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• RNAseq and T cell receptor (TCR) profiling of PBMC cells 3 months post Omicron exposure

  This dataset contains RNA-seq and T cell receptor (TCR) sequencing files from a cohort (n=20) 3 months post positive PCR for SARS-CoV-2. A total of 10 hospitalised (samples H1-10) and 10 non-hospitalised (samples NH1-10) are contained within this dataset. RNA sequencing was performed using the Illumina Stranded mRNA Prep Ligation kit to investigate the protein coding transcriptome of PBMC cells. T cell receptor (TCR) repertoire profiling was performed with the TakaraBio SMART-Seq Human TCR (with UMIs) on PBMC cells to investigate the depth and persistence of SARS-CoV-2 targeting TCRs.

  Dataset EGAD50000001356

• Single cell RNAseq and TCRseq data from tumor and blood samples from 4 patients with muscle invasive bladder cancer

  For this dataset we performed single cell RNAseq paired with single cell TCR-seq on tumor and blood samples from 4 patients. This dataset contains 4 tumor samples as well as 4 blood samples. Each sample is made up of 2 sets of paired fastq files. The first pair contains reads corresponding to RNA transcripts (_Transcripts in file name), while the second pair contain reads corresponding to TCRs (_VDJ in file name). Sequenced on the Illumina NovaSeq6000 platform in a paired-end run using an SP flow cell (v1.5, 300 cycles).

  Dataset EGAD50000001381

• Single cell RNA-seq of 24 samples from 13 individual human embryonic meninges of PCW 5.0-13.0 using 10X chromium technology

  A total of 24 samples of meninges from 13 normal human embryos of post-conceptional week (PCW) 5.0-13.0 were dissected and subject to 10Xgenomics chromium single cell RNA sequencing with the purpose of identifying cell types and gene expression programs for normal meninges development. All libraries were sequenced on an Illumina NovaSeq 6000 using S4 to a target sequencing depth of 100,000 reads/cell. Final data after processing with STARSolo 2.7.10a, using human genome GRCh38.p12 and transcript annotations from ENSEMBL release 93 from reference package GRCh38-3.0.0 as available from 10Xgenomics, consists of 24 BAM files.

  Dataset EGAD50000001434

• Sequence data to study genomic CNVs that drive apoptotic resistance and relapses on immune checkpoint inhibitors

  The dataset consists of bulk whole exome sequencing (WES) and whole genome sequencing (WGS) data from baseline and disease-progressed tumors after immune checkpoint inhibitor (ICI) treatment, derived from patients, human cell lines, and mouse models. Whole exome sequencing includes 17 clinical cases and one human cell line model with parental and acquired resistant cell lines (n = 5). Whole genome sequencing encompasses the YUMMER mouse model, including vehicle-treated controls (n = 2) and acquired resistant tumors (n = 3). The sequence reads have been aligned to hg19 and mm9 reference genomes, with mapped files (BAM) made available for analysis.

  Dataset EGAD50000001537

• Tumor gene expression profiles for the study "TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells"

  RNA was extracted from formalin-fixed and paraffin embedded tumors of a large cohort of bladder cancer patients before treatment with anti-PD-L1. RNA was sequenced using a capture based approach (exome capture, RNA access).

  Dataset EGAD00001003977

• A Study to Evaluate Denosumab in Young Patients With Primary Breast Cancer (D-Beyond)

  This is a prospective, single arm phase IIa trial in which patients with early breast cancer will receive pre-operatively two doses of denosumab 120mg subcutaneously one week apart (maximum 12 days) followed by surgery. Tumor, normal breast tissue and blood samples will be collected at baseline and at surgery. Post-operative treatment will be at the discretion of the investigator.Primary objective: to determine if a short course of RANKL inhibition with denosumab can induce a decrease in tumor proliferation rates as determined by Ki67 immunohistochemistry (IHC) in newly diagnosed, early stage breast cancer in pre-menopausal women.

  Dataset EGAD00001004391

• Multiple Malignancy Familial Comparison

  Patient (who has had multiple malignancies) has previously been found to harbour a pathogenic p53 variant which is probably mosaic. This finding is based on exome sequencing performed elsewhere. In this study we will resequence the locus in question to ascertain whether the variant is indeed mosaic.

  Dataset EGAD00001001062

• SCLC study George et al. - WGS data set

  Whole genome sequencing was performed with DNA extracted from fresh-frozen tumor and normal material. Short insert DNA libraries were prepared with the TruSeq DNA PCRfree sample preparation kit (Illumina) for paired-end sequencing at a minimum read length of 2x100bp. Human DNA libraries were sequenced to an average coverage of minimum 30x for both tumor and matched normal. Murine DNA libraries of tumor and matched normal were both sequenced to a coverage of 25x.

  Dataset EGAD00001001273

• C9orf72 region reads of 3001 samples

  This dataset includes cram files from 3,001 samples. These cram files include all read pairs where at least one of the reads aligns within 1kb of the C9orf72 repeat expansion. Additionally, these cram files also contain reads that are aligned to any of 29 pre-determined off target locations where the aligners are known to mis-align reads associated with this repeat expansion. These samples were sequenced using a combination of 2x100bp reads on an Illumina HiSeq2000 and 2x150bp reads on an Illumina HiSeqX sequencer and aligned using the Isaac aligner.

  Dataset EGAD00001004834

• Donor InSight III study: Participants typed during UK Biobank version 2 array development phase

  The Donor InSight III study, undertaken by Sanquin research, recruited 3,046 Dutch blood donors between 2015 and 2016. The purpose of the study was to gain more insight into characteristics of donors, their motivations and health. All participants were at the time of recruitment active blood donors. Genotyping data was produced using the Thermo Fisher Scientific Axiom Genotyping platform. The UK Biobank version 2 array design was used, content on this array has been added to allow for accurate DNA based identification of human blood group antigens.

  Dataset EGAD00001005026

• Colon Cancer Organoid Cultures and Tumors Whole Genome Sequencing Data

  Five hundred nanograms of genomic DNA was fragmented by Covaris S2, the fragmented DNAs were performed end-repair, A-tailing at the 3 prime end, adaptors ligation with an IDT dual-indexed UMI adaptor system at the terminal ends. The adapter ligated library with size range 300-750bp were selected by dual-SPRI method. Twenty percent of the size selected PCR-free libraries were enriched by 5 PCR cycles prior to library size assessment by Bioanalyzer Fragment Analyzer. The PCR-free libraries were quantified by qPCR.The PCR-free libraries were denatured and diluted to optimal concentration. Illumina NovaSeq 6000 was used for Pair-End 151bp sequencing.

  Dataset EGAD00001005759

• Dichotomous regulation of lysosomes by MYC and TFEB controls hematopoietic stem cell fate

  We show that lysosomes are antagonistically controlled by TFEB and MYC to balance catabolic and anabolic processes required for activating LT-HSC and guiding their lineage fate. TFEB-mediated induction of the endolysosomal pathway for membrane receptor degradation limits LT-HSC metabolic and mitogenic activation; this promotes quiescence and self-renewal and governs erythroid-myeloid commitment. By contrast, MYC engages biosynthetic processes while repressing lysosomal catabolism to drive LT-HSC activation. Collectively, our study identifies lysosomes as a central regulatory hub for proper and coordinated stem cell fate determination.

  Dataset EGAD00001006884

• Chracterising cellur pathways underlying CD3/CD28 activation of human CD4+ cells

  We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Sorted Tcons were activated using a titration of anti-CD3 and anti-CD28 in combination as well as individually. As a control we cultured cells in the same conditions but without the stimuli. In total, we defined seven conditions from four individuals for sequencing. 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/.

  Dataset EGAD00001006610

• Chracterising cellur pathways underlying CD3/CD28 activation of human CD4+ cells

  We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Sorted Tcons were activated using a titration of anti-CD3 and anti-CD28 in combination as well as individually. As a control we cultured cells in the same conditions but without the stimuli. In total, we defined seven conditions from four individuals for sequencing. 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/ .

  Dataset EGAD00001006612

• Transcriptome sequencing of hepatocellular carcinoma biopsies

  RNA-sequencing of 122 hepatocellular carcinoma biopsies and 15 normal liver biopsies. RNA-seq library prep was performed with 200 ng total RNA using the TruSeq Stranded Total RNA Library Prep Kit with Ribo-Zero Gold (Illumina) according to manufacturer’s specifications. Single-end 126-bp sequencing was performed on an Illumina HiSeq 2500 using v4 SBS chemistry at the Genomics Facility Basel according to the manufacturer’s guidelines. Primary data analysis was performed with the Illumina RTA version 1.18.66.3.

  Dataset EGAD00001008205

• RNA-seq data from 27 glioblastoma samples

  27 Fresh frozen tissue specimens were crushed by mortar and pestle, homogenized using the QIAShredder kit (Qiagen), and genomic DNA and total RNA were extracted using the AllPrep DNA/RNA Mini kit (Qiagen), according to the manufacturer’s instructions. RNA libraries were synthesized using 200 ng of total RNA using the Ilumina TruSeq Stranded RNA LT Sample Prep Kit (Illumina), and subsequently sequenced on the NextSeq550 platform to a read depth of 80 million clusters and 160 million paired end reads (75 bp X 75 bp) using V2 chemistry.

  Dataset EGAD00001008362

• Single cell sequencing of human normal luminal cells

  The dataset includes 12 paired FASTQ files (6 samples) with single cell transcriptome sequencing data of normal breast luminal cells from ducts and TDLUs derived from reduction mammoplasties from three patients. Chromium Single Cell 3’ Reagent Kit v2 or v3 (10x Genomics) were used for processing of cells, whereafter sequencing was performed using the Illumina® NextSeq500/550 High Output Kit v2. Cell Ranger was used for generating FASTQ files and files from different lanes were concatenated prior to uploading the data to EGA. "R1" files include the feature barcodes and UMIs, while "R2" files include the reads.

  Dataset EGAD00001008499

• Population-based analysis of POT1 variants in a cutaneous melanoma case-control cohort

  Pathogenic germline variants in the protection of telomeres 1 gene (POT1) have been associated with predisposition to a range of tumor types, including melanoma, glioma, leukemia and cardioangiosarcoma. We sequenced all coding exons of the POT1 gene in 2,929 European-descent melanoma cases and 3,298 controls, identifying 43 protein-changing genetic variants. We performed functional studies on each of these variants and explored their possible contribution to disease risk.

  Dataset EGAD00001009848

• Single-cell RNA sequencing of breast cancer lung metastasis and adjacent normal tissue

  This dataset contains single-cell RNA sequencing data from two samples: L1 (breast cancer metastasis to lung) and N3 (adjacent normal lung tissue) from a female patient. The samples were processed using 10X Chromium 3' technology and sequenced on Illumina NextSeq 500. This data supports the study "Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P-Rex1/Rac1 signalling" which investigates how endocrine therapy reprograms breast cancer cells, leading to upregulation of P-Rex1/Rac1 signalling pathways that facilitate metastatic escape. The single-cell analysis reveals cellular reprogramming mechanisms in endocrine therapy-resistant breast cancer cells that form metastases in the lung.

  Dataset EGAD00001015769

• RNAseq of baseline tumor tissue obtained during TUR to identify biomarkers for ICB response in MIBC

  RNAseq of baseline tumor tissue obtained during TUR to identify biomarkers for ICB response in MIBC. Constitutes the entire NABUCCO phase 1B clinical trial cohort. The NABUCCO 1 trial contains 18 single-end RNA sequenced samples and 6 paired end RNA sequenced samples. The NABUCCO 2 trial contains 25 paired end RNA sequenced samples. The file type for all of the samples is FASTQ. For single end RNA sequencing, Illumina HiSeq 2500 was used as the sequencing platform. For paired end RNA sequencing, the Illumina NovaSeq 6000 was used as the sequencing platform.

  Dataset EGAD50000002556

• The Gut Microbiome of renal transplant recipients – Cross-sectional

  TransplantLines is designed as a single-center, prospective cohort study and biobank including all different types of solid organ transplant recipients as well as living organ donors. In the TransplantLines gut microbiome study the gut microbiome of solid organ transplant recipients is characterized and linked to clinical phenotypes. This batch contains the cross-sectional data from renal transplant recipients is.

  Study EGAS00001006257

• Common Variant GWAS, Genetics & Epidemiology of Colorectal Cancer Consortium (GECCO)

  Genetics & Epidemiology of Colorectal Cancer Consortium (GECCO) is a collaborative effort which aims to accelerate the discovery of colorectal cancer-related variants by discovering, replicating and fine-mapping Genome Wide Association Study (GWAS) findings, conducting a meta-analysis of GWAS data, and investigating how genetic variants are modified by environmental risk factors. The coordinating center for this consortium is based at the Fred Hutchinson Cancer Research Center (Principal investigator: Ulrike Peters). The GECCO Consortium is utilized in the following dbGaP individual studies. To view genotypes, and derived variables collected in these individual studies, please click on the following individual studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs001078 GECCO Consortium. phs000965 VITAL phs001056 DALS phs001077 WHI Colorectal Cancer phs001092 PMH CCFR phs001094 PLCO phs001104 ASTERISK phs001113 DACHS phs001114 HPFS phs001128 PHS phs001129 NHS phs001170 Colo2and3 phs001171MEC Colorectal Cancer

  Study phs001078

• Genetic Study of Inflammatory Bowel Disease (IBD) in African Americans

  Association studies have previously identified 200 genome-wide significant (GWS) IBD susceptibility loci in European ancestry populations. At least thirty-five loci have been identified in Asians and a handful appear Asian specific. AAs have a higher risk for developing disease complications in IBD and worse disease outcome, suggesting that significant differences in pathological and molecular mechanisms may exist in AAs. It was therefore imperative to use more comprehensive genotyping platforms in more highly powered samples to detect AA-specific IBD loci and associations. We conducted two independent GWAS using a total of 2345 AA IBD cases and 5002 controls population from unrelated, self-identified AAs individuals. GWAS1 included 1258 IBD cases (843 CD, 368 UC, 47 IBD-U) and 1678 controls derived from the dbGaP Health and Retirement Study (phs000428). GWAS 2 included 1087 IBD cases (803 CD, 215 UC, 69 IBD-U) and 3324 controls obtained from the Kaiser RPGEH study (phs000788).

  Study phs001571

• Clonal Evolution of Pre-Leukemic Hematopoietic Stem Cells Precedes Human Acute Myeloid Leukemia

  Acute myeloid leukemia is an aggressive clonal malignancy of the bone marrow that is the direct result of sequential acquisition of mutations in a single lineage of cells. In this study, we investigate a model in which this mutational acquisition occurs serially in long-lived self-renewing hematopoietic stem cells eventually resulting in frank acute myeloid leukemia. Coding mutations in multiple AML patients were identified using exome sequencing followed by sanger sequencing validation. The level of these mutations was then assessed in residual hematopoietic stem cells from each patient using targeted deep sequencing. These population-level estimates of mutant allele burden were then validated in single cell assays targeted to the identified mutations. This allowed for determination of the order of acquisition of the mutations that preceded the development of the leukemia. The results of this study identify pre-leukemic hematopoietic stem cell clones that could contribute to patient relapse and outcome.

  Study phs000549

• Prospective Analysis of Genotypes in Adults Undergoing Therapy for Lung Cancer (Paclitaxel Cohort)

  Lung cancer is frequently treated with paclitaxel in combination with several other agents; however, paclitaxel treatment is often ineffective or limited by treatment-related toxicities. Heritable variants in genes associated with absorption, distribution, metabolism, and elimination may predict paclitaxel clinical outcome and toxicity. We designed a prospective multi-institutional study that recruited 546 patients receiving therapy with a 5-year follow up. All patients were genotyped using the Drug Metabolizing Enzymes and Transporters (DMET) platform, which ascertains 1931 genotypes in 235 genes. Genotypes were compared to the progression-free survival of paclitaxel therapy and clinically-significant paclitaxel toxicities. Seven genetic variants were associated with paclitaxel PFS (in ABCB11, ABCC3, ABCG1, CYP8B1, NR3C1, FMO6P, and GSTM3), whereas four genetic variants (in VKORC1, SLC22A14, GSTA2, and DCK) were associated with paclitaxel toxicities. The present SNPs have limited clinical utility but suggest that certain genes are related to important paclitaxel pathways in lung cancer.

  Study phs001660

• A Genome-Wide Association Study in Patients Experiencing Drug-Induced Long-QT Syndrome and/or Torsades de Pointes; A Collaboration Between the NIH Pharmacogenomics Research Network and the RIKEN Yokohama Institute Center for Genomic Medicine

  The goal of this study was to identify genetic risk factors for drug-induced prolongation of the QT interval (diLQT) and the ventricular arrhythmia torsades de pointes (TdP). We conducted a genome-wide association study (GWAS) focusing on subjects with a history of long QT and/or TdP after taking medication. Controls for this study were individuals with a history of cardiac arrhythmias who had begun treatment with potentially QT-prolonging antiarrhythmics. An additional control group of normal volunteers were given ibutilide, a drug with documented proarrhythmic properties. All study participants were recruited and treated/evaluated at Vanderbilt University Medical Center. This study was conducted by the Pharmacogenomics of Arrhythmia Therapy subgroup of the Pharmacogenetics Research Network, a nationwide collaboration of scientists studying the genetic contributions to drug response variability. Genotyping was performed by the RIKEN research institute in Japan using the Illumina 610 Quad Beadchip platform.

  Study phs000331

• Mitochondrial Abnormalities in Schizophrenia and Bipolar Disorder

  Mitochondrial DNA structural variation is one proposed indicator of mitochondrial dysfunction. The large common deletion of mitochondrial DNA (mtDNA) increases with aging across multiple brain regions. We found other large deletions of mtDNA in brain at levels comparable to the common deletion (PMID: 30869147). Since mtDNA molecules replicate independently of nuclear division, the mtDNA copy number is a measure of mitochondrial health; levels are negatively correlated with age and all-cause morbidity. Complex I activity is another functional measure of mitochondria. We previously published a subset of this data from DLPFC (PMID: 29594135) for three indicators (common deletion, mtDNA copy number, Complex I activity). For this study, four indicators (common deletion, large deletions, mtDNA copy number, Complex I activity) were measured in four brain regions from subjects with schizophrenia (SZ) and bipolar disorder (BD) and compared to controls. The four brain regions were: the dorsolateral prefrontal cortex, superior temporal gyrus, primary visual cortex (V1), and nucleus accumbens.    

  Study phs002395

• NHLBI TOPMed: Walk-PHaSST Sickle Cell Disease (SCD)

  Walk-PHaSST study is a multi-center clinical trial to evaluate the effects of sildenafil on Sickle Cell Disease (SCD) population with low exercise capacity associated with an increased Doppler-estimated pulmonary artery systolic pressure (as assessed by the tricuspid regurgitant velocity (TRV)). It is a double-blind, placebo-controlled trial to assess the safety, tolerability, and efficacy of sildenafil in patients with SCD who had both an elevated TRV and decreased exercise capacity. The screening phase of the study enrolled 720 subjects and 74 of them were randomized for the clinical trial. For the screening cohort, we have collected general demographics and race/ethnicity, hemoglobin genotype, physical examination, laboratory screening, transthoracic Doppler echocardiography, and 6 minute walk test in 9 US and 1 UK site. The walk-PHaSST biorepository have banked samples from 610 of the screening subjects. A total of 592 subjects from the screening phase are included in the TOPMed program for WGS.

  Study phs001514

• Genomic Studies for Understanding Etiology of Esophageal Adenocarcinoma (EsophagealAdenocarcinoma_Chinese)

  While the incidence of esophageal adenocarcinoma (EAC) has risen drastically in Western countries over the last 40 years, a similar trend has not been observed for EAC in China. Here we analyzed mutational spectrum, copy number alterations, and structural variants from whole-genome sequencing of ten Chinese EAC tumor samples and their matched normals, and compared them to EAC tumor specimens from Western countries previously reported. The mutational burden in Chinese EAC was significantly lower than that found in EAC from Western countries. The hallmark A>C mutational signature observed at high frequency in EAC from Western countries, which linked to acid reflux, is completely absent in Chinese samples. Furthermore, none of Chinese samples showed evidence of chromothripsis and genome doubling that often found in EAC from Western countries. In summary, Chinese EAC tumor samples revealed distinct genomic profiles and signatures, suggesting that Chinese EAC may arise from a different etiological pathway.

  Study phs001696

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

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

  Study phs001258

• Genetic Study of Vascular Anomalies

  Vascular anomalies are malformations or tumors of the vasculature that can result in significant morbidity and mortality. Vascular anomalies are caused by germline or post-zygotic pathogenic variants in genes that regulate cell growth and vascular development. Complex or extensive vascular anomalies are often intractable despite interventions such as sclerotherapy, embolization, or surgery. In recent years, targeted therapy has played an increasingly crucial role in the management of these diseases. Identification of the molecular causes of vascular anomalies is essential to provide efficacious therapy; however, genetic profiling is often limited by difficulty obtaining affected tissues and limited sequencing depth. The lack of this information limits treatment options and the precision of targeted therapy, especially for primary complex lymphatic anomalies. To address these limitations, we have applied novel techniques, including analysis of unconventional samples such as endothelial cells isolated from lymphatic fluid and cell-free DNA, deep coverage exome sequencing, and unique molecular identifier ultra-deep targeted sequencing, in the molecular profiling of these diseases.

  Study phs003197

• Rare Disease Susceptibility Alleles in Children with Crohn Disease

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

  Study phs000926

• Gene Expression between PMD and Control LCLs at Baseline, E2, and E2 Withdrawal

  In this study, lymphoblastoid cell lines (LCLs) derived from women with past perimenopausal depression (PMD) (n = 8) and asymptomatic controls (n = 9) were compared via poly(A)-selected transcriptome sequencing (RNA-seq). LCLs were cultured in three experimental conditions: at vehicle baseline (ovarian steroid-free), during estradiol (E2) treatment, and following E2-withdrawal. Transcriptomic analysis revealed significant differences in transcript expression in PMD LCLs compared to controls in all experimental conditions, and significant overlap in genes that were changed in PMD regardless of experimental condition. Among these, chemokine CXCL10 was upregulated in women with PMD, but most so after E2-WD and CYP7B1, an enzyme intrinsic to DHEA metabolism, was upregulated in PMD across experimental conditions. Finally, this in vitro model identified gene networks dysregulated in PMD which included inflammatory response, early/late E2-response, and cholesterol homeostasis. Data available will include the normalized counts for each subject in the study.

  Study phs003003

• Identification and Characterization of Skin-Resident Memory T cells in Patients with Melanoma-Associated Vitiligo

  Metastatic melanoma patients who develop melanoma-associated vitiligo, an autoimmune cutaneous side effect after receiving immunotherapy, have better overall survival than those who do not develop vitiligo. The objective of this study is to determine the tumor-specific memory T cell responses in the skin, tumor and blood of melanoma patients with vitiligo. Matched melanoma tumor, distant vitiligo-affected skin, and blood were collected and sorted for T cells to perform paralleled single-cell RNA sequencing (scRNA-seq) and single-cell TCR sequencing (scTCR-seq) on the day of tissue collection. The transcriptional analysis identified three resident memory T (TRM) cell subsets which were shared between tumors and vitiligo-affected skin. scRNA-seq identified CD8+ T-cell clonotypes in tumors that co-existed as TRM in skin and as effector memory T (TEM) cells in blood. This study revealed that long-term melanoma survivors maintained memory T cell responses as broadly-distributed TRM and TEM compartments. 

  Study phs002309

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

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

  Study phs000196

• Innate and Adaptive Immunity in Parkinson Disease-P20

  Increasing evidence supports the role of brain and systemic inflammation in the etiology of Parkinson disease (PD). We used gene expression profiling (RNA-seq) to examine the activation state of peripheral blood monocytes in 18 patients with early, untreated PD and 16 healthy control (HC) subjects. Monocytes were isolated by negative selection, and gene expression studied by RNA-seq and gene set enrichment analysis. A computational model that incorporated case/control status, sex, and the interaction between case/control status and sex was utilized. We found that there was a striking effect of sex on monocyte gene expression. There was inflammatory activation of monocytes in females with PD, with enrichment of gene sets associated with interferon gamma stimulation. In males, the activation patterns were more heterogeneous. These data point to the importance of systemic monocyte activation in PD, and the importance of studies which examine the differential effects of sex on pathophysiology of the disease.

  Study phs002063

• Epigenomics of Patient Outcomes after Aneurysmal SAH

  This project was focused on understanding the pathophysiology following aneurysmal subarachnoid hemorrhage (aSAH). DNA methylation is a key mechanism for regulation of gene expression and function in the adult brain and appears to play an important role in neuroprotection during ischemic events in the brain. Delayed cerebral ischemia (DCI), occurring during the acute phase following aSAH, is a major contributor to the complications that later develop; however, the pathophysiology of DCI and the development of complications is not known. We hypothesize that characterizing the methylome representing the CNS environment post aSAH will clarify the pathophysiology associated with DCI and patient outcomes. The aims of this project focused on the daily genome-wide methylomic changes that occur in DNA representing the CNS for the first 14 days after aSAH, as well as in peripheral blood in a subset of partcipants, and determining if this methylomic data impacts DCI and the development of complications after aSAH.

  Study phs001990

• Metastatic Colorectal Adenocarcinoma Tumor Purity Assessment from Whole Exome Sequencing Data

  As molecular medicine wields greater and greater influence on cancer patient care, including therapeutic selection, it becomes increasingly important to understand the power and deficiencies of computational tools used in decision making processes. Here we use a set of unselected metastatic colorectal tumor samples in a head-to-head comparison between the calculation of stromal content by a board certified pathologist, versus that derived from whole exome sequencing and purity assessment by a variety of common computational methods. We find that in about 1/2 of the samples the computational methods each do a poor job of assessing the percent stromal contamination, and as a result, tumor variant allele frequencies (VAFs) are low or undetected, whereas analysis of organoids derived from the same tumors yielded much higher VAFs in keeping with their lower stromal content. The whole exome sequence of our samples is available via dbGaP, accession phs003059.v1.p1.

  Study phs003059

• Gut Microbiome and Types of Colorectal Polyps

  Colorectal cancer is a heterogeneous disease arising from at least two precursors-the conventional adenoma and the serrated polyp. This dataset was used to test the relationship of the gut microbiota to specific colorectal polyp types. We included samples from two independent study populations based at colonoscopy clinics: the Centers for Disease Control and Prevention (CDC) Study of In-home Tests for Colorectal Cancer (SIT), and the New York University (NYU) Human Microbiome and Colorectal Tumor study. Gut microbiota were assessed in 667 colonoscopy-screened adults by 16S rRNA gene sequencing of stool samples, of which 540 were included in our analysis. Participants were categorized as conventional adenoma cases, serrated polyp cases, or polyp-free controls. CA cases were further classified as proximal or distal and as non-advanced or advanced. Serrated polyp cases were further classified as hyperplastic polyp or sessile serrated adenoma. Our results show associations between gut microbiome composition and presence of conventional adenomas, including reduced diversity and alterations in taxon abundance.

  Study phs001381

• Functional Genomic Landscape of Acute Myeloid Leukemia

  The implementation of targeted therapies for acute myeloid leukemia has been challenged by complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. The initial findings from the Beat AML program were from a cohort of 672 tumor specimens collected from 562 patients. Additional patients have been added in subsequent versions. We assessed these specimens using whole exome sequencing, RNA-sequencing, and ex vivo drug sensitivity analyses. Our data reveal novel mutational events not previously detected in AML. We show association of drug response with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA-sequencing also revealed gene expression signatures, which predict a role of specific gene networks in drug response. Collectively, this report offers a dataset, accessible by the Beat AML data viewer (www.vizome.org), that can be leveraged to address clinical, genomic, transcriptomic, and functional inquiries into the biology of AML.

  Study phs001657

• Integrative Analysis for Multi-Omics Data in Non-Small-Cell Lung Cancer

  We conducted epigenetic and transcriptomic mapping of primary non-small cell lung tumors and non-neoplastic tissues. 20 non-neoplastic lung tissues and 18 non-small cell lung tumors were obtained from Biorepository and Tissue Technology Shared Resource at Moores Cancer Center, UC San Diego. All tumor samples were in pathological stages I and II. 8 pairs of samples were "matched", meaning that the tumor and normal tissues came from the same patient. Microfluidic oscillatory washing–based chromatin immunoprecipitation followed by sequencing (MOWChIP-seq) was used to profile the binding of H3K4me1, H3K4me3, H3K9me3, H3K27ac and H3K27me3. SmartSeq-2 was used to map mRNA expression. We identified a large number of differentially modified regions for both epigenetic and transcriptomic markers between tumors and normal tissues. Deep learning model showed extensive transcription factor network rewiring. Raw sequencing data of the ChIP-seq and RNA-seq libraries are available through this dbGaP submission.

  Study phs003113

• KDM6A Loss Triggers an Epigenetic Switch that Disrupts Urothelial Identity and Drives Cell Proliferation in Bladder Cancer

  Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. How mutations of this chromatin modifier impact the epigenetic landscape to promote carcinogenesis is poorly understood. Here, we demonstrate that KDM6A loss triggers an epigenomic switch that disrupts urothelial identity and induces a neoplastic state characterized by increased cell proliferation. In bladder cancer cells with intact KDM6A, FOXA1 binds KDM6A at enhancers to activate genes instructing urothelial differentiation. In KDM6A-deficient cells, we observed simultaneous loss of FOXA1 target binding and genome-wide redistribution of the bZIP transcription factor ATF3, which in turn represses FOXA1 target genes and activates cell-cycle progression genes. Importantly, ATF3 depletion reverses the cell proliferation phenotype. These data establish that KDM6A loss creates an epigenetic state that drives tumor growth in an ATF3-dependent manner, forging a molecular vulnerability that can be targeted by novel therapeutic strategies.

  Study phs002801

• California Teachers Study (CTS): Whole Genome Sequences From Under-Represented Populations

  The California Teachers Study (CTS) is a prospective observational cohort of N=133,477 adult women who have been followed since 1995. Participants completed up to six surveys and have been linked with cancer, hospitalization, and mortality data. In 2013-2016, over 14,000 CTS participants donated blood samples for future research. For this project, DNA was extracted in 2023 from 1694 buffy coats and 56 blood clots from N=1750 CTS participants whose self-reported race/ethnicity was Asian (398), Asian or Pacific Islander (18), Black or African American (189), Native American (128), Native Hawaiian or Other Pacific Islander (66), White Hispanic (719), or more than one race (232). Whole genome sequencing (WGS) was performed at CIDR in 2023-2024. WGS data and accompanying phenotype data are available through dbGaP. In addition, all CTS data are available to the research community via the CTS Researcher Platform (www.calteachersstudy.org), a secure cloud-based environment that includes data, software, documentation, and collaboration workspaces.

  Study phs002918

• Aberrant RNA-splicing (neojunctions) offers a new source for targets, and our neoantigen discovery platform (SNIPP) characterizes a novel class of clonally-expressed splicing-derived neoantigens that elicit a CD8+ T-cell-mediated tumor killing response.

  RESULTS: Our pipeline identified 789 public neojunctions, with 32 neojunctions concurrently identified in transcriptomic and proteomic glioma data and predicted to be presented by HLA-A*02:01 with high confidence. IVS and subsequent 10x VDJ scRNA-seq identified TCR clonotypes reactive against neojunctions in RPL22 (n=7) and GNAS (n=1), the latter being highly intratumorally-conserved (detected in > 90% of spatially-mapped biopsies across 17/56 patients (26.78%)). TCR-transduced T-cells demonstrated recognition and immunogenic activation against endogenously processed and presented neoantigens in multiple GBM PDX cell lines. Furthermore, IDH1-mutant oligodendroglioma samples demonstrated significantly elevated expression of neojunctions over IDH1-mutant astrocytoma and IDH1wt subtypes. Differential gene expression (DESeq2) identified decreased expression of splicing factors due to oligodendroglioma-specific co-deletion of Chromosomes 1p/19q. siRNA knockdown of these splicing factors (e.g. SF3A3, SNRPD2) in IDH1wt glioma cells resulted in significantly increased expression of corresponding neojunctions.

  Study EGAS00001007986

• Targeted Mutational Analysis of Intestinal T-cell Lymphomas, Using a Customized Targeted Amplicon Panel on the Ion Torrent PGM

  Intestinal T-cell lymphomas (ITCL) are rare, aggressive T-cell lymphomas that are composed primarily of enteropathy-associated lymphomas Type 1 and type 2, and a small fraction of cases not classifiable as EATL that are classified as peripheral T-cell lymphoma, not otherwise classifiable. The molecular pathogenesis of these rare lymphomas is largely unknown. We studied a series of 34 ITCL cases using a combination of amplicon based targeted next generation sequencing and pyrosequencing for mutations in 34 genes previously reported to be mutated in other types of T-cell lymphomas and other genes known to have significant roles in normal T-cell proliferation. We identified a high percentage of cases with mutations in JAK/STAT signaling pathway members, and also in RAS family members. Notably, we did not detect GNAI-2 mutations in our North American cases of EATL type 2 by targeted pyrosequencing, which had been reported previously in Asian cases.

  Study phs001126

• High Resolution Maps of the HeLa 3D Genome Using Hi-C

  We use in situ Hi-C to probe the three-dimensional architecture of genomes, constructing haploid and diploid maps of nine cell types (including HeLa). The densest, in human lymphoblastoid cells, contains 4.9 billion contacts, achieving 1-kilobase resolution. We find that genomes are partitioned into contact domains (median length, 185kb), which are associated with distinct patterns of histone marks and segregate into six subcompartments. We identify ~10,000 loops. These loops frequently link promoters and enhancers, correlate with gene activation, and show conservation across cell types and species. Loop anchors typically occur at domain boundaries and bind CTCF. CTCF sites at loop anchors occur predominantly (>90%) in a convergent orientation, with the asymmetric motifs 'facing' one another. The inactive X-chromosome splits into two massive domains and contains large loops anchored at CTCF-binding repeats. The data for the other (non-HeLa) cell types has been uploaded to GEO.

  Study phs001010

• PD-1 antibody-bound progenitor-exhausted CD8+ T cells in lymph nodes boost PD-1-blockade anti-tumor immunity in gastrointestinal cancer

  While progenitor-exhausted T cells (Tpex) expressing TCF1 and PD-1 are crucial for the therapeutic effect of immune checkpoint inhibitors (ICIs; therapeutic anti-PD-1 antibodies), the dynamics of ICI-bound Tpex are not fully understood. In this study, we investigated ICI-bound T cells in detail using combined sequencing analysis at the single cell level. By analyzing samples from gastrointestinal cancer patients with or without ICI treatment, we found that Tpex were enriched in proximal lymph nodes (LNs) and proliferated at a high rate after ICI treatment. Importantly, ICI high-bound Tpex in LNs shared T-cell receptor clonotypes with intratumoral exhausted CD8+ T cells (Tex), suggesting their migration to tumor sites after ICI treatment. These findings indicate that ICIs initially target PD-1+CD8+ Tpex in LNs, prompting their proliferation. Subsequently, these cells migrate to tumors and differentiate into Tex, thereby exerting anti-tumor immunity.

  Study JGAS000720

• Genome analysis of common diseases among older Japanese adults and development of clinical genome information storage

  A comprehensive gene expression analysis of the process leading up to the onset of Alzheimer???s disease (AD) would be helpful for understanding the mechanism. We performed an RNA sequencing analysis on a cohort of 1227 Japanese blood samples, representing 424 AD patients, 543 individuals with mild cognitive impairment (MCI), and 260 cognitively normal (CN) individuals. A total of 883 and 1169 statistically significant differentially expressed genes (DEGs) were identified between CN and MCI (CN-MCI) and between MCI and AD (MCI-AD), respectively. Pathway analyses using these DEGs, followed by protein???protein interaction network analysis, revealed key roles of ribosomal genes (RPL7, RPL11, and RPL14) and phagosomes (CDC42, PTPRC, PLCG1, and ACTR2) in MCI progression, whereas immune-related genes were involved in AD progression. Given the known effectiveness of delaying MCI progression in preventing AD, the genes related to ribosomal function and phagocytosis might emerge as biomarkers for early diagnosis.

  Study JGAS000755

• Genomic Landscape of Apical Periodontitis

  We undertook the first genome-wide association (GWAS) study of apical periodontitis, enrolling 932 patients with deep carious lesions at UTHealth School of Dentistry and the University of Pittsburgh School of Dental Medicine. We used a case-control design to compare those with apical periodontitis to those without. Genotype data was generated for all participants and imputed using the TOPMed reference panel. We performed a single-variant association testing, a subphenotype analysis, and a genetically regulated expression association analysis, and generated a polygenic risk score and performed phenome-wide association analysis. We identified eight near-genome-wide significant loci for our primary outcome, eight genes where genetically regulated expression was associated with apical periodontitis status, and 33 phecodes that were associated with the generated polygenic risk score. We also replicated three loci previously reported in the literature. Genotype, phenotype, and results from the primary association analysis will be available via dbGaP.

  Study phs003252

• INCLUDE: Down Syndrome Early Post-Natal Brain Multiome

  Neurodevelopmental deficiencies and neuronal dysfunction contribute to cognitive impairment in individuals with Down syndrome, but what molecular pathways underlie the defects that lead to intellectual disability remain unclear. Human brain development is precisely choreographed through tightly regulated transcriptional programs. Proper regulation of these transcriptional programs is necessary for developing the numerous functionally distinct regions, cell types, and connections of the brain, and forming the basis for human-specific social, cognitive, and motor abilities. These data establish a reference of molecular features of the DS developing brain. Such foundational information will provide not only a reference for any existing and future models, but also a basis for understanding disrupted neural development and impaired cognition in DS.Dataset 1 contains single-nucleus RNAseq and ATACseq from frozen postmortem human basal forebrain tissue. Dataset 2 contains single-nucleus RNAseq and ATACseq from frozen postmortem human dorsolateral prefrontal tissue. Dataset 3 contains single-nucleus RNAseq and ATACseq from frozen postmortem human caudate nucleus tissue.

  Study phs004098