Search Results - EGA European Genome-Phenome Archive

Adipose Tissue Omics In Obesity

This project used a multi-omics approach to study the adipose tissue transcriptome in humans with and without obesity. Our human cohort included males and females between the ages of 18-80 who underwent elective abdominal surgery at the University of Michigan and the Ann Arbor Veterans Affairs Healthcare System.Patients with advanced cancer or immuncompromised status were excluded. Visceral adipose tissue (VAT/omental) and subcutaneous adipose tissue (SAT/abdominal wall) were collected from subjects with obesity (BMI>=35) at the beginning of elective surgical procedures, placed on ice, and transported back to the laboratory for immediate processing. For adipose tissue stromal cells (ASC) isolation, adipose tissue was digested with Type II collagenase (2 mg/mL in PBS/2% BSA) at 37oC, 60min, centrifuged at 250 rcf, and the stromal-vascular cell pellet was retrieved, plated overnight, and the adherent cells passaged three times to enrich for ASC, which were then frozen in DMEM/F12, 15% fetal calf serum, and 10% DMSO in liquid nitrogen until use. Single nuclear sequencing was performed on preparations from intact adipose tissue. Bulk RNA sequencing and single cell sequencing were performed on ASC isolated from intact adipose tissue and cultured in 2D and 3D culture systems. We currently apply bulk, single cell, and single nuclear sequencing analyses to these tissues. One component of this project studies single nuclear sequencing in nuclei isolated from intact adipose tissues from human subjects with obesity, focusing on depot comparisons (VAT vs. SAT). This cohort also permits comparisons of adipose tissue transcriptomes between male and female subjects, controlling for age and BMI. Primary findings to date include identification of multiple ASC, adipocyte, and endothelial cell (EC) subpopulations, T-cell, and macrophage (MAC) populations that are in concordance with and expand upon other published datasets. Of two dominant ASC subpopulations, one (inflammatory-mesothelial, IM- ASC) is present in VAT, but absent in SAT, while the other (fibroadipogenic, FA-ASC) is present in both VAT and SAT. We identified multiple EC subtypes with features of lymphatic, venous, and arterial EC, and a PRDM16 expressing population with features of an EC progenitor. Immune cell populations match recent experimental validation of lipid-activated macrophage (LAM) phenotypes, TIM4 macrophages, and a prominent population of MRC1/CD206+ resident AT macrophages with expression signatures related to glucocorticoid activation. These data support depot-specific differences in ASC subpopulations and previously unrecognized EC heterogeneity within human AT, with the potential to shed light on functional differences in AT depot and disease state. Planned future studies include ATAC-Seq and other omics analyses. Another component of this project studies transcriptional responses of ASC in vitro to various stimuli, including different matrix environments. Current data includes bulk RNA Sequencing of human ASC from VAT and SAT differentiated into mature adipocytes in hydrogels of differing stiffness (3%, 5%, 10%) to define transcriptional responses to matrix environments of different stiffness. Primary findings to date include enrichment of adipogenesis and lipid and oxidative metabolic gene pathways in adipocytes in 5% relative to 3% hydrogels, while fibrotic gene pathways have been enriched in 3% hydrogels. These data demonstrate that intermediate density matrix promotes a more adipogenic, less fibrotic adipocyte phenotype geared towards increased lipid and aerobic metabolism. Planned future studies include expansion of intact tissues from our cohort studied with single nuclear sequencing, as well as further study of ASC responses in vitro to different biologic stimuli, including different matrix environments.

Study phs003390

Coronary Artery Risk Development in Young Adults (CARDIA-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.Related Studies: Other CARDIA data available include:phs000236.v2.p2 PAGE: CALiCo: Coronary Artery Risk Development in Young Adults(CARDIA) phs000309.v3.p2 The CARDIA-GENEVA Study phs000399.v1.p2 NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (CARDIA) phs000613.v1.p2 NHLBI CARDIA Candidate Gene Association Resource (CARe) phs003675.v1.p1 CARDIA Multi-omics Obesity & CVD Substudy – Year 20 Untargeted Metabolomics Data phs001612.v3.p2 NHLBI TOPMed: CARDIA (Coronary Artery Risk Development in Young Adults) phs003045.v1.p1 Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Coronary Artery Risk Development in Young Adults Study (CARDIA) phs000285.v4.p3 CARDIA_Cohort Available Data: Available data for request include exam data through Year 30 and outcomes and death data through 2022. Additionally, data from 28 ancillary studies are available for request.Objectives: The original objectives of CARDIA were to document levels of risk factors for coronary artery disease and potential determinants of these risk factors in young adults; to study the interrelationships of risk factors and lifestyles and to document behavioral and environmental changes during the transition from young adulthood to middle age; to compare cross-sectional and longitudinal data on age-related trends in cardiovascular disease risk factors; and to compare levels and evolution of risk factors between men and women, blacks and whites, and in groups of differing socioeconomic status. Goals of the study have evolved to emphasize understanding determinants of left ventricular mass, emerging obesity and hypertension, and sequelae of hypertension in pregnancy.Background: CARDIA is designed to increase understanding of contributors to changes in cardiovascular disease (CVD) risk factors during the critical years of transition from young adulthood to middle age. CARDIA was funded initially in 1983 for a five-year cycle that included two rounds of examinations. Contract renewals have allowed for subsequent re-examinations.Participants: Black and white men and women; ages 18-30 years at entry with a range of attained education; original sample size: 5,115.Design: CARDIA is a population-based observational study of 5,115 participants aged 18-30 years recruited in 1985-1986. The sample was designed to achieve approximately balanced subgroups of race, gender, education (high school or less and more than high school) and age (18-24 and 25-30). Forty percent of the cohort had no more than a high school education. A total of nine examinations have been completed in the cohort with examination cycles at year 2 of the project and years 5, 7, 10 , 15, 20, 25, and 30.In addition to standard measurements of blood pressure, anthropometry, blood lipids, smoking behavior, physical activity, diet, pulmonary function, and many psychological factors, CARDIA has other included measurements (in subsets or in the full cohort) to obtain unique information on other aspects of risk factor development and early morbidity. These have included: graded exercise treadmill testing; echocardiography, particularly for measurement of left ventricular mass; cardiovascular reactivity; serum cotinine; Lp(a), apoE phenotype, apolipoprotein A1 and B; homocysteine; skin reflectance; body composition by dual X-ray absorptiometry; glucose tolerance testing; vascular resistance and compliance; and plasma renin activity and sympathetic nervous system activity.

Study phs003739

Study on the Genetics of Alcoholism (COGA): African American Family GWAS

COGA is a family study of alcoholism, in which the subjects have been drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), a large, ongoing family-based study that includes subjects from seven sites around the US. COGA has gathered detailed, standardized data on study participants, including diagnostic and neurophysiological assessments. This project has already proved successful in identifying several genes that influence the risk for alcoholism and neurophysiological endophenotypes, which have been independently replicated. COGA data were included as part of two Genetic Analysis Workshops, and the phenotypes are familiar to the genetics community. Alcoholic probands were recruited from treatment facilities, assessed by personal interview, and after securing permission, other family members were also assessed. A set of comparison families was drawn from the same communities as the families recruited through an alcoholic proband. Assessment involved a detailed personal interview developed for this project, the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), which gathers detailed information on alcoholism related symptoms along with other drugs and psychiatric symptoms. Many participants also came to the laboratories for electroencephalographic studies. Neurophysiological features that have been shown to be useful endophenotypes for which we have linkage and in some cases association results are included on a subset of the case-control sample: the beta power of the resting electroencephalogram (EEG), the P3(00) amplitude of the visual event-related potential (ERP), and the theta and delta event-related oscillations (EROs) underlying the P3. As part of COGA, a set of informative African American families were selected to have Genome-Wide Association data obtained within families. Genotyping was performed using the Illumina Omni2.5_080814_1 chip to genotype 3,438 subjects selected from densely affected families. Genotyping was performed at CIDR. This sample complements a set of densely affected European American families previously made available under dbGaP study accession phs000763. In addition, exome sequencing data on a subset of individuals with GWAS were added in version 2.For version 3, a subset had 30X Whole Genome Sequencing (WGS) as part of the NIDA Sequencing Initiative. The subset contained two distinct sets: Sibling pairs where one sibling had at least two dependence diagnoses in the set (alcohol, cannabis, cocaine, and opioid), and the other had none, and non-related Case-Control pairs matched for age and ethnicity where the cases had alcohol and at least 2 other dependence diagnoses and controls had none. After sequencing, some sibling pairs are re-classified as half siblings, Three VCF files (small variants, structural variants, and copy number variations) are provided. Additional substance abuse variables are made available in version 3. We note that the full sample data are deposited in four dbGaP submissions and the sequenced samples are split across all four: CIDR: Collaborative Study on the Genetics of Alcoholism Case Control Study (phs000125). GWAS data on cases (primarily probands) and controls drawn from the families. Families with highest density of alcohol dependence and/or extreme event-related oscillation data (phs000763). GWAS data on 119 extended families of European descent are available here, along with extensive documentation. Study on the Genetics of Alcoholism (COGA): African American Family GWAS (phs000976). GWAS data on all available COGA families of African descent are available. COGA: Smokescreen GWAS (phs001208). GWAS data on all remaining COGA DNA samples, primarily of other racial background, were genotyped on the Smoke Screen array. A listing of all sequenced pairs is provided in the documentation to facilitate the merging of these samples.

Study phs000976

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

Intra-tumor heterogeneity and clonal evolution of papillary renal cell carcinoma

Limited knowledge of intratumor heterogeneity (ITH), and clonal evolution of papillary renal cell carcinoma (pRCC) and rare kidney tumor subtypes hinders understanding of tumorigenesis and therapeutic efficacy. We conducted an integrative genomic and epigenomic ITH analysis and studied clonal evolutionary history of pRCC and rare kidney tumor subtypes. We dissected multiple consecutive samples from the center of the tumor towards the tumor's periphery, a normal sample ~5 cm distant from the tumor, and, where feasible, metastatic regions in the adrenal gland. Specifically, we performed 60X multi-region whole-genome sequencing (mWGS), both genome-wide methylation and SNP array profiling, and deep targeted sequencing (average 500X coverage) of 254 cancer driver genes (PMID:24390350). The study population comprises 39 patients with kidney cancers, including 23 with papillary type 1 (pRCC1), 12 with papillary type 2 (pRCC2), one of which also had areas of clear cell, and one each with collecting duct tumor (cdRCC), renal fibrosarcoma rSRC, mixed pRCC1/pRCC2, and an unclassified renal cancer with mixed features of pRCC2 and cdRCC. Based on DNA sample availability, we conducted whole genome sequencing (WGS) on 124 samples from 29 subjects, deep targeted sequencing on 139 samples from 38 subjects, SNP array genotyping on 101 samples from 38 subjects, and genome-wide methylation profiling on 139 samples from 28 subjects. All assays were performed on tumor, metastasis and normal tissue samples, with the exception of the SNP array genotyping, which was conducted only on tumor samples.

Study phs001573

Center for Craniofacial and Dental Genetics: Exome Sequencing of Orofacial Cleft Families

Orofacial Clefts (OFCs) are genetically complex structural birth defects caused by genetic factors, environmental exposures, and their interactions. OFCs are the most common craniofacial anomalies in humans. Affect about 1 in 800 newborns, OFCs are also one of the most common structural birth defects worldwide. OFCs can impose a substantial personal cost resulting from the associated emotional and financial burden. On average a child undergoes 6 surgeries, spends 30 days in hospital, receives 5 years of orthodontic treatment, and participates in ongoing speech therapy, leading to an estimated total lifetime treatment cost of about $200,000. Individuals born with an OFC have higher infant mortality (especially in developing countries with limited access to care), higher mortality rates at all other stages of life, increased incidence of mental health problems, and higher risk for other disorders (notably including breast, brain, and colon cancers). Prior genetic studies have focused on the contribution of common genetic variants through genome-wide linkage and association studies. These studies have revealed a significant etiologic heterogeneity. One promising approach to dissect the etiology of OFCs into focus on subclinical phenotypic features present in the non-cleft family members of affected individuals. These subclinical features are subtle phenotypic features that may represent mild manifestations of the same risk genes; thus, their inclusion in family-based studies may clarify the inheritance patterns in OFC families. In this project, we conducted whole exome sequencing in multiplex families with both overt OFCs and subclinical phenotypes to identify high-impact genes causing OFCs.

Study phs001675

National Heart Lung and Blood Institute Exome sequencing in SCID

Analysis of the molecular etiologies of severe combined immunodeficiency (SCID) has led to important insights into the control of immune cell development. Most cases of SCID result from either X-linked or autosomal recessive inheritance of mutations in a known causative gene. However, in some cases, the molecular etiology remains unclear. To identify the cause of SCID in a patient known to lack the protein tyrosine phosphatase CD45, we utilized single nucleotide polymorphisms (SNP) arrays and whole exome sequencing. The patient's mother was heterozygous for an inactivating mutation in CD45, while the paternal alleles lacked mutations. The patient exhibited a single CD45 mutation identical to the maternal allele. Patient SNP array analysis revealed no change in copy number but loss of heterozygosity for the entire length of chromosome 1 (Chr1), indicating that disease was caused by uniparental disomy (UPD) with isodisomy of the entire maternal Chr1 bearing the CD45 mutation. Non-lymphoid blood cells and other mesoderm and ectoderm-derived tissues retained UPD of the entire maternal Chr1 in this patient who had undergone successful bone marrow transplantation. Exome sequencing revealed mutations in 7 additional genes bearing nonsynonymous SNPs predicted to have deleterious effects. These findings represent the first reported case of SCID caused by UPD and suggest UPD should be considered in SCID and other recessive disorders, especially when the patient appears homozygous for an abnormal gene found in only one parent. Evaluation for alterations in other genes affected by UPD should also be considered in such cases.

Study phs000479

Genetic Modifiers of Syndromic Orofacial Clefts

Reduced penetrance and variable expressivity are common, but poorly understood, features of most monogenic diseases. Genetic modifiers are possible factors to contribute to this phenotypic variability and blur the traditional distinction between monogenic and complex disease. This study focuses on the most common orofacial cleft syndrome (Van der Woude syndrome, VWS) and nonsyndromic orofacial clefts (OFCs), which intersect both in phenotype and in genetic etiology, as a model to understand reduced penetrance and variable expressivity. VWS occurs in 1 in 35,000 individuals and accounts for 2% of all OFCs. The features of VWS include an OFC and/or lower lip pits, but 15% of VWS patients present with an isolated OFC, making them indistinguishable from nonsyndromic OFC patients. Mutations in the genes IRF6 or GRHL3 cause VWS, but approximately 20% of VWS patients currently lack a molecular diagnosis. Furthermore, there are few genotype-phenotype correlations for known mutations and patient phenotypes. By contrast, GWAS of nonsyndromic OFCs have identified a number of risk factors, some of which we have shown increase risk for specific types of OFCs or act as modifiers of OFC subtypes. Whole genome sequencing will be used to identify the remaining genetic mutations for VWS, determine the relationship between those genes/regions with nonsyndromic OFCs, and identify rare and common modifiers of VWS and OFC phenotypes. These analyses will provide further insight into the genetic architecture of VWS and OFCs and will serve as a model for exploring links between other Mendelian disorders that share phenotypes with complex traits.

Study phs002221

Melbourne Collaborative Cohort Study DNA Methylation Studies

This dataset contains raw Illumina 450K blood DNA methylation data from a subset of participants in the Melbourne Cohort Study (MCCS), a prospective study of 41,513 healthy adult volunteers (24,469 women) aged between 27 and 76 years when recruited between 1990 and 1994. Nested case-control studies: DNA methylation data were generated as part of cancer case-control studies nested in the MCCS. Participants were cancer-free at blood draw; blood samples were taken at baseline (1990-1994) for 97% of participants; and for 3% of participants at the second wave of follow-up (2003-2007). Eight separate studies were conducted of breast, prostate, colorectal, lung, kidney, urothelial and gastric cancer and B-cell lymphoma, for a total of > 3,500 cancer cases. Controls were individually matched to cases on age, sex, and country of birth using incidence density sampling. Additional matching on smoking history was made for the study of lung cancer. Longitudinal study: For a subset of 1,100 participants with baseline DNA methylation measures (from dried blood spots) who were selected as controls in the nested case-control studies, repeated methylation measures were made using wave 2 follow-up samples (also from dried blood spots) to study longitudinal DNA methylation changes. Project aims: 1. Nested case-control studies: To assess prospective associations between peripheral blood DNA methylation and risk of eight cancer types (breast, prostate, colorectal, lung, kidney, urothelial cell and gastric cancer, and mature B-cell neoplasms). 2. Longitudinal study: To assess associations between lifestyle changes and changes in peripheral blood DNA methylation.

Study phs003213

ILyAD (Indolent Lymphoma And vitamin D)

Indolent non-Hodgkin lymphomas are incurable diseases, and require intermittent and often morbid and expensive therapy during their prolonged natural history. Lower intensity and better-tolerated, cost-effective treatment strategies are needed for these patients. Low vitamin D levels at diagnosis of indolent lymphomas are strongly associated with inferior outcomes to treatment. Standard therapy for low tumor burden, indolent lymphoma includes a single agent monoclonal antibody (rituximab). In our double-blind, placebo-controlled, randomized trial we evaluated if vitamin D supplementation with 2000IU oral cholecalciferol daily for three years improved the progression-free survival of patients with indolent lymphoma treated with single agent rituximab. Stratification factors for randomization included histology and Follicular Lymphoma International Prognostic Index (FL-IPI) prognostic score. The primary endpoint of the trial was progression-free survival over three years; secondary endpoints included response at 13 weeks, and overall survival. Eligible participants were adults with biopsy proven follicular lymphoma (grades 1-3a), small lymphocytic lymphoma, marginal zone lymphoma and mucosal-associated lymphoid tissue with no prior anti-lymphoma systemic therapy. Participants had Ann Arbor stage II or greater, measurable disease defined by Lugano criteria. Participants with osteoporosis requiring prescription treatment, symptomatic primary hyperthyroidism, hypercalcemia, creatinine greater than 1.5 times the upper limit of normal or a history of calcium-related kidney stones were excluded. Germline DNA was isolated from saliva samples obtained from participants at baseline. Whole exome sequencing was performed and SNPs were analyzed using the Agilent SureSelectXT Human All Exon V6 +UTR array. SNP data from 185 participants are available through dbGaP.

Study phs003503

Center for Common Disease Genomics [CCDG] - Neuropsychiatric: Autism - Simons Simplex Collection (SSC)

In this study, we address the enormous challenges common complex diseases pose for genomic analysis and the enormous opportunities surmounting them offers for advancing healthcare. The common genetic disorders proposed for study here are believed to have extreme locus heterogeneity, requiring the analysis of large numbers of samples to comprehensively identify the genomic variants underlying them. We propose that a combination of deep population studies and joint analysis of SNPs, indels, and structural variants both in coding and noncoding regions will provide the next level of understanding of common genetic disorders. Whole genome sequencing (WGS) will be critical to this next-generation approach to the genomics of complex disease. WGS will need to be accompanied by the technical ability to generate and handle very large data sets, a particular focus and strength of New York Genome Center (NYGC). WGS will also need to be accompanied by new statistical tools and algorithms, which will be developed by the strong core group committed to this proposal. An overarching goal of this proposal, one that capitalizes on the power of WGS, is to identify disease-associated variants at the individual nucleotide level. In many cases pathogenic mutations fall in noncoding regions of the genome, which can only be fruitfully explored with WGS. A major effort was put into building new computational strategies to functionally annotate noncoding transcribed sequences, and to build new datasets to enable such strategies, opening new frontiers of understanding of disease-related regulatory variants.

Study phs001676

A Single Cell Transcriptomic Analysis of Human Neocortical Development

Defining the number, proportion, or lineage of distinct cell types in the developing human brain is an important goal of modern brain research. We produced single cell transcriptomic profiles for 40,000 cells at mid-gestation to define deep expression profiles corresponding to all known major cell types at this developmental period and compare this with bulk tissue profiles. We identified multiple transcription factors (TFs) and co-factors expressed in specific cell types, including multiple new cell-type-specific relationships, providing an unprecedented resource for understanding human neocortical development and evolution. This includes the first single-cell characterization of human subplate neurons and subtypes of developing glutamatergic and GABAergic neurons. We also used these data to deconvolute single cell regulatory networks that connect regulatory elements and transcriptional drivers to single cell gene expression programs in the developing CNS. We characterized major developmental trajectories that tie cell cycle progression with early cell fate decisions during early neurogenesis. Remarkably, we found that differentiation occurs on a transcriptomic continuum, so that differentiating cells not only express the few key TFs that drive cell fates, but express broad, mixed cell-type transcriptomes prior to telophase. Finally, we mapped neuropsychiatric disease genes to specific cell types, implicating dysregulation of specific cell types in ASD, ID, and epilepsy, as the mechanistic underpinnings of several neurodevelopmental disorders. Together these results provide an extensive catalog of cell types in human neocortex and extend our understanding of early cortical development, human brain evolution and the cellular basis of neuropsychiatric disease.

Study phs001836

International Verapamil SR/Trandolapril [INVEST] Genes Study

INternational VErapamil SR-Trandolapril STudy (INVEST) was a prospective, multicenter, randomized, open-label, parallel-clinical trial that evaluated blood pressure response and adverse outcomes in patients randomized to either an atenolol-based or a verapamil SR-based hypertension treatment strategy in 22,576 patients with documented coronary artery disease and hypertension (PMID: 9809930,14657064). Hydrochlorothiazide and trandolapril were added as needed to achieve BP control or end organ protection in a protocol-defined manner. Briefly, the protocol required patients to be followed up at bassline, 6, 12, 18 and 24 weeks and then every 6 months thereafter until 2 years after the last patient was enrolled. At each visit, patients had BP and heart rate measured, clinical assessment performed, and additional antihypertensive medications added as needed to meet JNC VI blood pressure goals. The primary outcome was the first occurrence of all-cause death, nonfatal myocardial infarction (MI), or nonfatal stroke (clinicaltrials.gov identifier: NCT00133692). The genetic substudy of INVEST, INVEST-GENES, collected genomic DNA samples from 5,979 INVEST study participants. INVEST-GENES samples were genotyped on the Illumina OmniExpressExome GWAS chip. This data release includes 1529 samples that passed quality control including 657 whites, 537 Hispanics and 155 blacks. Two case-control subsets were created: one for the primary outcome of all-cause death, nonfatal MI or nonfatal stroke; the other one is for new-onset diabetes. Resistant hypertension was also evaluated in 1349 participants based on the medication use and blood pressure measurements at the visit prior to experiencing study outcomes or censoring (PMID:30237584).

Study phs002319

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

Common Variation in Candidate Genes in the Diabetes Prevention Program

The Diabetes Prevention Program (DPP) was a multicenter controlled clinical trial examining the efficacy of an intensive lifestyle intervention or metformin to prevent or delay the development of diabetes in a population selected to be at high risk due to the presence of impaired glucose tolerance (IGT) and obesity. Development of diabetes, defined by 1997 American Diabetes Association (ADA) criteria, was the primary outcome while cardiovascular disease and its risk factors were important secondary outcomes. The pharmacological intervention was double blinded and placebo controlled. After randomization, participants had quarterly clinical evaluations and had, in addition, a fasting plasma glucose at semi-annual visits and a 75 gram oral glucose tolerance test at annual visits. Volunteers were recruited from populations known to be at particularly high risk for impaired glucose tolerance and type 2 diabetes including the following: persons with a family history of NIDDM, the elderly, overweight individuals, women with a history of diabetes during pregnancy ("gestational diabetes"), and minority populations including African Americans, Hispanic Americans, Asian and Pacific Island Americans, and Native Americans. The primary focus of the genetic investigations have been on candidate genes, including candidates derived from GWAS of diabetes, lipid and glycemia-related phenotypes. Please note more phenotype data for the DPPG cohort is available through the NIDDK Data Repository. Information on obtaining this phenotype data can be found by going to https://www.niddkrepository.org/studies/dppos/?query=DPP and https://www.niddkrepository.org/studies/dpp/?query=DPP. Data will need to be requested from both data sets. A linking file will be available to the NIDDK Data Repository.

Study phs000681

Liquid Biopsy Versus Tissue Biopsy to Assess Acquired Resistance and Tumor Heterogeneity in Gastrointestinal Cancers

Tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique molecular resistance alterations in different metastatic lesions in an individual patient, under the selective pressure of therapy1-3. Studies have suggested that liquid biopsy may better capture the heterogeneity of acquired resistance, but systematic, direct comparisons of post-progression liquid vs. standard single-lesion tumor biopsies are lacking. In a prospective cohort of 44 patients with molecularly-defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of post-progression liquid vs. tumor biopsy revealed that liquid biopsy more frequently identified clinically-relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not detected in matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cell-free DNA, tumor biopsies and rapid autopsy specimens elucidated geographic and evolutionary characteristics of heterogeneity. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity and highlight the potential clinical utility of liquid biopsy. Burrell, R. A. & Swanton, C. Tumour heterogeneity and the evolution of polyclonal drug resistance. Molecular oncology 8, 1095-1111, doi:10.1016/j.molonc.2014.06.005 (2014). Misale, S. et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486, 532-536, doi:10.1038/nature11156 (2012). Ahronian, L. G. et al. Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations. Cancer Disco 5, 358-367, doi:10.1158/2159-8290.Cd-14-1518 (2015).

Study phs001853

Center for Common Disease Genomics [CCDG] - Neuropsychiatric: SPARK Simons Foundation Powering Autism Research for Knowledge

In this study, we address the enormous challenges common complex diseases pose for genomic analysis and the enormous opportunities surmounting them offers for advancing healthcare. The common genetic disorders proposed for study here are believed to have extreme locus heterogeneity, requiring the analysis of large numbers of samples to comprehensively identify the genomic variants underlying them. We propose that a combination of deep population studies and joint analysis of SNPs, indels, and structural variants, both in coding and noncoding regions, will provide the next level of understanding of common genetic disorders. Whole genome sequencing (WGS) will be critical to this next-generation approach to the genomics of complex disease. WGS will need to be accompanied by the technical ability to generate and handle very large data sets, a particular focus and strength of New York Genome Center (NYGC). WGS will also need to be accompanied by new statistical tools and algorithms, which will be developed by the strong core group committed to this proposal.An overarching goal of this proposal, one that capitalizes on the power of WGS, is to identify disease-associated variants at the individual nucleotide level. In many cases, pathogenic mutations fall in noncoding regions of the genome, which can only be fruitfully explored with WGS. A major effort was put into building new computational strategies to functionally annotate noncoding transcribed sequences, and to build new datasets to enable such strategies, opening new frontiers of understanding of disease-related regulatory variants.

Study phs002511

National Institute of Neurological Disorders and Stroke (NINDS) Parkinson's Disease

This study utilized the well characterized collection of North American Caucasians with Parkinson's disease, and neurologically normal controls from the sample population which are banked in the National Institute of Neurological Disorders and Stroke (NINDS Repository) collection. Two sub-studies are included, in sub-study NINDS-Genome-Wide Genotyping in Parkinson's Disease, genome-wide, single nucleotide polymorphism (SNP) genotyping of these publicly available samples was originally done in 267 Parkinson's disease patients and 270 controls, and this has been extended to include genome wide genotyping in 939 Parkinson's disease cases and 802 controls; in sub-study NINDS-Exome Sequencing in Parkinson's Disease, genome wide exome DNA sequencing was done in 618 Parkinson's disease samples deposited in Coriell NINDS repository. The DNA comes from a mixture of blood, and from cell lines (lymphoblast cell lines) derived from blood. The GWAS data and exome sequencing data was generated and provided by the laboratory of Neurogenetics lead by Dr. Andrew Singleton, NIA, and Dr. John Hardy, a former chief at NIA, NIH. The NINDS Parkinson's Disease Cohort study is utilized in the following dbGaP individual studies. To view genotypes, whole exome sequencing, 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 phs001172 NINDS Parkinson's Disease Cohort study. phs000089 PD GWAS phs001103 PD Exome

Study phs001172

Genetics of Prostate Cancer in Africa

African Americans (AA) suffer from the highest rates of Prostate Cancer (CaP) in the world, but while men of African descent around the world suffer disproportionately from CaP compared to men of other races or ethnicities, our understanding of the reasons for these disparities remains incomplete. To date, few exposure, lifestyle, or environmental influences have been identified in CaP etiology. In contrast, CaP is among the most heritable of common cancers, and over 290 susceptibility loci have been identified. However, many of these loci have not been replicated in AA, in part because of limited African descent sample sizes, incomplete capture of African alleles, and a limited understanding of African genomic architecture. To better understand the etiology of CaP in African descent men, we established a large, multicenter consortium known as “Men of African Descent and Carcinoma of the Prostate” (MADCaP). Using resources of this consortium, we have undertaken a multicenter study of CaP in Sub-Saharan Africa, enrolling CaP cases from 7 institutions in 4 countries in Africa (Nigeria, Senegal, Ghana, and South Africa) and age matched controls from the same institutions. We designed a novel genotyping array, in partnership with Thermo Fisher Scientific, leveraging its Applied BiosystemTM AxiomTM Genotyping solution, to provide good coverage of African genomic variation, as well as incorporating cancer loci, with the goal of being able to fine-map existing prostate cancer loci, as well as mapping novel loci. The data available encompasses genotyping our Africa cohort on this array.

Study phs002718

Center for Common Disease Genomics [CCDG] - Neuropsychiatric: Victorian Collaborative AuTism Study (CATS): Family and Community Study of the Genetics of Autism Spectrum Disorder

In this study, we address the enormous challenges common complex diseases pose for genomic analysis and the enormous opportunities surmounting them offers for advancing healthcare. The common genetic disorders proposed for study here are believed to have extreme locus heterogeneity, requiring the analysis of large numbers of samples to comprehensively identify the genomic variants underlying them. We propose that a combination of deep population studies and joint analysis of SNPs, indels, and structural variants both in coding and noncoding regions will provide the next level of understanding of common genetic disorders. Whole genome sequencing (WGS) will be critical to this next-generation approach to the genomics of complex disease. WGS will need to be accompanied by the technical ability to generate and handle very large data sets, a particular focus and strength of NYGC. WGS will also need to be accompanied by new statistical tools and algorithms, which will be developed by the strong core group committed to this proposal. An overarching goal of this proposal, one that capitalizes on the power of WGS, is to identify disease-associated variants at the individual nucleotide level. In many cases pathogenic mutations fall in noncoding regions of the genome, which can only be fruitfully explored with WGS. A major effort was put into building new computational strategies to functionally annotate noncoding transcribed sequences, and to build new datasets to enable such strategies, opening new frontiers of understanding of disease-related regulatory variants.

Study phs002044

Genomic profiling for metastatic uveal melanoma from a phase I study of the protein kinase C inhibitor AEB071

Up to 50% of patients with uveal melanoma (UM) develop metastatic disease, for which there is no effective systemic treatment. This study aimed to evaluate the safety and efficacy of the orally available protein kinase C inhibitor, AEB071, in patients with metastatic UM, and to perform genomic profiling of metastatic tumor samples, with the aim to propose combination therapies. Metastatic UM patients (n=153) were treated with AEB071 in a Phase I, single-arm study. Patients received total daily doses of AEB071 ranging from 450 to 1400 mg. First-cycle dose-limiting toxicities (DLTs) were observed in 13 patients (13%). These were most commonly gastrointestinal system toxicities and were dose related, occurring at doses > 700 mg/day. Preliminary clinical activity was observed, with 3% of patients achieving a partial response and 50% with stable disease (median duration 15 weeks). High-depth, targeted next-generation DNA sequencing (NGS) was performed on 89 metastatic tumor biopsy samples. Mutations previously identified in UM were observed, including mutations in GNAQ, GNA11, BAP1, SF3B1, PLCB4, and amplification of chromosome arm 8q. GNAQ/GNA11 mutations were observed at a similar frequency (93%) as previously reported, confirming a therapeutic window for inhibition of the downstream effector PKC in metastatic UM. In conclusion, the protein kinase C inhibitor AEB071 was well tolerated and modest clinical activity was observed in metastatic UM. The genomic findings were consistent with previous reports in primary UM. Together, our data allow envisaging combination therapies of PKC inhibitors with other compounds in metastatic UM.

Study phs001953

Basal-to-Inflammatory Transition Contributes to Basal Cell Carcinoma Therapy Resistance via Crosstalk with a Pro-Inflammatory Stromal Niche

Overcoming tumor evolution and inducible resistance states remain the main challenge to creating successful anti-tumor therapies. The body's cancer-associated inflammatory response is a double-edged sword having ill-defined pro- and anti-tumor properties. Our group previously identified a basal cell carcinoma (BCC) tumor-intrinsic resistance pathway called basal to squamous cell carcinoma transition (BST). However, tumor resistance driven through the complex dynamics of tumor interactions with the inflammatory response remains poorly studied. Here, employing a multipronged approach combining human tumor single-cell transcriptomics, single-cell chromatin accessibility (scATAC-Seq) study, CODEX multiplexed imaging, spatial transcriptomic along with functional validation, we have identified a surprising inflammation-associated SMOi therapy enriched tumor epithelial cell state we term basal-to-inflammatory transition (BIT). Marked by CHI3L1, TAGLN, ITGAV, and VCAM1, BIT arises in spatially distinct neighborhoods from BST in a subset of naive BCCs. While BST tumor epithelium occurs within the central cores of tumor nodules, BIT tumor epithelium arises in a specialized inflammatory environment defined by a tumor associated TREM1 myeloid signature. IL1 and OSM secreted by TREM1 myeloid cells activate the inflammatory NF-kB family of transcription factors within the BIT tumor epithelium. Strikingly, IL1 and OSM ligands are sufficient not only in inducing the BIT tumor state in vitro and in vivo in a synergistic fashion but also in lowering the sensitivity of human BCC explant tumors to SMOi treatment. This work provides critical insights into the BIT-resistant state as a novel targetable tumor state driven by a specialized inflammatory microenvironment.

Study phs003437

Tumor Evolution Analysis Uncovered Immune-Escape Related Mutations in Relapsed Diffuse Large B-Cell Lymphoma

More than 60% of patients with primary diffuse large B-cell lymphoma (DLBCL) achieve durable remissions upon the chemoimmunotherapy with R-CHOP. However, the outcome of the relapse patients is extremely poor. To characterize the molecular features that underlie treatment resistance, we performed whole-exome sequencing (n=44) and deep targeted sequencing (n=27) of 44 diagnosis-relapse DLBCL pairs. We found that the overall landscape of genetic alterations was concordant between diagnosis and relapse DLBCL. By a deep comparison of the longitudinal sequencings, we identified relapse-enriched mutations that involved in evasion of immune surveillance (CD58, TNFRSF14, PKD1, FAS), resistance to DNA damaging agents (ATM, TP53), and critical tumor suppressor gene (ZFHX3). Knockdown of ATM and ZFHX3 resulted in increased drug resistance in both germinal center B cell like (GCB) and activated B cell like (ABC) DLBCL cell lines in vitro, while the knockdown of TNFRSF14 and FAS conferred resistance specifically in GCB cell lines. Furthermore, we summarized two evolutionary patterns of DLBCL relapse as the “durable retention” model with stable clone structure, and the “selective sweep” model which exhibited significant clonal switch. Of note, genetic alterations leading to attenuated immune responses usually presented as trunk mutations in the “durable retention” model (7/12) while were newly acquired or expanded upon relapse in the “selective sweep” model (9/16). Overall, our study demonstrated that relapse DLBCL derives from distinct clonal evolutionary patterns, and highlighted immune escape as an important contributor of tumor relapse.

Study EGAS50000000032

PCPT and SELECT Cohorts: Core Infrastructure Support for Cancer Research

SELECT study: SELECT was a phase III, double-blind, placebo-controlled 4-arm study of selenium, vitamin E, selenium and vitamin E together, and placebo designed to assess the effect of these supplements on the incidence of prostate cancer. Funded by the National Cancer Institute and conducted by SWOG, the study opened in August 2001 and quickly exceeded its accrual goal of 35,533 men.In the fall of 2008, the trial's Data Safety and Monitoring Committee recommended that participants discontinue taking study supplements due to convincing evidence (planned interim futility analysis) that neither vitamin E nor selenium supplements were associated with the prevention of prostate cancer. A subsequent analysis in 2011 showed a significant 17% increase in prostate cancer incidence in participants who were on the vitamin E only arm. Approximately 17,000 participants from the original trial recently completed an additional four years of centralized follow-up. This follow-up ended on May 31, 2014 and SELECT is now closed. PCPT study: The Prostate Cancer Prevention Trial (PCPT) was a SWOG Cancer Research Network-coordinated study designed to test whether the drug finasteride (Proscar®) would prevent prostate cancer in men ages 55 and older. This study was closed on June 24, 2003 because the study objective had been reached. The results of the study, which did find a preventive benefit for the drug, were published as "The Influence of Finasteride on the Development of Prostate Cancer," in the New England Journal of Medicine on July 17, 2003.

Study phs003382

Mayo Clinic - Fecal Microbiota and Adenomas

Background: Adenomatous polyps are the most common precursor to colorectal cancer (CRC), the second leading cause of cancer death in the United States. We sought to learn more about early events of carcinogenesis by investigating shifts in the gut microbiota of patients with adenomas. Methods: We analyzed 16S rRNA gene sequences from the fecal microbiota of patients with adenomas (n=233) and without (n=547). Results: Multiple taxa were significantly more abundant in patients with adenomas, including Bilophila, Desulfovibrio, pro-inflammatory bacteria in the genus Mogibacterium, and multiple Bacteroidetes species. Patients without adenomas had greater abundances of Veillonella, Firmicutes (Order Clostridia), and Actinobacteria (family Bifidobacteriales). Many of our findings were consistent with previously reported shifts in the gut microbiota of CRC patients. Importantly, the altered adenoma profile is predicted to increase primary and secondary bile acid production, as well as starch, sucrose, lipid, and phenylpropanoid metabolism. Conclusions: These data suggest that diets rich in refined sugar, protein, and lipids may lead to increased bile acid production, creating a colonic environment that promotes the growth of bile-tolerant microbes such as Bilophilia and Desulfovibrio. In turn, these microbes may produce genotoxic or inflammatory metabolites such as H2S and secondary bile acids, catalyzing adenoma development and eventually CRC. Impact: This study suggests a plausible biological mechanism to explain the links between diet, shifts in the microbiota, and CRC. This represents a first step toward resolving the complex interactions that shape the adenoma-carcinoma sequence of CRC and may facilitate personalized therapeutics focused on the microbiota.

Study phs001204

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