Titre
Pathway-Wide Association Study Implicates Multiple Sterol Transport and Metabolism Genes in HDL Cholesterol Regulation.
Type
article
Institution
Externe
Périodique
Auteur(s)
Wang, K.
Auteure/Auteur
Edmondson, A.C.
Auteure/Auteur
Li, M.
Auteure/Auteur
Gao, F.
Auteure/Auteur
Qasim, A.N.
Auteure/Auteur
Devaney, J.M.
Auteure/Auteur
Burnett, M.S.
Auteure/Auteur
Waterworth, D.M.
Auteure/Auteur
Mooser, V.
Auteure/Auteur
Grant, S.F.
Auteure/Auteur
Epstein, S.E.
Auteure/Auteur
Reilly, M.P.
Auteure/Auteur
Hakonarson, H.
Auteure/Auteur
Rader, D.J.
Auteure/Auteur
Liens vers les personnes
ISSN
1664-8021
Statut éditorial
Publié
Date de publication
2011
Volume
2
Première page
41
Langue
anglais
Notes
Publication types: Journal ArticlePublication Status: ppublish
Résumé
Pathway-based association methods have been proposed to be an effective approach in identifying disease genes, when single-marker association tests do not have sufficient power. The analysis of quantitative traits may be benefited from these approaches, by sampling from two extreme tails of the distribution. Here we tested a pathway association approach on a small genome-wide association study (GWAS) on 653 subjects with extremely high high-density lipoprotein cholesterol (HDL-C) levels and 784 subjects with low HDL-C levels. We identified 102 genes in the sterol transport and metabolism pathways that collectively associate with HDL-C levels, and replicated these association signals in an independent GWAS. Interestingly, the pathways include 18 genes implicated in previous GWAS on lipid traits, suggesting that genuine HDL-C genes are highly enriched in these pathways. Additionally, multiple biologically relevant loci in the pathways were not detected by previous GWAS, including genes implicated in previous candidate gene association studies (such as LEPR, APOA2, HDLBP, SOAT2), genes that cause Mendelian forms of lipid disorders (such as DHCR24), and genes expressing dyslipidemia phenotypes in knockout mice (such as SOAT1, PON1). Our study suggests that sampling from two extreme tails of a quantitative trait and examining genetic pathways may yield biological insights from smaller samples than are generally required using single-marker analysis in large-scale GWAS. Our results also implicate that functionally related genes work together to regulate complex quantitative traits, and that future large-scale studies may benefit from pathway-association approaches to identify novel pathways regulating HDL-C levels.
PID Serval
serval:BIB_168169954F39
PMID
Open Access
Oui
Date de création
2012-03-22T08:44:18.033Z
Date de création dans IRIS
2025-05-20T16:45:03Z