 genes and 20 gene fusions; Illumina HiSEQ Sequencing]*CNV: [via NGS or Affy SNP 6.0 or Illumina Omni (TBD)]Bioinformatics: Analysis will be performed using core Sanger informatics pipelines similar to those previously described (Papaemmanuil E et al. (2013) Blood. 22:3616 -3627). Briefly, copy number analysis will be performed using the ASCAT algorithm, and base substitutions, small insertions and deletions using the CAVEMAN and Pindel algorithms, respectively. Statistical approaches including generalized linear models will be used to predict clinical variables such as maximum clinical response and duration of response using genetic data. Sanger and EBI to conduct analysis; Raw data and correlation with clinical endpoints to be analyzed by both EBI/Sanger and GSK (unique pipeline analyses to increase call confidence)

  Dataset EGAD00001001375

• Whole blood RNA-sequencing of covid-19 patients and healthy controls

  This dataset contains whole blood transcriptome data generated from 93 patients with COVID-19 across a range of severities and 23 healthy controls. All patients were PCR positive for SARS-CoV-2 and disease severity ranged from asymptomatic to severe disease requiring ventilation. Individuals without symptoms, or with mild symptoms, were recruited from routine screening of healthcare workers, while COVID-19 patients were recruited at or soon after admission to Addenbrooke’s or Royal Papworth hospitals. Blood samples were taken at recruitment and then again four weeks later. Further details of the cohort and the generation of the RNA-Sequencing data can be obtained from Bergamaschi, L. et al. Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease. Immunity 54, 1257-1275 e8 (2021).

  Dataset EGAD00001007776

• RNA sequencing data of 257 samples from the CORALLEEN trial

  Early-stage Luminal B breast cancer is frequent and is a major cause of breast cancer death due to its poor prognosis. Our proposal aims to study the biology behind the sensitivity and resistance of Luminal B breast cancer to chemotherapy (CHT) or a non-CHT regimen composed of hormone therapy in combination with ribociclib, a CDK4/6 inhibitor. To accomplish this, we first completed the SOLTI-1402 CORALLEEN phase II trial, a study where 106 patients with early-stage Luminal B breast cancer were randomized to standard neoadjuvant CHT for 6 months, or neoadjuvant letrozole and ribociclib for 6 months. After treatment, patients underwent surgery. The primary results of the study, which showed that the response rate to letrozole+ribociclib was similar to CHT, was reported (Prat et al; Lancet Oncol). Tumor biopsies were available at baseline, week 3 and surgery. A total of 257 samples were analyzed using the Illumina TruSeq Stranded Total RNA w/Ribo Zero Gold with MiSeq in TGL (Sequencer NovaSeq S4/PE/100x)

  Dataset EGAD00001010121

• Genomic evolution and natural history of myeloproliferative neoplasms on therapy - triple-negative-ET

  Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts but disease can progress to myelofibrosis or acute myeloid leukaemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukaemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukaemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of haematopoietic colonies revealed age-appropriate polyclonal haematopoiesis in triple-negative essential thrombocythaemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C>G mutations following azacitidine and characteristic T>A/T>G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis.

  Dataset EGAD00001016066

• CCDG CVD: VIRGO - Variation in Recover-Role of Gender on Outcomes of Young Acute Myocardial Infarction (AMI) Patients

  The VIRGO study is a four year research project funded by the NHLBI to study young women and men with heart attacks. A total of 2,000 women who are 18 - 55 years of age and a smaller comparison group of 1,000 similarly aged men will be enrolled in this multi-site observational study from approximately 120 different hospitals across the country. Young women have a much greater risk of dying after an acute myocardial infarction (AMI) than similarly aged men. Their mortality risk is markedly higher than that of young men, and limited data on young minority women suggest that they may have the highest risk of any young subgroup. Findings from the small number of published studies of young women with ischemic heart disease suggest that the biology, epidemiology, care, and outcomes of this group are distinct from those of men. To date, there have been no large studies of this population, even as the death toll is comparable to that from breast cancer in this country. This study will help researchers identify key factors that influence recovery from a heart attack and potentially improve the care and outcomes of young women and men with AMI. Specific Aims: To investigate the excess risk in young women with AMI and to identify key demographic, clinical, metabolic, psychosocial, health care delivery, and biological determinants of prognosis, we propose a national, prospective, observational study of 2,000 women who are 55 years or younger with AMI and a smaller comparison group of 1,000 men. Our prior work and preliminary studies indicate that the sex differences are most prominent in this age group and suggest that by 1 year after discharge, there are substantial sex differences in outcomes. We will also develop risk stratification tools that will help clinicians to identify young women with the highest and lowest risk. Specific Aim 1: Determine sex differences in outcomes following AMI. Specific Aim 2: Determine sex differences in the prevalence and prognostic importance of demographic, clinical, and psychosocial risk factors. Specific Aim 3:Determine sex differences in quality of care. Specific Aim 4: Determine sex differences in the prevalence and prognostic importance of selected biochemical biomarkers following AMI. These samples have been whole genome sequenced as part of the NHGRI's Center for Common Disease Genetics at the Broad Institute.

  Study phs001259

• Heart Failure Network Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure (HFN IRONOUT-BioLINCC)

  ObjectivesTo test the hypothesis that, compared to placebo, oral iron repletion in heart failure patients with iron deficiency improves exercise capacity after 16 weeks of therapy.Background Iron deficiency affects approximately one half of patients with symptomatic heart failure. The presence of iron deficiency in patients with heart failure is associated with reduced functional capacity, poorer quality of life, and increased mortality. Despite growing recognition of the significance of iron deficiency, randomized multicenter trials exploring the utility of oral iron supplementation, a therapy that is inexpensive, readily available, and safe, have not been performed in patients with heart failure. Moreover, patient characteristics and biochemical profiles that may influence responsiveness to oral iron in patients with heart failure have not been defined. Results of intravenous iron repletion trials have been favorable, but regularly treating patients with intravenous iron products is expensive and poses logistical challenges for outpatients. Therefore, the HFN-IRONOUT study was initiated to investigate the efficacy of oral iron in patients with heart failure with reduced ejection fraction (HFrEF). ParticipantsA total of 225 participants were enrolled, 111 randomized to receive oral iron and 114 randomized to receive the placebo. Design The HFN-IRONOUT study was a phase 2, double-blind, placebo-controlled randomized clinical trial that enrolled participants at 23 sites in the United States. Participants were randomly assigned, in a 1:1 ratio, to receive either oral iron polysaccharide or placebo with the use of an automated web-based system. A permuted block randomization method (with 4 participants per block) was stratified by enrolling site and anemia status (defined as hemoglobin At baseline, 8 weeks, and 16 weeks participants underwent studies including history and physical examination, cardiopulmonary exercise testing (CPET), Kansas City Cardiomyopathy Questionnaire (KCCQ), and 6-minute walk test. CPETs were performed using a 10 Watt/minute incremental ramp protocol and breath-by-breath measures of oxygen uptake were uniformly analyzed by the CPET Core Lab. Participants also underwent phlebotomy for biomarkers. Iron studies, including iron, total iron binding capacity, and ferritin, were measured at baseline and after 16 weeks to determine the extent to which oral iron led to iron repletion. The primary end point was the change in peak oxygen uptake (peak VO2) after 16 weeks of therapy. Conclusions Among participants with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks.

  Study phs003557

• Jackson Heart Study (JHS-BioLINCC)

  Accessing Data: Please refer to “Authorized Access” below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP.Related Studies: Other Jackson Heart Study data available include: Imaging studies (JHS-Imaging), Genetics and genomics (The Jackson Heart Study, phs000286.v7.p2), and Collaborative Cohort of Cohorts for COVID-19 Research (C4R-JHS, phs002907.v1.p1): Jackson Heart Study (phs002907.v1.p1).Available Data: Data available for request include Jackson Heart Study visit 1-3 examination cycles, collated annual follow-up communication data through 2016, and follow-up for mortality, heart disease, and stroke events through 2014.Objectives: The objectives of the Jackson Heart Study are to: 1) investigate the associations of biological, psychosocial, and behavioral factors with the incidence atherosclerotic events and health outcomes in an African American cohort; and 2) increase access to and the participation of African American populations and scientists in biomedical research and professions.Background: It has long been recognized that African Americans share a disproportionate burden of deleterious health outcomes including diabetes, hypertension, kidney disease and early onset of cardiovascular disease. The Jackson Heart Study was initiated in 2000 to explore potential mechanisms and mediators of health outcomes in a large African American cohort. In addition, the JHS conducts a variety of community education and outreach activities to promote healthy lifestyles to reduce disease risk burden and student training programs to promote and support public health research.Participants: African American men and women, age 35-84 at entry. Of the 5306 cohort members enrolled in the study, the data repository contains data from 3,883 that provided informed consent to share their data with investigators not affiliated with the study.Design: Participants were enrolled in the study from 2000-2004 from urban and rural areas of three counties (Hinds, Madison and Rankin) in the Jackson, MS metropolitan statistical area. Participants were enrolled from each of 4 recruitment pools: a random sample component (17%), volunteer component (30%), currently enrolled in the Atherosclerosis Risk in Communities (ARIC) Study (31%), and secondary family members (22%). Recruitment was limited to non-institutionalized adult African Americans age 35-84 years, except in the family cohort where those age ≥21 years were eligible. The final cohort of 5,306 participants includes 6.59% of all African American residents aged 35-84 (N=76,426, US Census 2000). Data collection at the baseline exam included a medical history, physical examination, blood/urine analytes and interview questions on areas such as: physical activity; stress, coping and spirituality; racism and discrimination; socioeconomic status; and health care access.The current release of the Jackson Heart Study includes data collected at baseline, exam 2 (2005-2008), and exam 3 (2009-2013). Annual follow-up and surveillance of clinical cardiovascular events is ongoing.

  Study phs003740

• The Environmental Determinants of Diabetes in the Young Study (TEDDY)

  The Environmental Determinants of Diabetes in the Young (TEDDY) Study investigates genetic and genetic-environmental interactions, including gestational infection or other gestational events, childhood infections and other environmental factors after birth, in relation to the development of pre-diabetic islet autoimmunity and type 1 diabetes (T1D). Beginning in 2002, a consortium of six centers assembled to participate in the development and implementation of studies to identify environmental factors that trigger the development of islet autoimmunity and T1D in genetically susceptible individuals. The TEDDY study screened around 400,000 newborns and recruited 7,749 neonates from the general population with a pre-determined T1D risk of 3% and 919 neonates with first degree relatives who have T1D and who have a pre-determined T1D risk of 10%. Thus, TEDDY proposes to follow over 8,000 participants across six clinical centers worldwide (Finland, Germany, Sweden and three in the United States) until the age of 15. Participants are followed every three months for islet autoantibody measurements with blood sampling until four years of age and then at least every six months until the age of 15. After the age of four, autoantibody positive subjects continue to be followed at 3 month intervals and autoantibody negative subjects are followed at six month intervals. In addition to the analysis of autoantibodies, additional data and sample collection is performed at each visit. The parents collect monthly stool samples in early childhood. The parents also fill out questionnaires at regular intervals in connection with study visits and record information about diet and health status in the child's TEDDY Book between visits. Continued long-term follow-up of the currently active TEDDY participants will provide important scientific information on early childhood diet, reported and measured infections, vaccinations, and psychosocial stressors that may contribute to the development of type 1 diabetes and islet autoimmunity. DNA extracted from the 9-month TEDDY blood sample was used for SNP genotyping. Samples were available for 7,082 participants. SNPs were genotyped by the Center for Public Health Genomics at the University of Virginia, using the Illumina ImmunoChip SNP microarray of around 196,000 SNPs selected from 186 regions associated with 12 autoimmune diseases (including T1D) (Hadley et al., 2015). "Data quality control (QC) steps included eliminating subjects with a low call rate (> 5% SNPs missing) and discrepancies between reported gender and prior genotyping at the HLA laboratory. Secondly, SNPs were removed from analysis due to low call rate, Hardy-Weinberg equilibrium P value < 10-6, except for chromosome 6 due to HLA eligibility requirements)" (Törn et al., 2015). QC resulted in a total of 7,023 subjects with data on 176,586 SNPs. Additional information on the TEDDY study are available in the following articles: The Environmental Determinants of Diabetes in the Young (TEDDY) Study. TEDDY Study Group. Annals of the New York Academy of Science, 2008 and TEDDY - The Environmental Determinants of Diabetes in the Young - An Observational Clinical Trial. Annals of the New York Academy of Science, 2006 Details of the TEDDY protocol can be found in The Environmental Determinants of Diabetes in the Young (TEDDY): Genetic Criteria and International Diabetes Risk Screening of 421,000 infants. Pediatric Diabetes, 2011

  Study phs001037

• CIDR, NCI, NIDA Sequencing of Targeted Genomic Regions Associated with Smoking

  This study includes samples from two projects: Collaborative Genetic Study of Nicotine Dependence (COGEND; PI: Laura Bierut) and Genetic Study of Nicotine Dependence in African Americans (AAND; PI: Laura Bierut and Eric Johnson). The majority of the COGEND subjects included in the current study overlap with the two datasets already available on dbGaP. GWAS data are available for COGEND subjects through the Study of Addiction: Genetics and Environment (SAGE), dbGaP study accession phs000092. It should be noted that the case definition in the SAGE study is DSM-IV alcohol dependence. GWAS data are available for additional COGEND subjects through The Genetic Architecture of Smoking and Smoking Cessation, dbGaP study accession phs000404. The overall goal of this project is to apply deep sequencing to key genomic regions associated with nicotine dependence in order to accelerate the discovery of variation in molecular pathways that govern the development of nicotine dependence. The sample includes unrelated cases and controls of European American and African American descent. Cases are defined by a commonly used definition of nicotine dependence, a current score of 4 or more (maximum score of 10) on the Fagerstrom Test for Nicotine Dependence (FTND). Control status is defined as an individual who smoked at least 100 cigarettes during their lifetime, yet never became dependent (lifetime FTND<2). By selecting controls who smoked cigarettes, we focus on those genetic effects that are specific to the development of nicotine dependence. COGEND: COGEND was initiated in 2001 as a three-part program project grant funded through the National Cancer Institute (NCI; PI: Laura Bierut). The three projects included a study of the familial transmission of nicotine dependence, a genetic study of nicotine dependence, and a study of the relationship of nicotine dependence with nicotine metabolism. The primary goal was to detect, localize, and characterize genes that predispose or protect an individual with respect to heavy tobacco consumption, nicotine dependence, and related phenotypes and to integrate these findings with the family transmission and nicotine metabolism findings. The primary design was a community based case-control study. Nicotine dependent cases and non-dependent, smoking controls were identified and recruited from Detroit and St. Louis. More than 54,000 subjects aged 25-44 years were screened by telephone; more than 3,100 subjects were personally interviewed; and more than 2,900 subjects donated blood samples for genetic studies. AAND: AAND was initiated in 2009 to identify and characterize genetic determinants of nicotine dependence in a large African American population. Community-based recruitment of approximately 100,000 people was conducted to ascertain 1,000 African American nicotine dependent cases and 1,000 African American non-dependent, smoking controls. All subjects were between the ages of 25-44. Subjects were screened by telephone; if they qualified as a case or control, they completed the same interview that was used in COGEND and donated a blood sample. Both studies (COGEND and AAND) included measures of basic socio-demographic variables, including age, sex, race/ethnicity, family income, and educational attainment using the Semi-Structured Assessment for the Genetics of Nicotine Dependence. Information on nicotine dependence, as assessed by the Fagerstrom Test for Nicotine Dependence (FTND) is available for all subjects. In addition, participants also completed the Nicotine Dependence Syndrome Scale (NDSS; Shiffman et al., 2004) and the Wisconsin Inventory of Smoking Dependence Motives (WISDM-68; Piper et al, 2004). All subjects were assessed in person by trained research assistants.

  Study phs000813

• Northwestern NUgene Project: Type 2 Diabetes

  The ability to correlate genetic variation with disease susceptibility and response to drug therapy depends on genotype or sequence analysis of large numbers of richly characterized DNA samples. Eight years agoWe are a part of NHGRI's electronic Medical Records and Genomics (eMERGE) Network, whose goal is to conduct genome-wide association studies in thousands of individuals using EMR-derived phenotypes and DNA from linked biorepositories. For eMERGE, Northwestern University (NU) is studying type 2 diabetes as a phenotype. In addition, in order to explore race differences in the prevalence of type 2 diabetes, NU collaborated with Vanderbilt University to study a mix of both Caucasian and African-Americans. Northwestern University: In 2002, Northwestern committed to the development of a DNA repository to serve as a platform for the identification and validation of genotype-phenotype associations that will impact healthcare. The NUgene Project is a repository with longitudinal medical information from participating patients at affiliated hospitals and outpatient clinics from the Northwestern University Medical Center. Participants' DNA samples are coupled with data from a questionnaire (2 versions were used, 1 before and 1 after February 2006, both are included) and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 2 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators. Vanderbilt University: BioVU, Vanderbilt's DNA databank, is an enabling resource for exploration of the relationships among genetic variation, disease susceptibility, and variable drug responses, and represents a key first step in moving the emerging sciences of genomics and pharmacogenomics from research tools to clinical practice. BioVU acquires DNA from discarded blood samples collected from routine patient care. The biobank is linked to de-identified clinical data extracted from Vanderbilt's EMR, which forms the basis for phenotype definitions used in genotype-phenotype correlations.

  Study phs000237

• Exceptional Responders Initiative

  The Exceptional Responders Initiative is a pilot study to investigate the underlying molecular factors driving exceptional treatment responses of cancer patients to drug therapies. Study researchers will examine molecular profiles of tumors from patients either enrolled in a clinical trial for an investigational drug(s) and who achieved an exceptional response relative to other trial participants, or who achieved an exceptional response to a non-investigational chemotherapy. An exceptional response is defined as achievement of either a complete response or a partial response for at least 6 months duration in a trial or treatment where the overall response rate is < 10%. The hope is to discover underlying molecular features that can be further investigated and may eventually predict benefit from a given drug or class of drugs for a particular patient. This pilot project will successfully characterize approximately 100 cases of tumor tissue and, when available, case-matched germline DNA. All samples will undergo whole exome sequencing, and cases with sufficient nucleic acids will undergo additional analyses (e.g. whole genome sequencing, mRNA-sequencing, mi RNA sequencing, promoter methylation analysis, SNP etc). Each case will be annotated with demographic and clinical information, along with follow-up information minimally sufficient to correlate molecular profiles with response. Both retrospective and prospective collections will be considered. The project will also accept sequencing data and clinical data from patients who have had sequencing performed outside of this project. All data will be de-identified and placed in a controlled access database so other investigators may use them for additional insights. Clinically annotated tissue specimens meeting the criteria will be provided by groups participating in the Exceptional Cases Initiative to a Biospecimen Core Resource (BCR), which will perform quality control on the tissues, and will use a standard operating procedure to isolate nucleic acids. The nucleic acids will be shipped to a sequencing center to perform whole exome sequencing and analysis. These findings will be made available to the broader cancer research community in a controlled access database.

  Study phs001145

• 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

• Gabriella Miller Kids First (GMKF) Pediatric Research Program in Susceptibility to Ewing Sarcoma Based on Germline Risk and Familial History of Cancer

  Ewing sarcoma (EWS) is a deadly bone cancer that occurs in children and adolescents. Mounting evidence suggests that a genetic predisposition exists for this pediatric cancer, although the specific genetic contribution has yet to be identified. EWS has never been linked to a specific cancer predisposition syndrome, although several case reports have been published that describe siblings and cousins with EWS. Furthermore, neuroectodermal tumors appear to occur more commonly in families with EWS. The two consistent epidemiology findings in EWS include a very strong Caucasian predilection and increased rates of hernia in EWS patients and their family members. Finally, the role of genetic microsatellite repeats in EWS tumorigenesis has been recently described, and these GGAA microsatellites are polymorphic in repeat size and location across the genome. The study goals of this Kids First project include (1) To identify cancer predisposition genes in EWS trios increasing disease risk, (2) To identify genome-wide GGAA microsatellite repeats in EWS trios increasing disease risk, and (3) To identity de novo mutation and structural variant rates in EWS trios reflecting underlying DNA repair defects that increase disease risk. As part of the Kids First Common Fund initiative, this study proposal will further elucidate the genetic contribution to pediatric cancer development. Around 375 of these trios were selected for whole genome sequencing as part of the Gabriella Miller Kids First fund. The EWS trios have been collected as part of the Children's Oncology Group's AEPI10N5 Study ("Genetic Epidemiology of Ewing Sarcoma"), and each trio has associated phenotypic data including a detailed family history. We will interrogate the sequence data using our genomic analysis pipeline at the University of Utah and the Utah Science Technology and Research initiative's (USTAR) Center for Genetic Discovery. We will look for the genetic contribution to EWS and the sequence data with be shared in a repository designated by the Kids First Common Fund. The WGS of these ~375 EWS trios will help us to understand the genetic origins of a deadly childhood cancer and may lead to novel strategies for prevention and treatment.

  Study phs001228

• Identification of Modifiers of 22q11.2 Deletion Syndrome in Whole Genome Sequence - CIDR

  This project aims to identify genetic modifiers of congenital heart disease (CHD), which occurs among 22q11.2 deletion syndrome (22q11.2DS; also known as DiGeorge syndrome/velo-cardio-facial syndrome) patients. In contrast to the prevalence of ~0.8% in the general population, about 60%-70% of 22q11.2DS patients have CHD, of which most are conotruncal heart defects, making 22q11.2DS a very ideal model to study the genetic underpins of CHD. The chromosome 22q11.2 region is susceptible to meiotic chromosome rearrangements leading to hemizygous deletions, because there are large blocks of low copy repeats, termed LCR22s, that are dispersed in the region. Non-allelic homologous recombination during meiosis can lead to specific-sized deletions. Approximately 90% have a typical hemizygous 3 million base pair (Mb) deletion between LCR22-A and -D, while some have nested deletions between LCR22-A and B or LCR22-A and C. Our goal is to perform a case-control association study, in which cases have CHD, while controls have normal heart structures, all with 22q11.2DS. All individuals are unrelated and have been collected from collaborators in the US, Canada and Europe. All subjects received a clinical diagnosis of 22q11.2DS and signed informed consent to allow a blood sample to be collected for research. The DNA samples were de-identified in 2 steps to protect their privacy. We then determined deletion type using multiplex ligation-dependent probe amplification (MLPA). This information is provided for the great majority of subjects. We also obtained cardiac phenotype information from echocardiogram reports as well as reported race and ethnicity (Hispanic vs. non-Hispanic information), which is required for the analysis. We will obtain 30X whole-genome sequence data from NIH CIDR. We will first annotate the sequence variants identified to uncover rare ( For genotype data, we will provide the raw fastq data from whole-genome sequencing as well as the called variants file in a VCF file. For phenotype data, we will provide the sample relationship files (ped files), CHD affection status, deletion type, and race.

  Study phs002514

• Profiling Genome-Wide Circulating ncRNAs for the Early Detection of Lung Cancer

  Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases. Although imaging techniques such as low-dose computed tomography (LDCT), combined with tissue biopsies, have improved early detection rates, current diagnostic approaches are often limited by high false-positive rates, invasiveness, and radiation exposure, which lead to misdiagnosis and increased patient burden. Therefore, there is an urgent need for minimally invasive, accurate, and safe diagnostic biomarkers, particularly those derived from liquid biopsies such as blood-based exosomal RNA.This dataset specifically focuses on plasma-derived exosomal small non-coding RNAs (sncRNAs).A total of 233 de-identified plasma samples were obtained from Rush University Medical Center, including 116 NSCLC patients and 117 non-cancer controls. Exosomes were isolated from plasma, RNA was extracted, and small RNA sequencing was performed using the Illumina NextSeq 500 platform. Data available through dbGaP include individual-level raw sequencing files (FASTQ) and basic phenotype annotations of the plasma cohort.A diagnostic model was initially developed using small RNA-seq data from 1,446 tissue samples obtained from TCGA and GEO, identifying a robust sncRNA signature that distinguished NSCLC from non-cancer samples with an AUC of 0.90 in hold-out tissue validation. This signature was subsequently validated in the plasma exosome cohort, achieving an AUC of 0.84 in independent validation. The model demonstrated consistent diagnostic performance across subgroups stratified by age, sex, smoking history, cancer stage, and NSCLC subtype. Survival and functional analyses further supported the clinical and biological relevance of the identified sncRNAs. It is hoped that this resource will contribute to a better understanding of the sncRNA expression landscape in NSCLC and promote the development of non-invasive biomarkers for early cancer detection. These data may be applied to the investigation of transcriptomic and other risk factors, provide insight into cancer screening, tumor progression mechanisms, and prognosis prediction, and ultimately support precision medicine for NSCLC.

  Study phs004166

• Gabriella Miller Kids First Pediatric Research Program in Pediatric T-Cell Acute Lymphoblastic Leukemia

  The outcome for patients with relapsed T-ALL is dismal with 3-year event free survival of AALL0434 was a Children's Oncology Group-initiated phase 3 randomized clinical trial comparing Capizzi-style escalating methotrexate plus pegaspargase (CMTX) vs. high dose methotrexate (HDMTX), with/without six 5-day courses of nelarabine. Survival on this study was superior to any prior trial for de novo T-ALL, changing the standard of care. Yet, a substantial minority (~15%) of patients had relapsed or refractory (r/r) disease. Through the TARGET initiative, RNA sequencing (RNA-Seq), DNA copy number analysis, and whole-exome sequencing (WES) were performed on 264 T-ALL patients treated on AALL0434, demonstrating recurrent alterations could be grouped into 10 different potentially targetable functional pathways. This analysis was not powered to examine associations between genetic lesions with outcome, because too few patients with r/r disease were included. This project is dedicated to testing the hypothesis that comprehensive genomic profiling of the entire AALL0434 cohort will identify recurrent genetic alterations that can be segregated into biologically relevant deregulated pathways that can be combined with MRD to identify patients at risk for poor outcomes before they relapse and provide rationale for treatment with alternative therapies. In addition, a number of small recent studies demonstrated that many of the biologically relevant alterations in T-ALL occur in non-coding regions of the genome, but no large studies have performed whole genome sequencing (WGS) in T-ALL. This project also tests the hypothesis that WGS of a large cohort of patients with T-ALL will identify novel lesions in coding and non-coding regions that will be highly impactful in the understanding of T-ALL pathogenesis.These hypotheses are tested by performing comprehensive genomic profiling (WGS, WES, RNA-Seq, and copy number analysis) of the entire AALL0434 cohort with available samples with the following specific aims: (1) identify recurrent genetic alterations that predict poor outcome in T-ALL; (2) identify novel alterations, including non-coding alterations in T-ALL; and (3) identify germline genetic variants that predispose to T-ALL and to increased toxicity to chemotherapy.

  Study phs002276

• Somatic Genome Dynamics of Barrett's Esophagus Patients with Non-Cancer and Cancer Outcomes

  A case-control study was designed with 80 participants diagnosed with Barrett's Esophagus (BE) selected from a larger case-cohort study (Li et al., 2014, PMID: 24253313) within the Seattle Barrett's Esophagus Program (SBEP) at the Fred Hutchinson Cancer Research Center. The study included 40 cases with BE with non-cancer outcomes, "NCO", who did not progress to esophageal adenocarcinoma (EA), and 40 controls who progressed to an endoscopically detected, incident EA (cancer outcome, "CO"). For each patient, two timepoints were evaluated (T1 and T2). NCO were matched to CO based on age at T1 (T1=first endoscopy with sufficient sample availability), and time between T1 and T2 (T2 in CO=time of diagnosis of incident EA). In 10 NCO, a third time point (T3), a mean of 13.2 years after T1, was also sequenced. Mapped endoscopic biopsies, at 1/3 and 2/3 annotated distances from the gastroesophageal junction within the Barrett's segment, were sampled per patient at each timepoint. Each biopsy was purified to separate BE epithelium from stroma, and DNA was extracted from purified epithelium for 60X WGS and 2.5M SNP array; normal control blood (N=62) or normal gastric sample (N=18) were analyzed by 30X WGS and 2.5M SNP array. An additional seven normal gastric biopsy samples in seven patients with normal control blood were also sequenced at 60X as controls. All research participants contributing clinical data and esophageal samples to this study provided written informed consent, subject to oversight by the Fred Hutchinson Cancer Research Center IRB Committee D (Reg ID 5619).

  Study phs001912

• SLCO1B1 Variants and Methotrexate Clearance

  Methotrexate plasma concentration is related to its clinical effects. To identify the genetic basis of interindividual variability in methotrexate pharmacokinetics in children with newly diagnosed acute lymphoblastic leukemia (ALL), we performed a genome-wide analysis (GWAS) of 500,568 germline single-nucleotide polymorphisms (SNPs) in 434 children with ALL who received 3,014 courses of methotrexate at 2 to 5 g/m2. SNPs were validated in an independent cohort of 206 patients. Adjusting for age, race, sex, and methotrexate regimen, the most significant associations were with SNPs in the organic anion transporter polypeptide, SLCO1B1 (rs11045879 (P = 1.7 x 10-10) and rs4149081 (P = 1.7 x 10-9) (Trevino et al, PMID: 19901119). To test whether rare variants in SLCO1B1 could alter its function, we genotyped SLCO1B1 exons in a slightly larger group of 699 children with ALL who received methotrexate and identified 93 single nucleotide polymorphisms (SNPs). We found several common and rare non-synonymous (NS) SNPs associated with methotrexate clearance. NS SNPs predicted to be functionally damaging (common or rare) were more likely to be found among patients with the lowest adjusted methotrexate clearance (lowest 10%) than patients with high clearance (highest 10%). Four SLCO1B1 haplotypes were associated with reduced methotrexate clearance and we verified that these haplotypes have lower function with in vitro transport assays. We were able to quantitatively account for a third of the population variability in clearance of methotrexate with clinical and genetic covariates. This data set includes the dependent variable of methotrexate clearance and all of the SNP data available from arrays, sequencing, and genotyping.

  Study phs000426

• Age related Macular Degeneration (AMD)-- Michigan, Mayo, AREDS, Pennsylvania (MMAP) Cohort Study: A Joint Genome Wide Association Study

  Age-related Macular Degeneration (AMD) is a leading cause of incurable blindness in people over the age of 65. AMD is a late-onset multi-factorial neurodegenerative disease and its pathogenesis involves interaction of genetic and environmental factors. Several chromosomal regions have been associated with AMD susceptibility through linkage analysis (Swaroop et al., 2009). More recent studies provide strong evidence that variants within the CFH gene cluster on chromosome 1 and at/near LOC387715/ARMS2 on chromosome 10 are strongly associated with disease. Variants at other genes including C2/BF, C3, CFI and APOE4, also contribute to AMD susceptibility. Our primary goals are to identify genetic variants and haplotypes that are associated with AMD. The underlying hypothesis is that DNA variation(s) in multiple genetic susceptibility loci will predispose individuals to AMD pathogenesis, and comparison of DNA of cases and controls should identify these susceptibility variants. Our studies are focused on the genetic analysis of advanced AMD and should provide novel insights into disease diagnosis, progression and pathology. We have assembled a collaborative group of researchers from the University of Michigan, Mayo Clinic, University of Pennsylvania, and the AREDS group including National Eye Institute intramural investigators, who collected clinical data and DNA from a large number of patients affected with AMD and from unaffected controls. The primary source of funding was National Eye Institute. Through this collaborative effort, we submitted and obtained usable genotyping data on 2184 patients and 1155 controls from the Center for Inherited Disease Research (CIDR).

  Study phs000182

• Decoding Human Heart Morphogenesis through Single-cell Multi-modal Analyses

  The heart, which is the first organ to develop, is highly dependent on its form to function. However, how diverse cardiac cell types spatially coordinate to create complex morphological structures critical for heart function remains to be elucidated. Here, we show that integration of single cell RNA-sequencing with high-resolution multiplexed error-robust fluorescent in situ hybridization (MERFISH) not only resolves the identity of cardiac cell types developing the human heart but also provides a spatial mapping of individual cells that enables illumination of their organization into cellular communities forming distinct cardiac structures. We discovered that many of these cardiac cell types further specified into subpopulations exclusive to specific communities, supporting their specialization according to cellular ecosystem and anatomic region. In particular, ventricular cardiomyocyte subpopulations displayed an unexpected complex laminar organization across the ventricular wall and formed, with other cell subpopulations, several cellular communities. Interrogating cell-cell interactions within these communities revealed signaling pathways orchestrating the spatial organization of cardiac cell subpopulations during ventricular wall morphogenesis. In vivo conditional genetic mouse models and in vitro human pluripotent stem cell studies confirmed an intricate multicellular PLXN-SEMA crosstalk among specific ventricular cardiomyocyte, fibroblast and endothelial cell subpopulations that directs the compaction of the ventricular wall layers. Thus, these detailed findings into the cellular social interactions and specialization of cardiac cell types constructing and remodeling the human heart offer new insights into structural heart diseases as well as engineering complex multi-cellular tissues for human heart repair. Reprinted from Farah et al. (In press), with permission from Nature.

  Study phs002031

• Genomic Characterization of Duke Melanoma Brain Metastases

  Previous work has shown that melanoma brain metastases (MBM) have a unique molecular profile compared to extracranial metastases (ECM). Description of the biology of MBM and associations between biological features and clinical outcomes will facilitate the design of rational therapies for patients with MBM. To better characterize the molecular profile of MBM, we conducted whole exome sequencing (WES) and total RNA sequencing on MBM tissues obtained from an independent cohort of 14 patients from Duke University Medical Center. This cohort adds valuable patient samples to the field and enables strengthened investigation of somatic mutations and gene expression profiles within and between cohorts. The mutational landscape and gene expression of MBM from the Duke cohort resembled those previously reported in a previously published dataset of WES and RNA sequencing in MBM and matched ECM tissues from UT MD Anderson Cancer Center (Fischer et al., 2019 30787016). Duke MBM demonstrated similar rates of mutations in genes associated with melanoma, including BRAF, NRAS, and PTEN, as the MD Anderson cohort. Immune populations in MBM were similar between Duke and MD Anderson MBM, though Duke samples demonstrated more resting CD4+ memory T cells. The ratio of M2 to M1 macrophages in the Duke cohort was similar to that of the MD Anderson cohort. In MBM, a higher M2:M1 ratio may contribute to an immune-suppressive tumor microenvironment. Sequencing data and sample attributes from MBM tissues obtained from 14 patients from Duke University Medical Center will be available through dbGaP.

  Study phs003009

• Healthy_ageing_thymus

  Single cell RNA sequencing of immune and non-immune cells from healthy ageing thymus Thymus is a primary lymphoid organ that creates an environment for the T lymphocyte precursors differentiation into the naive T cells, which involves TCR gene rearrangement, negative and positive selection. Despite thymus critical function for the recognition of the pathogens it starts to atrophy very early in life. Thymic Epithelial Space (TES), where thymocyte education occurs, starts to decline rapidly just after birth, while with the onset of puberty thymus is also progressively replaced with adipose tissue. This leads to a reduced naive T cell output,which decreases an organism's ability to recognize pathogens. In our lab, we have already collected and characterized cell type composition and gene regulatory networks of the fetal tand adult human thymus (Park et al, Science 2020). In the current project we plan to expand the number of paediatric and adult samples in the study with the aim to understand how the process of thymic involution happens. We will use single-cell transcriptomics to zoom on changes that occur in immune and non-immune cell types in different phases of thymic involution with the hope to understand which gene expression changes are causal for the thymic involution process and how naïve T cell production can be increased in elderly. 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 EGAS00001004311

• 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

• Barcoding reveals complex clonal dynamics of de novo transformed human mammary cells

  Most human breast cancers have already diversified genomically when they first become clinically evident, by which time extensive heterogeneous histopathologies, transcriptomes and growth patterns are also apparent. Accordingly, important initial events and the cellular context in which they occur have been difficult to characterize. Using DNA barcoding, we now demonstrate the high efficiency with which both purified basal and luminal cells isolated directly from normal adult human mammary tissue can be rapidly transformed by a single oncogene (KRASG12D) resulting in the production within 8 weeks in vivo of serially transplantable, polyclonal, invasive ductal carcinomas that are phenotypically heterogeneous and transcriptionally distinct from the initial cells transduced. Barcoding also revealed a consistent dramatic change in the clonal content of passaged tumours. This system thus provides a powerful new platform for examining early events in the genesis, evolution and treatment response of malignant human mammary cells generated using defined mutations.

  Study EGAS00001001310

• A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma

  Osteosarcoma is the most common primary bone cancer. It can be cured by aggressive surgery and chemotherapy, but outcomes for metastatic or chemoresistant disease remain dismal. Cancer sequencing studies have shown that the p53 pathway is dysregulated in nearly every case, often by translocation; however, no studies of osteosarcoma evolution or intratumor heterogeneity have been done to date. We studied a patient with chemoresistant, metastatic disease over the course of three years. We performed exome sequencing on germline DNA and DNA collected from tumor at three separate timepoints. We compared variant calls and variant allele frequencies between different samples. We identified subclonal driver mutations in several different genes in the primary tumor sample and found that one particular subclone dominated subsequent tumor samples at relapse. This clone was marked by a novel TP53-KPNA3 translocation and loss of the opposite-strand wild-type TP53 allele. Future research must focus on functional significance of such clones and strategies to eliminate them.

  Study EGAS00001001805

• Using de novo assembly to identify structural variation of complex immune system gene regions

  Driven by the necessity to survive environmental pathogens, the human immune system has evolved exceptional diversity and plasticity. Several factors contribute to this including inheritable structural polymorphism of the underlying genes. To investigate this we generated data for a single healthy European individual (identified as HV31) using multiple long-read (PacBio Sequel II and Oxford Nanopore), short-read (Illumina HiSeq and MGI G400) and linked-read (10X Chromium and stLFR) sequencing platforms, and optical mapping using the Bionano Saphyr platform. DNA was extracted from monocytes or from peripheral blood mononuclear cells. We used these data to assemble a set of regions encoding components of the immune system and to investigate structural variation. The raw data and analysis results are deposited here for generate research use. A complete description of these data and results can be found in the accompanying article at https://doi.org/10.1101/2021.02.03.429586.

  Study EGAS00001005046

• Genomics of Malignant Peripheral Nerve Sheath Tumor (MPNST)

  The Genomics of MPNST (GeM) Consortium dataset includes de-identified whole genome sequencing data (.bam) for germline samples (DNA primarily derived from blood) sequenced at standard (30x) coverage (n=88) and for tumor samples (DNA derived from fresh frozen tissue) sequenced at 90x coverage (n=105). This dataset also includes transcriptome profiling data (.fastq) for paired normal nerve samples (n=7) and for tumor samples (n=132).

  Dataset EGAD00001008608

• Single cell transcriptional consequences of leukaemogenic SETBP1 mutations

  The SETBP1 gene encodes a DNA-binding nuclear protein that regulates gene expression across multiple tissues. Precise control of SETBP1 dosage is essential for normal cellular function, as both loss- and gain-of-function variants of SETBP1 can lead to severe phenotypic consequences. De novo germline gain-of-function point mutations that prolong SETBP1 half-life result in Schinzel-Giedion syndrome (SGS), an ultra-rare and severe congenital disorder associated with extensive developmental abnormalities and health complications. These SGS-associated variants cluster within a hotspot in the SKI-homology domain of SETBP1, overlapping with somatic mutations recurrently observed in myeloid leukaemia with poor prognosis. Thus far, the precise mechanisms by which these SETBP1_mutations drive disease remain largely unclear. Here, through single-cell and single-nucleus mRNA sequencing of a rare collection of primary patient samples with SGS, we examined the transcriptional consequences of _SETBP1 gain-of-function variants in haematopoietic cells from natural variation.

  Dataset EGAD00001015829