Use of Genome-Wide Expression Data to Mine the "Gray Zone" of GWA Studies Leads to Novel Candidate Obesity Genes
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Naukkarinen-2010-Use of Genome-Wide E.pdf
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Author(s)
Peltonen, Leena
Naukkarinen, Jussi
Surakka, Ida
Pietiläinen, Kirsi H.
Rissanen, Aila
Salomaa, Veikko
Ripatti, Samuli
Yki-Järvinen, Hannele
van Duijn, Cornelia M.
Wichmann, H.-Erich
Date Issued
June 2010
Journal
PLoS Genetics
Publisher
Public Library of Science
Citation
Naukkarinen, Jussi et al. “Use of Genome-Wide Expression Data to Mine the “Gray Zone” of GWA Studies Leads to Novel Candidate Obesity Genes.” PLoS Genet 6.6 (2010): e1000976.
Version
Final published version
Abstract
To get beyond the “low-hanging fruits” so far identified by genome-wide association (GWA) studies, new methods must be developed in order to discover the numerous remaining genes that estimates of heritability indicate should be contributing to complex human phenotypes, such as obesity. Here we describe a novel integrative method for complex disease gene identification utilizing both genome-wide transcript profiling of adipose tissue samples and consequent analysis of genome-wide association data generated in large SNP scans. We infer causality of genes with obesity by employing a unique set of monozygotic twin pairs discordant for BMI (n = 13 pairs, age 24–28 years, 15.4 kg mean weight difference) and contrast the transcript profiles with those from a larger sample of non-related adult individuals (N = 77). Using this approach, we were able to identify 27 genes with possibly causal roles in determining the degree of human adiposity. Testing for association of SNP variants in these 27 genes in the population samples of the large ENGAGE consortium (N = 21,000) revealed a significant deviation of P-values from the expected (P = 4×10−4). A total of 13 genes contained SNPs nominally associated with BMI. The top finding was blood coagulation factor F13A1 identified as a novel obesity gene also replicated in a second GWA set of ~2,000 individuals. This study presents a new approach to utilizing gene expression studies for informing choice of candidate genes for complex human phenotypes, such as obesity.
MIT Department
Broad Institute of MIT and Harvard
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DOI of Published Version
https://doi.org/10.1371/journal.pgen.1000976
