Search Results - EGA European Genome-Phenome Archive

Biological insights from the whole genome sequences of human embryonic stem cell lines

Human embryonic stem cells (hESCs) are a powerful tool for the study of human development and can form the basis of cellular disease models or therapies. However, the genetic make-up and stability of hESCs has not been systematically studied at a genome-wide level with single nucleotide resolution. We therefore sequenced the whole genome and whole exomes of widely available hESC. This online resource will enable investigators to access raw sequencing data in order to interrogate cell lines for different disease- and trait-associated genetic variants.

Study EGAS00001002400

CNV detection in targeted NGS panel data

The aim of this study was to compare copy-number-variation (CNV) detection methods for targeted NGS panel data in a clinical diagnostic setting. We present targeted NGS panel data from 170 samples that were processed using the TruSight(TM) Cancer (TSC) panel (Illumina, San Diego, CA, USA), which targets 94 genes and 284 SNPs associated with a predisposition towards cancer. The samples are enriched for CNVs in the genes of interest. All CNVs have previously been assessed with MLPA and can therefore be considered as confirmed.

Study EGAS00001002481

Transcriptome analysis of samples derived from GBM tumors, and relevant cell lines established and maintained at 5% or 20% oxygen.

The goal of the study was to compare the transcriptome of patient-derived serum-free GBM cell lines to that of parental GBM tumors. For each patient, three samples were analyzed: GBM tumor, cell line growing at 5% oxygen, and cell line growing at 20% oxygen. Analysis demonstrated the enrichement in cell cycle and DNA repair gene expression in cell lines when compared to parental tumor sample. Moreover, cells cultured at 5% oxygen maintained hypoxia, carbon metabolism and tumor progression transcriptional pattern characteristic for GBM.

Study EGAS00001006267

Genomic profiling of Follicular thyroid adenomas and carcinomas using exome-sequencing analyses

While thyroid nodules per se are frequent (4%–50%), thyroid cancer is rare (∼5% of all thyroid nodules). The minimally invasive Fine Needle Aspiration Cytology (FNAC) is the current gold standard for the diagnosis thyroid nodule malignancy. However, proper discrimination of follicular neoplasias often require more invasive diagnostic techniques. To develop a novel molecular classification system for thyroid cancer malignancy, we performed an genomic profiling of 54 fresh frozen Follicular like thyroid samples using a whole exome sequencing approach (SureSelect V6 Target enrichment protocol and the Illumina Novaseq 6000 platform)

Study EGAS00001005561

CUT&RUN of AML1-ETO binding occupancy following miR-130a KD in Kasumi-1 cells

We performed CUT&RUN assay with control Ig , anti-Flag and anti-ETO antibodies in Flag-tag AML1-ETO Kasumi-1 cells to determine binding occupancy of AML1-ETO following miR-130a KD. Kasumi-1 cells were transduced in 3 independent replicates for control and miR-130a KD samples with lentiviruses containing GFP reporter gene. GFP+ cells were sorted 3 days post-transduction and the cells were used in the CUT&RUN assay. Three antibodies were used for each biological sample.

Study EGAS00001005867

ChIP-seq profiling of H3K4me1 and H3K27ac in iPSCs and iPSC-derived endoderm cells in CPRF patients with LSD1 mutations and healthy controls

LSD1 patient (children) and control (healthy fathers) derived iPSCs and endoderm differentiated cells were expanded and harvested for ChIP-seq experiment following the procedure described in Trovato et al, PMID: 39214979. Cells were cross-linked in PFA, sonicated and soluble fractions were collected for IP with H3K4me1 or H3K27ac antibodies. Sequencing libraries were prepared using the NEBNext Ultra II DNA Library Preparation Kit (New England Biolabs) and sequenced on Illumina NextSeq 500 (75 bp in single-end mode).

Study EGAS00001008242

Gene_regulation_of_human_CD4__Treg_cells_

This dataset maps gene expression regulation in human primary regulatory CD4+ T cells (Tregs). It includes whole genome sequence data for ChM-seq (118 H3K4me3, 118 H3K27ac and 6 inputs), ATAC-seq (114 samples) and whole transcriptome (141 samples). All individuals were genotyped (130 samples) using coreExome Illumina SNP chip array. The final quality filtered set included 123 individuals with RNA-seq data, 73 with ATAC-seq, 91 with H3K27ac ChM-seq and 88 with H3K4me3 ChM-seq data. A total of 62 individuals had QCed data for all the assays.

Study EGAS00001003516

Cystic fibrosis multi-omics study

Cystic fibrosis (CF) is a genetic disorder affecting approximately 1 in 2,500 people in the UK. Here, we generated a number of high-throughput sequence data sets for monocytes and neutrophils from CF patients and matched healthy volunteers (HV); including ChIP-Seq (H3K27Ac), chromatin accessibility (ATAC-Seq), and transcript/gene expression (RNA-Seq) data. Analysis of gene expression and epigenetic profiles demonstrates a robust innate immune gene expression profile that distinguishes CF and HV during periods of disease exacerbation. Upregulation of pathways responsible for the production of proinflammatory cytokines is described.

Study EGAS00001006421

Immuno-genomic landscape of osteosarcoma

Osteosarcoma is an orphan disease affecting children and young adults that has seen little to no progress in survival outcomes for >30 years. Despite having heavily rearranged genomes, to date, clinical trials with immunotherapy have shown no benefit for patients with osteosarcoma. In this study, we conducted the first multi-platform immune profiling (whole genome, transcriptome, T-cell receptor sequencing, immunohistochemistry and reverse phase protein array) on every available pediatric and adult osteosarcoma patients from our institution (N = 48) with the goal of describing immune features that may contribute to immunotherapy resistance.

Study EGAS00001003887

scRNA-seq of human follicular lymphoma and lymph node

Cryopreserved cells from human nodal follicular lymphoma and lymph node samples were thawed and processed for scRNA-seq analysis. CD3+ CD19− 7-AAD− live T cells (six FL samples from the Original cohort) or 7-AAD− whole live hematopoietic cells (five lymph node and nine FL samples from Validation cohort 1) were sorted using a FACS Aria II or III instrument (BD Biosciences). To generate single-cell emulsions, 6,000–10,000 live cells were loaded into the 10X Genomics Chromium Controller for single-cell partitioning, along with the reverse transcriptase reagent mixture and 3' or 5' gel beads. Sorted T or whole hematopoietic cells were converted to barcoded scRNA-seq libraries using 10X Genomics Chromium single cell 3' reagent kits (v3) for the Validation cohort 1, 5' reagent kits (v1) for the Original cohort, according to the manufacturer’s instructions. The libraries were sequenced on an Illumina HiSeq X Ten or NovaSeq X Plus system, mapped to the human genome (build GRCh38), and demultiplexed using CellRanger pipelines (v3.1.0, 10x Genomics).

Dataset EGAD50000001143

Long read mRNA sequencing of human neural retinal samples - Usher syndrome transcript landscape

Long-read (PacBio) RNA sequencing dataset of three neural retinal samples. Three PacBio libraries were prepared according the 'standard workflow' optimized for sequencing transcripts centered around 2kb. Additionally one Library (input HNR_S2) was prepared according an optimized 'long workflow' to enrich for larger transcripts up to >10kb. To further enhance the capture of full-length transcripts for USH2A and ADGRV1 (USH2C) genes, we also employed a targeted enrichment approach using the Samplix Xdrop System, followed by PacBio long-read sequencing. USH2A and ADGRV1 enrichment was performed by targeting '5- mid and 3' targets of the respective genes. Finally, we also added ONT (Oxford Nanopore technology) long-read mRNA sequencing of three independent neural retina samples. These data were used for the validation of events observed from the Iso-Seq and Samplix data. The ONT datasets contain sequencing data of the Usher-associated genes. Files are raw BAM, and CRAM format files generated by a Sequel II machine. Additionally, the ccs3 BAM format files are included.

Dataset EGAD50000000720

Elucidation of factors involved in the progression of diabetic kidney disease

A new concept of diabetic kidney disease has been proposed as a more comprehensive disease concept for chronic kidney disease associated with diabetes.The factors and molecular mechanisms that determine the course of diabetic nephropathy, whether it is the classic diabetic nephropathy or the rapid decliner, are unknown.In order to develop effective diagnostic and therapeutic methods for individual cases and conditions of diabetic nephropathy patients, it is necessary to elucidate the molecular mechanisms.We performed single-cell RNA sequencing and analyzed the characteristics of 3 cases of rapid decline in diabetic kidney disease.

Study JGAS000802

Mapping genetic variants that underlie gene regulation in intestinal cell types to identify novel, validated, Crohn’s disease drug targets

Biopsies from the terminal ileum and rectum of healthy individuals and terminal ileum and blood from Crohns disease patients are collected and processed single cells and processed for single-cell RNA-sequencing using 10X Genomics 3' v3 and v3.1 and Illumina 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/

Study EGAS00001003647

Analyzing the expression profiles of genes in ureters with and without indwelling stents using RNAseq

The objective of the work is to explore the pathways and mechanisms driving inflammation and fibrosis in stented ureters. In total, 6 pigs underwent cystoscopic unilateral ureteral stent insertion for 14 days. Ureteral tissue was harvested in 3 pigs, while the remaining 3 pigs had their stents removed, and were recovered for 7 days. Three separate pigs served as controls. Stents cause significant inflammation and fibrosis of ureters. Gene set enrichment analysis confirmed fibrotic changes and tissue proliferation and suggests that epithelial-mesenchymal transition is a driver of fibrosis.

Study EGAS00001006855

Transcriptional_analysis_of_cells_from_lungs

To capture the full heterogeneity of the cellular types and states during HSPCs differentiation, haematopoietic progenitors will be obtained through column-enrichment of cells expressing CD34, a pan-progenitor marker for HSPCs. The samples from tumour and non-tumour lung tissue from different patients will be processed using the 10x Genomics platform. 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 EGAS00001002649

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

SardiNIA Medical Sequencing Discovery Project

The SardiNIA Medical Sequencing Discovery Project studies the genetics of blood lipid levels and personality in a Sardinian population cohort. The project has generated draft genome sequences for approximately 2,000 individuals using whole genome shotgun sequencing. The draft sequences will allow investigators to evaluate the contribution of common and rare single nucleotide polymorphisms, short insertions and deletions, large copy number polymorphisms and other structural variants to blood levels of low density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c) and triglycerides (TG), all of which are key risk factors for cardiovascular disease, and to the 5 domains of personality as assessed by the NEO-PI-R questionnaire. The two traits represent different ends of the spectrum of medically interesting complex traits. Blood lipid levels are a risk factor for cardiovascular disease for which genetic studies have been very successful. In contrast, personality traits and other behavioral phenotypes represent a set of phenotypes that have proven more challenging to dissect using standard genetic tools. In both cases, we expect whole genome sequencing to improve our understanding of the underlying biology. The isolated Sardinian population is ideal for this type of study for several reasons, in particular because: (i) the bottleneck that occurred after colonization of the island attenuated natural selection against alleles with phenotypic consequences, increasing the odds that functional alleles will reach modest frequencies (0.5 - 5.0%) and will be detected in the present study and (ii) sharing of long haplotype stretches surrounding rare variants will facilitate imputation based analyses of shotgun sequence data, which improve the accuracy of individual genotype calls and thus increase power. This research helps advance NIH's mission by furthering our understanding of the genetic factors contributing to blood lipid levels and coronary heart disease and to personality, behavior and mental health. In addition, these data should facilitate development of analysis tools and strategies that can be used to study the genomes of hundreds to thousands of individuals and further our understanding of the genetics and biology of many different traits and conditions.

Study phs000313

National Eye Institute (NEI) Ocular Hypertension Treatment Study (OHTS)

The Ocular Hypertension Treatment Study (OHTS) is an National Eye Institute-sponsored multi-center, randomized, prospective treatment trial designed to determine whether lowering intraocular pressure (IOP) in individuals with ocular hypertension delays or prevents the development of primary open angle glaucoma (POAG). A total of 1,636 individuals with ocular hypertension between 40 and 80 years old were enrolled in the study. In addition to ocular hypertension, subjects in the OHTS were required to have normal optic nerve appearance as determined by the OHTS Optic Disc Reading Center and normal and reliable visual field tests at the time of enrollment by the OHTS Visual Field Reading Center. OHTS subjects were randomly assigned to either an observational group which received close observation or a topical medication group which received medication as needed to achieve a 20% reduction in IOP from their baseline levels. Subjects then were examined at regular intervals for optic disc cupping or visual field defects. Other clinical measures were also obtained from OHTS subjects including central corneal thickness (CCT) and intraocular pressure. The primary outcome monitored for the OHTS was the development of glaucoma in one or both eyes as defined by reproducible visual field abnormality or reproducible optic disc deterioration attributed to POAG by the masked OHTS Endpoint Committee. The OHTS study design has been reported in detail (Gordon, 1999; PMID: 10326953). The OHTS confirmed that ocular hypertension is a risk factor for developing POAG and showed that lowering IOP reduced the risk for developing POAG (Kass, 2002; PMID: 12049574). The OHTS also demonstrated that thin CCT is a significant risk factor for the development of POAG (Gordon, 2002; PMID: 12049575). Blood samples were also collected from 1,077 OHTS participants for an ancillary genetics study. DNA was prepared from these samples and used in a genome-wide association scan (GWAS) designed to identify genetic factors that control the magnitude of quantitative features of glaucoma (baseline IOP, baseline cup-to-disc ratio, and CCT). Genotypes from the GWAS and these clinical data (IOP, cup-to-disc ratio, and CCT) have been provided to dbGaP.

Study phs000240

Research of factors related to diagnosis, progression, prognosis and treatment of hepato-biliary-pancreatic malignancies

Advanced cancers with metastasis and/or recurrence are usually resistant and refractory to treatment. In our studies, whole exome sequencing analysis, comprehensive epigenetic analysis and genome-wide expression analysis were performed using cancerous and non-cancerous tissues derived from multicentric cohort study of hepatocellular carcinoma (HCC). The aim of the studies is identification of the refractoriness-related deriver genes for application to novel molecular targeted therapy and preventive medicine. The studies are intended for refractory HCC. High frequency of the tumor recurrence even after curative resection is one of the major difficulties in the treatment of HCC. According to our previous studies, not the recurrence itself, but the recurrence pattern has critical effects on prognosis of the patient with HCC. Then, we analyzed the cancerous and non-cancerous tissues of primary HCC on the point of the recurrence patterns in accordance with or without Milan criteria. The materials were obtained from thirty three patients underwent curative hepatectomy for HCC at Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University Hospital. Written informed consent from these patients, as well as the institutional review board approved was obtained. The determination of the refractory HCC group (16 cases) was based on the point of the recurrence patterns in accordance with Milan criteria for the recurrent tumor (solitary <5cm, or up to 3 nodules <3 cm, without major vascular invasion or distant metastasis) that has been proposed as the useful criteria of the liver transplantation for HCC. The cellular DNA was extracted from the cancerous and non-cancerous tissues of primary HCC by the phenol-chloroform method. After SNP certification using Genome-Wide Human SNP Array 6.0 (Affymetrix), whole exome sequencing was performed at the Cancer Institute of JFCR, as the support infrastructure. Exome sequencing was performed using HiSeq 2000 (Illumina), and the obtained reads were mapped to the human reference genome (hg19) using BWA software. GATK software was used for local realignment base call recalibration. Single nucleotide variants (SNVs) and indels were analyzed by MuTect and SomaticIndelDetector, as well as visual confirmation by IGV software.

Study JGAS000052

Knoll et al.: The life-saving benefit of dexamethasone in severe COVID-19 is linked to a reversal of monocyte dysregulation

Following the demonstration of its life-saving effect in clinical trials, dexamethasone quickly became standard-of-care in the treatment of severe COVID-19. Beneficial effects were reported for patients requiring supplemental oxygen or invasive mechanical ventilation. Yet, a substantial proportion of patients still progressed to a critical condition or succumbed to the disease, despite timely initiation of glucocorticoid treatment. No molecular or cellular correlate of this beneficial treatment response has been defined. Here, we identify distinct cellular and molecular changes in circulating immune cells in patients with COVID-19 elicited in response to dexamethasone treatment. The most profound transcriptional changes in response to dexamethasone treatment were noted in monocytes and in B cells. In monocytes, we observed a reversal of hallmark signatures previously associated with COVID-19 severity, and the induction of a specific monocyte substate enriched in glucocorticoid response gene expression which we here refer to as dexamethasone response cluster. Molecular responses to dexamethasone treatment were directly linked to clinical outcome, since the reversal of pathogenic signatures and induction of glucocorticoid response genes were enriched in patients who survived the disease in response to dexamethasone treatment. Cellular responsiveness of circulating monocytes was thus identified as a correlate of clinical response to dexamethasone treatment. Changes in monocyte transcriptomes could also be linked to epigenetic alterations highlighting early differences in monocytes of dexamethasone responders and non-responders. Further, monocyte single-cell transcriptome-derived signatures were enriched in whole blood transcriptomes from patients with fatal outcome in two independent cohorts, highlighting the potential clinical value for early identification of non-responders who are refractory to dexamethasone treatment. Overall, our findings indicate that the life-saving effects of dexamethasone in COVID-19 patients are linked to a specific immunomodulatory effect based on the reversion of monocyte dysregulation. Our study elucidates the potential mechanism of action of one of the most efficient and cost-effective drugs for the treatment of COVID-19. It further highlights the potential of single-cell omics for monitoring target engagement of immunomodulatory drugs and for the stratification of patients for precision medicine approaches.

Study EGAS00001007461

Genetic Factors associated with Conversion from Active Surveillance to Treatment for Prostate Cancer

This is a genome-wide association study (GWAS) of conversion from active surveillance (AS) for prostate cancer (PC) to treatment. AS is the monitoring with screening tests and/or biopsies over time of men usually with low-risk, early-stage PC to avoid harmful side effects of PC treatment. "Conversion" refers to patients who withdraw from AS (switch to active treatment) due to changes in their cancer development, anxiety about delayed treatment, or other reasons. Patients who converted because of anxiety alone were censored in the GWAS analysis. The overall goal of this study is to develop an easily measurable, germline-based panel of genetic variants to aid in selecting PC patients appropriate for AS and/or the intensity of monitoring. In total, 6,324 PC patients from 28 collaborating institutions are included in this study. Patients are those with PC who are either on AS or who have previously converted from AS to treatment. In this study, 70% of all subjects were diagnosed with very low-risk, low-risk, or low-volume intermediate-risk PC (Kryvenko and Epstein, 2016; PMID: 26709152) and have been enrolled in an AS program. DNA was extracted from blood, saliva, or formalin-fixed, paraffin-embedded (FFPE) tissue collected from the study subjects at the participating sites. Genotyping, quality control processes, and imputation were performed at the Center for Inherited Disease Research (CIDR) at Johns Hopkins University. CIDR used the Illumina Infinium Multi-Ethnic Global Array (MEGA) version 1, which included genome-wide tag SNPs and 10,000 SNPs selected with custom content. Quality control and assurance (QC/QA) checks on genotyped data involved four domains: sample-level checks, batch effects, SNP-level checks, and preliminary association tests. Samples and SNPs passing the QC/QA checks were imputed to appropriate reference panels (HRC r1.1 for patients of European ancestry) using the Michigan Imputation Server (PMID: 27571263). Unmeasured genetic variants were imputed using the Trans-Omics for Precision Medicine (TOPMed) Imputation Server, with 97,256 reference samples and 308,107,085 SNPs. Variants with imputation quality (INFO) score < 0.3 were excluded, leaving a total of 22,691,641 SNPs successfully imputed. After QC steps, a total of 5,936 samples genotyped at CIDR remained for inclusion in the GWAS.

Study phs002056

Data Use Ontology (DUO)

Data Use Ontology Data Use Ontology at EGA The EGA is committed to its involvement in the work of GA4GH. In an effort to enhance data discoverability and streamline data access, EGA have implemented the use of the Data Use Ontology (DUO), based on consent codes as described in Dyke et al. 2017. The Data Use Ontology codes will be displayed on the live dataset page of your submission to advise any would be requestor on how the data can be used and also to enhance data discoverability as users will be able to search on these codes to find applicable datasets. DUO can be browsed online via the Ontology Lookup Service Learn more reading the Data Use Ontology publication and the GA4GH Machine-Readable Consent Guidance! Check our DAC Portal Take The Tour and learn how to add DUO codes to your policy! Term Shorthand Label Description DUO:0000004 NRES no restriction This data use permission indicates there is no restriction on use. DUO:0000042 GRU general research use This data use permission indicates that use is allowed for general research use for any research purpose. DUO:0000006 HMB health or medical or biomedical research This data use permission indicates that use is allowed for health/medical/biomedical purposes; does not include the study of population origins or ancestry. DUO:0000007 DS disease specific research This data use permission indicates that use is allowed provided it is related to the specified disease. DUO:0000011 POA population origins or ancestry research only This data use permission indicates that use of the data is limited to the study of population origins or ancestry. DUO:0000012 RS research specific restrictions This data use modifier indicates that use is limited to studies of a certain research type. DUO:0000015 NMDS no general methods research This data use modifier indicates that use does not allow methods development research (e.g., development of software or algorithms). DUO:0000016 GSO genetic studies only This data use modifier indicates that use is limited to genetic studies only (i.e., studies that include genotype research alone or both genotype and phenotype research, but not phenotype research exclusively) DUO:0000018 NPUNCU not for profit, non commercial use only This data use modifier indicates that use of the data is limited to not-for-profit organizations and not-for-profit use, non-commercial use. DUO:0000019 PUB publication required This data use modifier indicates that requestor agrees to make results of studies using the data available to the larger scientific community. DUO:0000020 COL collaboration required This data use modifier indicates that the requestor must agree to collaboration with the primary study investigator(s). DUO:0000021 IRB ethics approval required This data use modifier indicates that the requestor must provide documentation of local IRB/ERB approval. DUO:0000022 GS geographical restriction This data use modifier indicates that use is limited to within a specific geographic region. DUO:0000024 MOR publication moratorium This data use modifier indicates that requestor agrees not to publish results of studies until a specific date. DUO:0000025 TS time limit on use This data use modifier indicates that use is approved for a specific number of months. DUO:0000026 US user specific restriction This data use modifier indicates that use is limited to use by approved users. DUO:0000027 PS project specific restriction This data use modifier indicates that use is limited to use within an approved project. DUO:0000028 IS institution specific restriction This data use modifier indicates that use is limited to use within an approved institution. DUO:0000029 RTN return to database or resource This data use modifier indicates that the requestor must return derived/enriched data to the database/resource. DUO:0000043 CC clinical care use This data use modifier indicates that use is allowed for clinical use and care. DUO:0000044 NPOA population origins or ancestry research prohibited This data use modifier indicates use for purposes of population, origin, or ancestry research is prohibited. DUO:0000045 NPU not for profit organisation use only This data use modifier indicates that use of the data is limited to not-for-profit organisations. DUO:0000046 NCU non-commercial use only This data use modifier indicates that use of the data is limited to not-for-profit use. Point to Notice: For the consent code DUO:0000007 where data is restricted to use on a specific disease, please accompany it with an appropriate ontology from MONDO e.g., If the data is restricted to the use of research into juvenile idiopathic arthritis the code should be displayed as DUO:0000007; MONDO:0011429.

Documentation access/data-access-committee/data-use-ontology

Molecular Biomarkers Predicting Lung Cancer Response Phenotypes

We have used a "chemistry first" approach to discover druggable acquired vulnerabilities that arised in the pathogenesis of non-small cell lung cancer (NSCLC). We screened chemical libraries (~200,000 compounds) for chemical toxins that killed subsets of NSCLC but not normal human lung epithelial cells (HBECs). We first screened a panel of 12 NSCLC lines that represented a variety of known oncogenotypes and identified chemicals with large Z scores and appropriate properties including re-supply, chemistry, and reproducible drug response phenotypes. This was then narrowed down to a list of 202 chemicals and 18 drugs with known targeting (henceforth called "Precision Oncology Probe Set", or POPS). These, and a panel of 30 clinically available drugs, targeted therapies, and drug combinations, already in use or in trials for NSCLC treatment, were then tested on a panel of 96 NSCLC lines for their drug response phenotypes in 12-point dose response curves. This information was analyzed using scanning ranked KS (Kolmogorov-Smirnov) and elastic net biostatistics approaches to identify molecular biomarkers (mutations, mRNA expression, copy number variation, protein expression, and metabolomics) which could predict for sensitivity or resistance to a particular chemical toxin or treatment regimen. From this we have discovered that: our approach identifies already known molecular biomarker of drug sensitivities (e.g. EGFR mutations and EGFR TK inhibitors); many clinically available chemotherapy agents have molecular biomarkers predicting preclinical model drug responses; the POP set of chemical toxins provides novel drug response phenotype patterns in the large NSCLC panel different from those found with clinically available agents including a therapeutic window; many of the POP toxins only hit a small percentage (~5%) of the NSCLC panel but the POP set as a whole provides "coverage" of the entire NSCLC panel; there are simple, one or 2 component molecular biomarkers (mutations, mRNA expression) that predict responses to the different chemical toxins in the NSCLC panel; and that the molecular biomarkers provide some information on the targets and pathways involved in response to the chemical toxins. Thus, we have identified a group of chemical toxins with selectivity for subsets of NSCLC and associated tumor molecular biomarkers to facilitate their development for precision medicine, and also, in some cases, information on the targets and pathways interdicted by these chemical compounds. In addition, we have discovered NSCLC predictive biomarkers for clinically available agents.

Study phs001823

African American Multiple Myeloma GWAS

The case set is from a case-control study designed to identify common genetic risk factors for multiple myeloma in African Americans, the population with the highest risk for this cancer. We conducted two GWAS and combined each of these with convenience controls consisting of unaffected African American participants in cohorts with existing GWAS data. We then conducted a meta-analysis of the two sets. Cases were persons of African ancestry with smoldering or active multiple myeloma identified at participating oncology clinics or through SEER registries, as part of the African American Multiple Myeloma Study (AAMMS) diagnosed from Jan 1, 1988 through July 31, 2016. The majority of the samples were collected from incident and prevalent cases diagnosed since Jan 1, 2008 (80.9%), with a minority obtained from biobanks from cases diagnosed prior to 2008 (19.1%). Additional samples were obtained from the Multiethnic Cohort (USC and University of Hawaii) (n=40), the University of California at San Francisco Multiple Myeloma Study (n=27), and from the Multiple Myeloma Research Consortium for secondary analysis (samples originally provided to MMRC by 8 additional sites (n=84)). We have identified the phenotype (smoldering myeloma, plasma cell multiple myeloma, or myeloma not otherwise specified (myeloma NOS) when myeloma phenotype was not known), sex and age at diagnosis in this data set. The initial GWAS set consisted of 1308 (1,305 passed QC) cases with DNA samples, with a GWAS performed on the Illumina Human Core. Controls consisted of 7,078 unaffected African American subjects who were participants in the African American Prostate and Breast Consortium, with existing GWAS data from the Illumina1M Duo BeadChip. The second GWAS set consisted of 529 African American multiple myeloma patients with samples (406 from University of Arkansas, results not contained in this dataset because NCI funds were not used for the collection and genotyping) with GWAS data resulting from the Illumina Mega-BeadChip v1.1. Controls were 2,390 unaffected African American participants in the Multiethnic Cohort with existing GWAS data from the same array. After QC and removal of duplicates within sets, sex mismatches, and removal of plasmacytoma cases (ICD-0 code 9731), this deposited data set contains the typed GWAS data for the Illumina Human Core (set 1) (n=1298), and for the MegaBead Chip v1.1 (set 2) (n=123), with the University of Arkansas samples removed, for a total of 1,421 case genotypes. Note that 13 samples that overlap set 1 and set 2 were included.

Study phs001632

NEI CIDR Methylation Profiling of Primary Open Angle Glaucoma in NEIGHBOR Samples

This is a case-control study of Primary Open Angle Glaucoma (POAG). POAG is a progressive optic neuropathy that eventually leads to blindness. More than 30 million people worldwide have Primary Open Angle Glaucoma (POAG), of which greater than 3 million are blind. Gene expression changes in the retina have been observed for POAG. Several recent studies, including the NEIGHBOR consortium (NEI Glaucoma Human genetic collaboration) have used GWAS to identify correlative regions of the genome. Despite this, the genetic basis of Glaucoma is not well understood. Epigenetic variation may account for low heritability and environmental effects on human disease. Despite the significant advances being made in understanding the role of epigenetics in gene regulation in other fields, little is known about the relationship between DNA methylation patterns, retinal gene expression, and retinal disease. The goal of this study is to identify differentially methylated regions in the peripheral blood of patients with POAG. The case identification is as per the NEIGHBOR description: Cases and controls were recruited from ophthalmology clinics and were examined by ophthalmologists. For cases the clinical exam included intraocular pressure measurements, optic nerve assessment and visual field evaluation. Controls had no family history of glaucoma, normal intraocular pressure and normal optic nerves. POAG and control samples come from two sources: Duke University and Massachusetts Eye and Ear Infirmary (MEEI). These samples were collected and genotyped as part of the NEIGHBOR study. From the 219 POAG cases contributed to NEIGHBOR by Duke, 75 samples were selected for exome sequencing by Dr. Terry Gaasterland (UCSD) as part of an ARRA grant. These samples were selected to mirror the distribution of the entire set of Duke patients for variables such as age, cup-to-disc ratio, CCT, and IOP. From these 75 patients, 43 were selected for our study and an additional seven patients chosen at random, for a total 50 patients from Duke. From the 219 Duke controls, 50 were selected to match the age (at the time of blood draw) and sex of the 50 Duke POAG patients. From the NEIGHBOR control samples from MEEI, 27 were selected who best matched the age (at blood draw), time since sample collection and sex of the POAG probands from GLAUGEN. Additional individual-level phenotype and genotype data may be obtained through the authorized access portal of phs000238 (Neighbor - Glaucoma GWAS Study).

Study phs000458

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