Search Results - EGA European Genome-Phenome Archive

Whole genome sequencing of 98 tumour-normal pairs for the pancreatic neuroendocrine cancer project

Whole genome sequencing of 98 tumour-normal pairs for the PAEN-AU pancreatic neuroendocrine cancer project.

Dataset EGAD00001002684

Hospital for Sick Children Infant Glioma RNA Sequencing

Whole transcriptome (n=4) and targetted RNA sequencing (n=15) .bam files of infantile glioma samples reported on at the Hospital for Sick Children

Dataset EGAD00001005092

Whole genome sequencing of AML samples at presentation, remission, and relapse

Whole genome sequencing of AML blood or bone marrow at presentation and remission for 5 patients. Relapse samples are included for 2 patients, totaling 12 WGS BAM files.

Dataset EGAD00001005120

T-WGBS for Naive B Cell

Tagged-WGBS for 3 Naive B Cell samples of the CancerEpiSys-PRECiSe project.

Dataset EGAD00001005966

A molecular signature for IL-10-producing Th1 cells in protozoan parasitic diseases

Dataset EGAD00001007532

ATAC data for Glioblastoma (EGAS00001003953, H016)

ATAC-seq data for 2 glioblastoma cell lines (LN229, ZH487), NT and SOX10KD.

Dataset EGAD00001006544

Trio Sequencing results for the AnkyrinG MIPS screening study

Approximately 1000 trio's with varying degrees of cognitive disorders. All samples have been sequenced for the AnkyrinG interactome using MIPS technology. Data is presented as BAM and unfiltered VCF files.

Dataset EGAD00001006823

RNAseq for Patients of NIBIT-M4 clinical trial

Dataset EGAD00001009702

Human Origins array data for 1510 individuals

Genotype data typed on the Human Origins array for 1510 individuals published in "Dense sampling of ethnic groups within African countries reveals fine-scale genetic structure and extensive historical admixture."

Dataset EGAD00001010015

Dataset for transcriptomic sequencing of Merkel cell carcinoma(MCC) samples

This dataset contains transcriptome sequencing for 5 samples of MCC tumors . The sequencing was performed on Illumina NextSeq 6000 . The sequencing was always paired.

Dataset EGAD00001015702

International Consortium on the Genetics of Systemic Lupus Erythematosus (SLEGEN)

The genetic makeup of an individual strongly influences the risk of developing systemic lupus erythematosus (SLE). The identification of genes that predispose an individual to SLE will lead to earlier and better diagnosis, better treatments, and possibly prevention. To this end, the International Consortium on the Genetics of Systemic Lupus Erythematosus (SLEGEN) was formed in 2005 and is composed of lupus researchers who agreed to pool their knowledge and resources to search for genes that predispose to lupus. Eight laboratories contributed DNA samples for genotyping at the Broad Institute and association with SLE was performed by the Data Coordinating Center (Wake Forest University), as part of a four stage study design. Stages one and two of this design were graciously funded by the Alliance for Lupus Research (www.lupusresearch.org). In this stage of the study, approximately 767 SLE patients (cases) were compared to approximately 383 non-SLE patients (controls) for differences among the Illumina HumanHap300. The affected individuals are all females of European decent. 82% of the cases are the index case from multiplex pedigrees for SLE and the remaining 18% have self-reported first degree relatives with SLE. A detailed summary of the methods and results can be found in the manuscript in Nature Genetics February 2008 by SLEGEN "Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants ITGAM, PXK, KIAA1542 and other loci". (Please see also Study Accession: phs000202.v1.p1)

Study phs000216

Biomarkers in Transplant Recipients

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

Study phs000960

A Phase I/II Study of Revlimid (lenalidomide) in Combination with Vidaza (azacitidine) in Patients with Advanced Myelodysplastic Syndrome (MDS)

This single-arm study design has been selected to investigate the safety of combination therapy with Vidaza® (azacitidine) and Revlimid® (lenalidomide) in a population of 18 participants with advanced MDS for the Phase I portion, and 18 participants for the Phase II portion. The multi-center nature of the study should enhance the general applicability of the results. Participants with advanced MDS were chosen because it is expected that the combination of the two drugs will by myelosuppressive, which can be considered a necessary toxicity to effect improvements in PR and CR rates in this advanced population, akin to participants with AML. Finally, the combination was chosen to be studied because currently available therapies in this population, and their effectiveness, are limited, and single-agent Vidaza® (azacitidine), while effective at delaying transformation to AML or death, is not curative. The doses of Revlimid® (lenalidomide) in this study are similar to those that were demonstrated to have an effect and to be well-tolerated in participants with MDS. Doses for Vidaza® (azacitidine) are similar to those used in the pivotal trial, though for a 5-day treatment period instead of 7 to minimize toxicity for the first 3 blocks of participants, and then at a lower dose over a protracted period of time to explore the safety of a 10-day treatment course.

Study phs001318

Genomic Architecture of Progression and Treatment Response in AMD

Numerous studies have identified common and rare genetic variation associated with risk of advanced age-related macular degeneration (AMD). However, risk is just one facet of AMD disease architecture. Both disease progression and response to treatment are two critical elements that may also be influenced by genetic variation. The primary aim of this study was to identify genetic variation influencing progression and response to treatment for AMD, with a secondary aim of further elucidating the genetic etiology of AMD risk. We ascertained AMD cases and controls of European ancestry from Vanderbilt Eye Institute (VEI) and the Bascom Palmer Eye Institute (BPEI) and obtained blood samples from all participants. Eyes were examined using standard ophthalmological methods, and graded according the modified Age-Related Eye Disease Study scale (AREDS grades 1-5) using fundus photography. Individuals were re-examined in follow-up exams at regular intervals to assess any change in AMD grade. Eyes with advanced neovascular AMD that were examined using ocular coherence tomography imaging (OCT), treated with anti-angiogenesis therapy and monitored for response to treatment. All individuals ascertained for the study were exome-chipped for genome-wide single nucleotide variation coverage. To target rare genetic variation, whole exome sequencing was performed on individuals at the phenotypic extremes based on 1) AMD grade, 2) rate of progression from intermediate to advanced AMD and 3) response to anti-VEGF treatment for eyes with advanced neovascular AMD.

Study phs001046

University of Texas PDX Development and Trial Center Grant

The goal for the University Texas PDX Development and Trial Center (UTPDTC) is to optimize personalized biomarker-based cancer therapy and identify effective targeted drugs based on the molecular characteristics of each tumor. Our short-term goals are to establish a biobank of clinically, and molecularly-annotated Patient-Derived Xenografts (PDXs) and to use PDXs as a platform for preclinical drug development and biomarker discovery. The primary goal for UTPDTC investigators will be to develop PDX trial strategies for preclinical testing of single agents and drug combinations. These models will allow the determination of the optimal treatments (single drugs or combinations) that should be tested in clinical trials in increasingly individualized, molecularly defined subsets of tumors. The goal of the Patient-Derived Xenograft Core is to provide high-quality clinically relevant and molecularly annotated PDX models for the research projects proposed in the University of Texas PDX Development and Trial Center (UTPDTC) grant application and to the research activity of the NCI PDX Development and Trial Centers Research Network (PDXNet) by leveraging PDX resources at our institutions and developing new PDX models from human cancer specimens using rigorous quality standards so that the models can be used to guide clinical trial development. The PDX models developed and/or characterized by the PDX Core will be available to other cancer researchers through the PDXNet and NCI Patient-Derived Models Repository (PDMR).

Study phs001980

Genome-wide analysis of genetic risk factors for rheumatic heart disease in Aboriginal Australians provides support for pathogenic molecular mimicry

Background. Rheumatic heart disease (RHD) following Group A Streptococcus (GAS) infections is heritable and prevalent in Indigenous populations. Molecular mimicry between human and GAS proteins triggers pro-inflammatory cardiac valve-reactive T-cells. Methods. Genome-wide genetic analysis was undertaken in 1263 Aboriginal Australians (398 RHD cases; 865 controls). Single nucleotide polymorphisms (SNPs) were genotyped using Illumina HumanCoreExome BeadChips. Direct typing and imputation was used to fine-map the human leukocyte antigen (HLA) region. Epitope binding affinities were mapped for human cross-reactive GAS proteins, including M5 and M6. Results. The strongest genetic association was intronic to HLA-DQA1 (rs9272622; P=1.86x10-7). Conditional analyses showed rs9272622 and/or DQA1*AA16 account for the HLA signal. HLA-DQA1*0101_DQB1*0503 (OR 1.44, 95%CI 1.09-1.90, P=9.56x10-3) and HLA-DQA1*0103_DQB1*0601 (OR 1.27, 95%CI 1.07-1.52, P=7.15x10-3) were risk haplotypes; HLA_DQA1*0301-DQB1*0402 (OR 0.30, 95%CI 0.14-0.65, P=2.36x10-3) was protective. Human myosin cross-reactive N-terminal and B repeat epitopes of GAS M5/M6 bind with higher affinity to DQA1/DQB1 alpha/beta dimers for the two risk haplotypes than the protective haplotype. Conclusions. Variation at HLA_DQA1-DQB1 is the major genetic risk factor for RHD in Aboriginal Australians studied here. Cross-reactive epitopes bind with higher affinity to alpha/beta dimers formed by risk haplotypes, supporting molecular mimicry as the key mechanism of RHD pathogenesis.

Study EGAS00001002678

Evolution of the African pygmy phenotype

The evolutionary history of the human ‘pygmy’ phenotype (small body size), a characteristic of African and Southeast Asian rainforest hunter-gatherers, is largely unknown. Here we use a genome-wide admixture mapping analysis to identify 16 genomic regions that are significantly associated with the pygmy phenotype in the Batwa, a rainforest hunter-gatherer population from Uganda (East Central Africa). The identified genomic regions have multiple attributes that provide supporting evidence of genuine association with the pygmy phenotype, including enrichments for SNPs previously associated with stature variation in Europeans and for genes with growth hormone receptor and regulation functions. To test adaptive evolutionary hypotheses we computed the haplotype-based iHS statistic and the level of population differentiation (FST) between the Batwa and their agricultural neighbors, the Bakiga, for each SNP. Both |iHS| and FST values were significantly higher for SNPs within the Batwa pygmy phenotype-associated regions than the remainder of the genome, a signature of polygenic adaptation. In contrast, when we expanded our analysis to include Baka rainforest hunter-gatherers from Cameroon and Gabon (West Central Africa) and Nzebi and Nzime neighboring agriculturalists, we did not observe elevated |iHS| or FST values in these genomic regions. Together, these results suggest adaptive and at least partially convergent origins of the pygmy phenotype even within Africa, supporting the hypothesis that small body size confers a selective advantage for tropical rainforest hunter-gatherers but raising questions about the antiquity of this behavior.

Study EGAS00001000908

Cistrome-partitioning reveals convergence of somatic mutations and risk-variants on master transcription regulators in primary prostate tumors

Thousands of noncoding somatic Single Nucleotide Variants (SNVs) of unknown function are reported in tumors. Partitioning the genome according to cistromes, reveals the enrichment of somatic SNVs in prostate tumors as opposed to adjacent normal tissue cistromes of master transcription regulators, including AR, FOXA1 and HOXB13. This parallels enrichment of prostate cancer genetic predispositions over these transcription regulators’ tumor cistromes, exemplified at the 8q24 locus harboring both risk-variants and somatic SNVs in cis-regulatory elements, upregulating MYC expression and altering the binding of transcription regulators to DNA. However, Massively-Parallel Reporter Assays reveal that few SNVs can alter the transactivation potential of individual CREs. Instead, SNVs accumulate, similarly to inherited riskvariants, in cistromes of master transcription regulators required for prostate cancer development. Difficulties in inferring the biological significance of noncoding mutations have limited their inclusion in precision genomics medicine pipelines. Most attempts to delineate a role for noncoding mutations relied on detecting evidence for positive selection within individual CREs, such as reported for the TERT gene promoter. By considering the enrichment of noncoding mutations in cistromes as opposed to individual CREs, we reveal their specificity towards master transcription regulators that promote prostate cancer development, a feature shared with inherited risk-variants. Overall, our work provides a blueprint for the functional interpretation of noncoding mutations in genomic tests relying on defining cis-regulatory units according to cistrome-partitioning to identify cancer driver transcription regulators.

Study EGAS00001003928

UK10K_RARE_HYPERCHOL

In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches.Familial Hypercholesterolemia is a condition where the affected person has a consistently high level of LDL which can lead to early clogging of the coronary arteries. All patients selected for this study will have been found not to carry the common APOB and PCSK9 mutations, and to have no detectable LDLR mutations by testing for 18 common mutations. For further information with regard to this cohort please contact Steve Humphries(steve.humphries@ucl.ac.uk).

Study EGAS00001000129

The Medical Genome Reference Bank: a whole genome data resource of 4,000 healthy elderly individuals.

Allele frequency data from human reference populations is of increasing value for filtering and assignment of pathogenicity to genetic variants. Aged and healthy populations are more likely to be selectively depleted of pathogenic alleles, and therefore particularly suitable as a reference populations for the major diseases of clinical and public health importance. However, reference studies of the healthy elderly have remained under represented in human genetics. We have developed the Medical Genome Reference Bank (MGRB), a large scale comprehensive whole genome dataset of confirmed healthy elderly individuals, to provide a publicly accessible resource for health related research, and for clinical genetics. It also represents a useful resource for studying the genetics of healthy aging. The MGRB comprises 4,000 healthy, older individuals with no reported history of cancer, cardiovascular disease or dementia, recruited from two Australian community based cohorts. DNA derived from blood samples will be subject to whole genome sequencing. The MGRB will measure genome wide genetic variation in 4,000 individuals, mostly of European decent, aged 60 to 95 years (mean age 75 years). The MGRB has committed to a policy of data sharing, employing a hierarchical data management system to maintain participant privacy and confidentiality, whilst maximizing research and clinical usage of the database. The MGRB will represent a dataset of international significance, broadly accessible to the clinical and genetic research community.

Study EGAS00001003511

Non-muscle Invasive Bladder Cancer Molecular Subtypes Predict Differential Response to Intravesical Bacillus Calmette-Guérin

The recommended treatment for patients with high-risk non-muscle invasive bladder cancer (HR-NMIBC) is tumor resection followed by adjuvant Bacillus Calmette-Guérin (BCG) bladder instillations. However, only 50% of patients benefit from this therapy. In case of progression to advanced disease, patients must undergo a radical cystectomy with significant morbidity and have a poor clinical outcome. Identifying tumors least likely to respond to BCG can translate into alternative treatments, such as early radical cystectomy or novel targeted or immunotherapies. Here we present molecular profiling of 132 BCG-naive, HR-NMIBC patients, and 44 post-BCG recurrences (34 matched), which uncovered three distinct BCG Response Subtypes (BRS1-3). Patients with BRS3 tumors have reduced recurrence and progression-free survival compared to BRS1-2. BRS3 tumors expressed high EMT-basal markers and had an immunosuppresive profile, which was confirmed with spatial proteomics. Tumors which recurred post-BCG were enriched for BRS3. BRS stratification was validated in a second cohort of 151 BCG-naive HR-NMIBC patients and the molecular subtypes outperformed guideline recommended risk stratification based on clinicopathological variables. For clinical application, we validated that a commercially approved assay was able to accurately predict BRS3 tumors (AUROC 0.86). Our findings provide a potential clinical tool for improved identification of HR-NMIBC patients at the highest risk of progression, which can be used to select patients for early radical cystectomy or novel subtype-directed therapies.

Study EGAS00001006879

H3Africa - Stroke Investigative Research and Education Networks

Although stroke is a discrete phenotype, it is the clinical culmination of several complex and interacting biological processes, precipitated by various genetic and environmental factors, thereby making ready analyses of its underlying mechanisms a challenge. However, the formulation of successful tailor-made prevention strategies for limiting the immense personal and societal burden of stroke in Sub-Saharan Africa (SSA) is contingent on a better understanding of the predisposing risk factors for stroke in the region, which may not necessarily match the nature of stroke risk factors described among other people on other continents. Indeed, the underlying risk factors for stroke in SSA have hitherto not been comprehensively characterized, and currently there is a paucity of expertise, experience, and infrastructure in genomics and environmental research in SSA, to initiate and sustain such investigation. We seek to establish the Stroke Investigative Research and Education Network (SIREN) as a multidisciplinary collaborative research network of investigators in SSA and the United States collectively focused on exploring ways to promote a better understanding of the genetic and environmental risk factors for stroke among people of African ancestry. SIREN will evaluate unique contributors to stroke in SSA and compare these findings with those in a cohort of African American stroke survivors, all while simultaneously building sustainable capacities in phenomics, biobanking, genomics, biostatistics and bioinformatics for future high-level investigation of stroke and other vascular disease entities in SSA.

Study EGAS00001007331

Mucociliary Clearance Consortium (MCC) Rare Genetic Disorders of the Airways: Cross-section Comparison of Clinical Features, and Development of Novel Screening and Genetic Test

We have established a consortium of 7 geographically-dispersed clinical research sites that are designed to study rare diseases of the airways, which involve defects in clearance of mucus secretions from the airways (defective "mucociliary clearance"). These sites will collaborate in diagnostic, genetic, and other studies in patients with impairments of mucociliary clearance, including primary ciliary dyskinesia (PCD), variant cystic fibrosis (CF), and pseudohypoaldosteronism (PHA). These disorders reflect genetic defects in airway host-defense, and typically result in chronic infection of the airways. Patients with these disorders of the conducting airways and sinuses have delayed (or incorrect) diagnoses, because diagnostic tests are not readily available. These patients may also have sub-optimal management of their clinical disease, because the cause of these disorders is not well-defined, and treatment regimens are usually not driven by evidence-based medicine. This current protocol is designed to employ a systematic approach to the diagnostic evaluation of these patients with chronic airways disease, which will yield precise diagnoses in individual patients, and will be associated with development of better diagnostic techniques, including genetic testing. In addition, we will compare/contrast clinical features (phenotype) across these disorders. A rigorous cross-sectional comparison of the clinical features will provide better understanding of the clinical disease of these disorders; in turn, this will lead not only to a better standard of clinical care, but will also assist in the identification of novel therapeutic approaches. The patient population for these studies includes individuals carrying a tentative diagnosis of the three disorders (PCD, variant CF or PHA), plus individuals suspected to have one of these disorders, but with inadequate or inconclusive diagnostic tests. Individuals in this latter category must have a preliminary clinical evaluation to evaluate for other more common disorders that may have similar manifestations including classical CF, immunodeficiency, asthma, and severe gastroesophageal reflux. We have an informal agreement with a network of pulmonologists across the United States to perform clinically-indicated (not research) preliminary clinical testing, if not directly available to patients who inquire about these studies. Blood will be collected for DNA to test for genetic mutations. The blood samples will be processed to establish a cell line (lymphocyte transformation) for a source of DNA for future genetic studies, in participants with disease. For participants unable to provide a blood sample, a buccal sample will be obtained for DNA.

Study phs000595

ADAGESIII: Contribution of genotype to glaucoma phenotype in African Americans

Glaucoma results in vision loss due to damage of the optic nerve that is irreversible if undetected or untreated. The most common form of glaucoma is primary open angle glaucoma (POAG). While glaucoma affects all races, persons of African descent are disproportionately affected; studies show African-Americans (AAs) are about four to five times more likely than Caucasian Americans to develop the disease. Glaucoma is the leading cause of irreversible blindness in Americans of African descent, and the second leading cause in all Americans. The lack of understanding about the etiology of POAG impedes our ability to identify and treat it early in its development. Evidence of genetic contribution in the pathogenesis of POAG is well established. Since POAG tends to run in families, it is critical to identify the genetic basis of the disease in order to develop effective therapies for early intervention. While genome wide association studies (GWAS) for glaucoma have been completed for Caucasian populations, evidence from other studies suggests that a GWAS of glaucoma specific genes to the African-American population will yield unique and important findings for both this population and for glaucoma in general. A better understanding of the relationship among the stage of disease, the rate of change, ancestry, and other important risk factors being tracked in the ongoing African Descent and Glaucoma Study (ADAGES) will allow us to evaluate the relationship between genetics, visual loss and structural damage in this high-risk cohort. The scientific plan for this new study focuses on glaucoma in ∼2058 African-Americans by detailed phenotyping of new subjects, acquisition of samples from both new and established previously phenotyped study subjects for a repository, establishment of a data coordinating center, and genome wide association studies. The recruitment, enrollment, and phenotyping of both established and new subjects occurs at five clinical centers, University of California (UCSD), New York Eye and Ear Infirmary (Mt Sinai) and Columbia University Medical Center, a private practice in the Atlanta area, the University of Alabama at Birmingham, and the Robert Cizik Eye Clinic in Houston, TX. UCSD is also the location for the Data Coordinating Center and the Repository with Robert N. Weinreb as Principal Investigator. LA BioMed at Harbor-UCLA did the genotyping with a GWAS panel of ∼1 million single nucleotide polymorphisms (SNPs) using the Illumina MEGA array under the direction of Jerome Rotter, Ida Chen, and Kent Taylor.

Study phs001673

University of Washington Center for Mendelian Genomics (UW-CMG): Atrioventricular Septal Defects (AVSD) Study

The Centers for Mendelian Genomics project uses next-generation sequencing and computational approaches to discover the genes and variants that underlie Mendelian conditions. By discovering genes that cause Mendelian conditions, we will expand our understanding of their biology to facilitate diagnosis and new treatments.

Study phs001774

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