Excess of Rare Variants in Genes Identified by Genome-wide Association Study of Hypertriglyceridemia

Authors

Christopher T. Johansen, The University of Western Ontario
Jian Wang, The University of Western Ontario
Matthew B. Lanktree, The University of Western Ontario
Henian Cao, The University of Western Ontario
Adam D. McIntyre, The University of Western Ontario
Matthew R. Ban, The University of Western Ontario
Rebecca A. Martins, The University of Western Ontario
Brooke A. Kennedy, The University of Western Ontario
Reina G. Hassell, The University of Western Ontario
Maartje E. Visser, Academic Medical Center Amsterdam, Amsterdam, The Netherlands
Stephen M. Schwartz, University of Washington
Benjamin F. Voight, Massachusetts General Hospital, Boston, MA
Roberto Elosua, Institut Municipal D'investigacio Medica, Barcelona, Spain
Veikko Salomaa, National Institute for Health and Welfare, Helsinki, Finland
Christopher J. O'Donnell, Harvard University
Geesje M. Dallinga-Thie, Academic Medical Center Amsterdam, Amsterdam, The Netherlands
Sonia S. Anand, McMaster University
Salim Yusuf, McMaster University
Murray W. Huff, The University of Western Ontario
Sekar Kathiresan, Massachusetts General Hospital, Boston, MA
Robert A. Hegele, The University of Western Ontario

Document Type

Article

Publication Date

8-2010

Journal

Nature Genetics

Volume

42

Issue

8

First Page

684

Last Page

687

URL with Digital Object Identifier

http://dx.doi.org/10.1038/ng.628

Abstract

Genome-wide association studies (GWAS) have identified multiple loci associated with plasma lipid concentrations. Common variants at these loci together explain <10% of variation in each lipid trait. Rare variants with large individual effects may also contribute to the heritability of lipid traits; however, the extent to which rare variants affect lipid phenotypes remains to be determined. Here we show an accumulation of rare variants, or a mutation skew, in GWAS-identified genes in individuals with hypertriglyceridemia (HTG). Through GWAS, we identified common variants in APOA5, GCKR, LPL and APOB associated with HTG. Resequencing of these genes revealed a significant burden of 154 rare missense or nonsense variants in 438 individuals with HTG, compared to 53 variants in 327 controls (P = 6.2 x 10(-8)), corresponding to a carrier frequency of 28.1% of affected individuals and 15.3% of controls (P = 2.6 x 10(-5)). Considering rare variants in these genes incrementally increased the proportion of genetic variation contributing to HTG.