Mapping the Genetic Architecture of Gene Expression in Human Liver

By Eric E. Schadt, C. Molony, E. Chudin, K. Hao, Xia Yang, P. Lum, Andrew Kasarskis, Bin Zhang, Susanna S. Wang, Christine Suver and 21 more. PLoS Biology, 2008

1,063 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Epidemiology, Genetics

View Paper: https://www.semanticscholar.org/paper/c0ca80da0a512b35f0b66106d016c9b5080cb95f

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Citations in the corpus

Multiple New Loci Associated with Kidney Function and Chronic Kidney Disease: The CKDGen consortium (2010, positive): “We therefore focused on SNPs previously identified in genome-wide studies as being significantly related to gene expression in liver ( n = 3,322”
Genome-wide association study of blood pressure and hypertension (2009, background): “5 million HapMap SNPs in our analysis those that were previously reported from GWAS to be associated with altered gene expression in live”
Trimethylamine-N-Oxide, a Metabolite Associated with Atherosclerosis, Exhibits Complex Genetic and Dietary Regulation (2013, neutral): “1F) (Schadt et al., 2008).”
Trait-Associated SNPs Are More Likely to Be eQTLs: Annotation to Enhance Discovery from GWAS (2010, result): “Our results build on those of previous studies, particularly those of Schadt and colleagues [12–15] that focused on using transcriptome information to improve understanding of genetic signals, but the rapid accumulation of trait-associated SNPs through GWAS, coupled with the systematic efforts to ca”
Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. (2013, background): “Several genome-wide association studies with a total number of >800 human liver samples failed however to identify novel significant markers of CYP3A4 expression and function (Schadt et al., 2008; Yang et al., 2010; Innocenti et al., 2011; Schröder et al., 2013; Glubb et al., 2012).”
How Common are Extra-ribosomal Functions of Ribosomal Proteins? (2009, background): “A recent genome-wide association study has implicated S26, based on its reduced expression level, as a susceptibility gene for a form of type 1 diabetes (Schadt et al., 2008).”
Common variants at 30 loci contribute to polygenic dyslipidemia (2008, neutral): “03) TG 2p23 rs1260326 2 10 31 19,840 465 (22) GCKR C, T (0.”
Integrative Analysis of Multi-omics Data for Discovery and Functional Studies of Complex Human Diseases (2016, background): “Since then, numerous human studies have generated eQTLs maps in multiple tissues such as brain, liver, skin, immune cells, and lymphoblastoid cell lines (Ding et al., 2010; Fairfax et al., 2012; Myers et al., 2007; Pickrell et al., 2010; Schadt et al., 2008; Veyrieras et al., 2008; W. Zhang et al., ”