Identification, Replication, and Functional Fine-Mapping of Expression Quantitative Trait Loci in Primary Human Liver Tissue

Innocenti, Federico; Cooper, Gregory M.; Stanaway, Ian B.; Gamazon, Eric R.; Smith, Joshua D.; Mirkov, Snezana; Ramirez, Jacqueline; Liu, Wanqing; Lin, Yvonne S.; Moloney, Cliona; Aldred, Shelly Force; Trinklein, Nathan D.; Schuetz, Erin; Nickerson, Deborah A.; Thummel, Ken E.; Rieder, Mark J.; Rettie, Allan E.; Ratain, Mark J.; Cox, Nancy J.; Brown, Christopher D.

doi:10.1371/journal.pgen.1002078

Title: Identification, Replication, and Functional Fine-Mapping of Expression Quantitative Trait Loci in Primary Human Liver Tissue

Journal Article · Thu May 26 00:00:00 EDT 2011 · PLoS Genetics

DOI:https://doi.org/10.1371/journal.pgen.1002078· OSTI ID:1627291

Innocenti, Federico ^[1]; Cooper, Gregory M. ^[2]; Stanaway, Ian B. ^[2]; Gamazon, Eric R. ^[3]; Smith, Joshua D. ^[2]; Mirkov, Snezana ^[4]; Ramirez, Jacqueline ^[4]; Liu, Wanqing ^[4]; Lin, Yvonne S. ^[5]; Moloney, Cliona ^[6]; Aldred, Shelly Force ^[7]; Trinklein, Nathan D. ^[7]; Schuetz, Erin ^[8]; Nickerson, Deborah A. ^[2]; Thummel, Ken E. ^[5]; Rieder, Mark J. ^[2]; Rettie, Allan E. ^[9]; Ratain, Mark J. ^[1]; Cox, Nancy J. ^[3]; Brown, Christopher D. ^[10]

Univ. of Chicago, IL (United States). Dept. of Medicine. Committee on Clinical Pharmacology and Pharmacogenomics. Cancer Research Center
Univ. of Washington, Seattle, WA (United States). Dept. of Genome Sciences
Univ. of Chicago, IL (United States). Dept. of Medicine. Section of Genetic Medicine
Univ. of Chicago, IL (United States). Dept. of Medicine.. Section of Hematology/Oncology
Univ. of Washington, Seattle, WA (United States). School of Pharmacy. Dept. of Medicinal Chemistry; Univ. of Washington, Seattle, WA (United States). Dept. of Pharmaceutics
Merck Research Laboratories, Boston, MA (United States)
SwitchGear Genomics, Menlo Park, CA (United States)
St. Jude Children’s Research Hospital, Memphis, TN (United States)
Univ. of Washington, Seattle, WA (United States). School of Pharmacy. Dept. of Medicinal Chemistry
Argonne National Lab. (ANL), Argonne, IL (United States). Inst. for Genomics and Systems Biology; Univ. of Chicago, IL (United States). Depts. of Human Genetics and Ecology and Evolution

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 39UTRs 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 liverspecific 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1627291

Journal Information:: PLoS Genetics, Vol. 7, Issue 5; ISSN 1553-7404

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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