Mapping the genetic architecture of gene expression in human liver

被引：741

作者：

Schadt, Eric E. ^{[1
]}

Molony, Cliona ^{[1
]}

Chudin, Eugene ^{[1
]}

Hao, Ke ^{[1
]}

Yang, Xia ^{[1
]}

Lum, Pek Y. ^{[1
]}

Kasarskis, Andrew ^{[1
]}

Zhang, Bin ^{[1
]}

Wang, Susanna ^{[1
]}

Suver, Christine ^{[1
]}

Zhu, Jun ^{[1
]}

Millstein, Joshua ^{[1
]}

Sieberts, Solveig ^{[1
]}

Lamb, John ^{[1
]}

GuhaThakurta, Debraj ^{[1
]}

Derry, Jonathan ^{[1
]}

Storey, John D. ^{[1
,2
,3
]}

Avila-Campillo, Iliana ^{[1
]}

Kruger, Mark J. ^{[1
]}

Johnson, Jason M. ^{[1
]}

Rohl, Carol A. ^{[1
]}

van Nas, Atila ^{[6
]}

Mehrabian, Margarete ^{[4
,5
]}

Drake, Thomas A. ^{[7
]}

Lusis, Aldons J. ^{[4
,5
,6
]}

Smith, Ryan C. ^{[1
]}

Guengerich, F. Peter ^{[8
,9
]}

Strom, Stephen C. ^{[10
]}

Schuetz, Erin ^{[11
]}

Rushmore, Thomas H. ^{[12
]}

Ulrich, Roger ^{[1
]}

机构：

[1] Rosetta Inpharmat, Seattle, WA USA

[2] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[3] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[4] Univ Calif Los Angeles, Dept Microbiol Mol Genet & Immunol, Los Angeles, CA USA

[5] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA

[6] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA

[7] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA USA

[8] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37212 USA

[9] Vanderbilt Univ, Sch Med, Ctr Mol Toxicol, Nashville, TN 37212 USA

[10] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA

[11] St Jude Childrens Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA

[12] Merck & Co Inc, Drug Metab, West Point, PA USA

来源：

PLOS BIOLOGY | 2008年 / 6卷 / 05期

关键词：

D O I：

10.1371/journal.pbio.0060107

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Genetic variants that are associated with common human diseases do not lead directly to disease, but instead act on intermediate, molecular phenotypes that in turn induce changes in higher-order disease traits. Therefore, identifying the molecular phenotypes that vary in response to changes in DNA and that also associate with changes in disease traits has the potential to provide the functional information required to not only identify and validate the susceptibility genes that are directly affected by changes in DNA, but also to understand the molecular networks in which such genes operate and how changes in these networks lead to changes in disease traits. Toward that end, we profiled more than 39,000 transcripts and we genotyped 782,476 unique single nucleotide polymorphisms (SNPs) in more than 400 human liver samples to characterize the genetic architecture of gene expression in the human liver, a metabolically active tissue that is important in a number of common human diseases, including obesity, diabetes, and atherosclerosis. This genome-wide association study of gene expression resulted in the detection of more than 6,000 associations between SNP genotypes and liver gene expression traits, where many of the corresponding genes identified have already been implicated in a number of human diseases. The utility of these data for elucidating the causes of common human diseases is demonstrated by integrating them with genotypic and expression data from other human and mouse populations. This provides much-needed functional support for the candidate susceptibility genes being identified at a growing number of genetic loci that have been identified as key drivers of disease from genome-wide association studies of disease. By using an integrative genomics approach, we highlight how the gene RPS26 and not ERBB3 is supported by our data as the most likely susceptibility gene for a novel type 1 diabetes locus recently identified in a large-scale, genome-wide association study. We also identify SORT1 and CELSR2 as candidate susceptibility genes for a locus recently associated with coronary artery disease and plasma low-density lipoprotein cholesterol levels in the process.

引用

页码：1020 / 1032

页数：13

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