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Title: Genetic identification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue [Illumina SNP array]      
keywords:
Variation
ID:
PRJNA142295
description:
Most loci identified in genome wide association studies (GWAS) of complex traits reside in non-coding DNA and may contribute to phenotype via changes in gene regulation. The discovery of expression quantitative trait loci (‘eQTLs’) can thus be used to more precisely identify modest but real disease associations and provide insights into their underlying molecular mechanisms. This is particularly true for analyses of expression in non-transformed cells from tissues relevant to the complex traits of interest. We have conducted two independent studies to identify genetic, including both SNPs and copy-number variants, and environmental determinants of human liver gene expression variation. We analyzed two sets of primary livers (primary dataset: n=220; replication dataset: n=60) using Agilent and Illumina expression arrays and Illumina SNP genotyping (550K). At least 30% of genetic and non-genetic factors that meet genome-wide significance (p <1 x10-9) in one study fail to replicate in the second study, suggesting that artifacts, like unknown SNPs that affect RNA-probe hybridization or hidden confounding variables, often result in statistically significant but biologically irrelevant correlations. These data confirm the value of independent replications to enrich for truly predictive eQTLs, and given our study design we are able to identify hundreds of reproducible correlations. We show that such information can be used to provide insights into disease-relevant phenotypes, with specific examples including eQTLs related to lipid levels (e.g. LDL cholesterol), immune system function (e.g. HLA), and drug response (e.g. warfarin). Furthermore, in the interest of both fine-mapping and mechanistic annotation, we hypothesized that promoters and 3’UTRs are enriched for causal eQTL variants. Therefore, we re-sequenced the promoter and 3’UTR regions of 25 genes with eQTLs, cloned each discovered haplotype, and quantified their impact on transcription using a luciferase-based assay. These data reveal multiple examples of robust, haplotype-specific in vitro functional differences that correlate directly with in vivo expression levels. This suggests that many eQTLs can be rapidly fine-mapped to one or a few single-nucleotide variants and mechanistically characterized using such assays. Integration of functional assays with eQTL discovery, and eQTLs with complex trait associations, is a powerful means to exploit GWAS data and improve their biological interpretability. Overall design: RNA expression levels were quantified on Agilent gene expression microarrays for 224 normal human livers. Genotypes were also derived from these samples using Illumina SNP chips. Expression quantitative trait loci were identified by genome wide association mapping.
accesstypes:
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landingpage: http://www.ncbi.nlm.nih.gov/bioproject/PRJNA142295
authentication:
none
authorization:
none
ID:
pmid:21637794
dateReleased:
06-27-2011
name:
Homo sapiens
ncbiID:
ncbitax:9606
abbreviation:
NCBI
homePage: http://www.ncbi.nlm.nih.gov
ID:
SCR:006472
name:
National Center for Biotechnology Information
homePage: http://www.ncbi.nlm.nih.gov/bioproject
ID:
SCR:004801
name:
NCBI BioProject
  • N01-DK-7-0004/HHSN267200700004C/DK/NIDDK NIH HHS/United States

  • R21 DK081157/DK/NIDDK NIH HHS/United States

  • P01 GM32165/GM/NIGMS NIH HHS/United States

  • U01 HL66682/HL/NHLBI NIH HHS/United States

  • R01 NS053646/NS/NINDS NIH HHS/United States

  • 1KL2RR025015/RR/NCRR NIH HHS/United States

  • U01 GM061393/GM/NIGMS NIH HHS/United States

  • P30 CA014599/CA/NCI NIH HHS/United States

  • R01GM094418/GM/NIGMS NIH HHS/United States

  • K07 CA140390/CA/NCI NIH HHS/United States

  • K07CA140390-01/CA/NCI NIH HHS/United States

  • HHSN267200700004G/LM/NLM NIH HHS/United States

  • R21DK081157-01A2/DK/NIDDK NIH HHS/United States

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