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PLoS Genet ; 7(5): e1002078, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21637794

RESUMO

The discovery of expression quantitative trait loci ("eQTLs") can help to unravel genetic contributions to complex traits. We identified genetic determinants of human liver gene expression variation using two independent collections of primary tissue profiled with Agilent (n = 206) and Illumina (n = 60) expression arrays and Illumina SNP genotyping (550K), and we also incorporated data from a published study (n = 266). We found that ∼30% of SNP-expression correlations in one study failed to replicate in either of the others, even at thresholds yielding high reproducibility in simulations, and we quantified numerous factors affecting reproducibility. Our data suggest that drug exposure, clinical descriptors, and unknown factors associated with tissue ascertainment and analysis have substantial effects on gene expression and that controlling for hidden confounding variables significantly increases replication rate. Furthermore, we found that reproducible eQTL SNPs were heavily enriched near gene starts and ends, and subsequently resequenced the promoters and 3'UTRs for 14 genes and tested the identified haplotypes using luciferase assays. For three genes, significant haplotype-specific in vitro functional differences correlated directly with expression levels, suggesting that many bona fide eQTLs result from functional variants that can be mechanistically isolated in a high-throughput fashion. Finally, given our study design, we were able to discover and validate hundreds of liver eQTLs. Many of these relate directly to complex traits for which liver-specific analyses are likely to be relevant, and we identified dozens of potential connections with disease-associated loci. These included previously characterized eQTL contributors to diabetes, drug response, and lipid levels, and they suggest novel candidates such as a role for NOD2 expression in leprosy risk and C2orf43 in prostate cancer. In general, the work presented here will be valuable for future efforts to precisely identify and functionally characterize genetic contributions to a variety of complex traits.


Assuntos
Genoma Humano , Fígado/metabolismo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Regiões 3' não Traduzidas , Fatores Etários , População Negra , Mapeamento Cromossômico , Clonagem Molecular , Feminino , Perfilação da Expressão Gênica , Vetores Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Células Hep G2 , Hispânico ou Latino , Humanos , Medições Luminescentes , Masculino , Análise de Componente Principal , Regiões Promotoras Genéticas , Reprodutibilidade dos Testes , Fatores Sexuais , Transfecção , População Branca
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