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Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n=197, temporal cortex n=202) and with other brain pathologies (non-AD, cerebellar n=177, temporal cortex n=197). We conducted an expression genome-wide association study (eGWAS) using 213,528 cisSNPs within ± 100 kb of the tested transcripts. We identified 2,980 cerebellar cisSNP/transcript level associations (2,596 unique cisSNPs) significant in both ADs and non-ADs (q<0.05, p=7.70 × 10(-5)-1.67 × 10(-82)). Of these, 2,089 were also significant in the temporal cortex (p=1.85 × 10(-5)-1.70 × 10(-141)). The top cerebellar cisSNPs had 2.4-fold enrichment for human disease-associated variants (p<10(-6)). We identified novel cisSNP/transcript associations for human disease-associated variants, including progressive supranuclear palsy SLCO1A2/rs11568563, Parkinson's disease (PD) MMRN1/rs6532197, Paget's disease OPTN/rs1561570; and we confirmed others, including PD MAPT/rs242557, systemic lupus erythematosus and ulcerative colitis IRF5/rs4728142, and type 1 diabetes mellitus RPS26/rs1701704. In our eGWAS, there was 2.9-3.3 fold enrichment (p<10(-6)) of significant cisSNPs with suggestive AD-risk association (p<10(-3)) in the Alzheimer's Disease Genetics Consortium GWAS. These results demonstrate the significant contributions of genetic factors to human brain gene expression, which are reliably detected across different brain regions and pathologies. The significant enrichment of brain cisSNPs among disease-associated variants advocates gene expression changes as a mechanism for many central nervous system (CNS) and non-CNS diseases. Combined assessment of expression and disease GWAS may provide complementary information in discovery of human disease variants with functional implications. Our findings have implications for the design and interpretation of eGWAS in general and the use of brain expression quantitative trait loci in the study of human disease genetics.
Pubmed ID: 22685416
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Portal to interactively visualize genomic data. Provides reference sequences and working draft assemblies for collection of genomes and access to ENCODE and Neanderthal projects. Includes collection of vertebrate and model organism assemblies and annotations, along with suite of tools for viewing, analyzing and downloading data.
View all literature mentionsNational genetics data repository facilitating access to genotypic and phenotypic data for Alzheimer's disease (AD). Data include GWAS, whole genome (WGS) and whole exome (WES), expression, RNA Seq, and CHIP Seq analyses. Data for the Alzheimer’s Disease Sequencing Project (ADSP) are available through a partnership with dbGaP (ADSP at dbGaP). Repository for many types of data generated from NIA supported grants and/or NIA funded biological samples. Data are deposited at NIAGADS or NIA-approved sites. Genetic Data and associated Phenotypic Data are available to qualified investigators in scientific community for secondary analysis.
View all literature mentionsCatalog of published genome-wide association studies. Genome-wide set of genetic variants in different individuals to see if any variant is associated with trait and disease. Database of genome-wide association study (GWAS) publications including only those attempting to assay single nucleotide polymorphisms (SNPs). Publications are organized from most to least recent date of publication. Studies are identified through weekly PubMed literature searches, daily NIH-distributed compilations of news and media reports, and occasional comparisons with an existing database of GWAS literature (HuGE Navigator). Works with HANCESTRO ancestry representation.
View all literature mentionsDatabase of the results of the ADNI study. ADNI is an initiative to develop biomarker-based methods to detect and track the progression of Alzheimer's disease (AD) that provides access to qualified scientists to their database of imaging, clinical, genomic, and biomarker data.
View all literature mentionsCell repository for Alzheimer's disease that collects and maintains biological specimens and associated data. Its data is derived from large numbers of genetically informative, phenotypically well-characterized families with multiple individuals affected with Alzheimer's disease, as well as individuals for case-control studies.
View all literature mentionsResearch institute for basic and translational research, clinical care, prevention and education in age-related conditions such as Alzheimer's and Parkinson's diseases, arthritis and cancer. Founded as a private, nonprofit biomedical research center, they now have nearly 100 international scientists and research staff. Their research programs have had significant impact on how physicians diagnose and treat diseases such as Alzheimer's, Parkinson's and arthritis. Sun Health is also internationally recognized for research on inflammation damage to brain tissue and how that affects Alzheimer's disease. They are one of just 31 national Alzheimer's Disease Core Centers in the nation. The Institute maintains collaborations with nationally-recognized institutions such as Johns Hopkins, Boston University and the University of Washington. In 2007, the institute opened a new research facility that allowed them to expand into areas such as orthopedics and fibromyalgia.
View all literature mentionsSoftware application designed to facilitate meta-analysis of large datasets (such as several whole genome scans) in a convenient, rapid and memory efficient manner. (entry from Genetic Analysis Software)
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