title: Identification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue.
abstract: 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.
authors.affiliation: Cancer Research Center, Committee on Clinical Pharmacology and Pharmacogenomics, Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Federico
authors.initials: F
authors.lastname: Innocenti
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Cooper
authors.forename: Ian B
authors.initials: IB
authors.lastname: Stanaway
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gamazon
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.forename: Snezana
authors.initials: S
authors.lastname: Mirkov
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ramirez
authors.forename: Wanqing
authors.initials: W
authors.lastname: Liu
authors.forename: Yvonne S
authors.initials: YS
authors.lastname: Lin
authors.forename: Cliona
authors.initials: C
authors.lastname: Moloney
authors.forename: Shelly Force
authors.initials: SF
authors.lastname: Aldred
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Trinklein
authors.forename: Erin
authors.initials: E
authors.lastname: Schuetz
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Ken E
authors.initials: KE
authors.lastname: Thummel
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: Allan E
authors.initials: AE
authors.lastname: Rettie
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Brown
mesh_terms: D020413:3' Untranslated Regions; D000367:Age Factors; D044383:Black People; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D005260:Female; D020869:Gene Expression Profiling; D005822:Genetic Vectors; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D056945:Hep G2 Cells; D006630:Hispanic or Latino; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008163:Luminescent Measurements; D008297:Male; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci; D015203:Reproducibility of Results; D012737:Sex Factors; D014162:Transfection; D044465:White People
chemical_list: D020413:3' Untranslated Regions