Identification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue.
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 Ill...
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Public Library of Science (PLoS)
2011
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oai:doaj.org-article:3d934a1f80b8416d99b7b08cd2c4008a2021-11-18T06:17:24ZIdentification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue.1553-73901553-740410.1371/journal.pgen.1002078https://doaj.org/article/3d934a1f80b8416d99b7b08cd2c4008a2011-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21637794/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404The 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.Federico InnocentiGregory M CooperIan B StanawayEric R GamazonJoshua D SmithSnezana MirkovJacqueline RamirezWanqing LiuYvonne S LinCliona MoloneyShelly Force AldredNathan D TrinkleinErin SchuetzDeborah A NickersonKen E ThummelMark J RiederAllan E RettieMark J RatainNancy J CoxChristopher D BrownPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 7, Iss 5, p e1002078 (2011) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
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| topic |
Genetics QH426-470 |
| spellingShingle |
Genetics QH426-470 Federico Innocenti Gregory M Cooper Ian B Stanaway Eric R Gamazon Joshua D Smith Snezana Mirkov Jacqueline Ramirez Wanqing Liu Yvonne S Lin Cliona Moloney Shelly Force Aldred Nathan D Trinklein Erin Schuetz Deborah A Nickerson Ken E Thummel Mark J Rieder Allan E Rettie Mark J Ratain Nancy J Cox Christopher D Brown Identification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue. |
| description |
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. |
| format |
article |
| author |
Federico Innocenti Gregory M Cooper Ian B Stanaway Eric R Gamazon Joshua D Smith Snezana Mirkov Jacqueline Ramirez Wanqing Liu Yvonne S Lin Cliona Moloney Shelly Force Aldred Nathan D Trinklein Erin Schuetz Deborah A Nickerson Ken E Thummel Mark J Rieder Allan E Rettie Mark J Ratain Nancy J Cox Christopher D Brown |
| author_facet |
Federico Innocenti Gregory M Cooper Ian B Stanaway Eric R Gamazon Joshua D Smith Snezana Mirkov Jacqueline Ramirez Wanqing Liu Yvonne S Lin Cliona Moloney Shelly Force Aldred Nathan D Trinklein Erin Schuetz Deborah A Nickerson Ken E Thummel Mark J Rieder Allan E Rettie Mark J Ratain Nancy J Cox Christopher D Brown |
| author_sort |
Federico Innocenti |
| title |
Identification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue. |
| title_short |
Identification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue. |
| title_full |
Identification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue. |
| title_fullStr |
Identification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue. |
| title_full_unstemmed |
Identification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue. |
| title_sort |
identification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/3d934a1f80b8416d99b7b08cd2c4008a |
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