title: Mapping the genetic architecture of gene expression in human liver.
abstract: 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.
authors.affiliation: Rosetta Inpharmatics, Seattle, Washington, United States of America. eric_schadt@merck.com
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: Cliona
authors.initials: C
authors.lastname: Molony
authors.forename: Eugene
authors.initials: E
authors.lastname: Chudin
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.forename: Pek Y
authors.initials: PY
authors.lastname: Lum
authors.forename: Andrew
authors.initials: A
authors.lastname: Kasarskis
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Susanna
authors.initials: S
authors.lastname: Wang
authors.forename: Christine
authors.initials: C
authors.lastname: Suver
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Joshua
authors.initials: J
authors.lastname: Millstein
authors.forename: Solveig
authors.initials: S
authors.lastname: Sieberts
authors.forename: John
authors.initials: J
authors.lastname: Lamb
authors.forename: Debraj
authors.initials: D
authors.lastname: GuhaThakurta
authors.forename: Jonathan
authors.initials: J
authors.lastname: Derry
authors.forename: John D
authors.initials: JD
authors.lastname: Storey
authors.forename: Iliana
authors.initials: I
authors.lastname: Avila-Campillo
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kruger
authors.forename: Jason M
authors.initials: JM
authors.lastname: Johnson
authors.forename: Carol A
authors.initials: CA
authors.lastname: Rohl
authors.forename: Atila
authors.initials: A
authors.lastname: van Nas
authors.forename: Margarete
authors.initials: M
authors.lastname: Mehrabian
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Drake
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Smith
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Strom
authors.forename: Erin
authors.initials: E
authors.lastname: Schuetz
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Rushmore
authors.forename: Roger
authors.initials: R
authors.lastname: Ulrich
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002648:Child; D002675:Child, Preschool; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics; D003324:Coronary Artery Disease / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005802:Genes, MHC Class II / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D007223:Infant; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D008078:Cholesterol, LDL; D012333:RNA, Messenger