Abstract 9468: Exploring the Missing Heritability of Complex Traits: Multiple Associated Variants Increase the Heritability Explained for Plasma Lipids and Coronary Artery Disease
Background: Plasma lipid levels as well as coronary artery disease (CAD) have been shown to be highly heritable-estimates range from 40%-60%. However, top variants detected by large-scale genome-wide association studies (GWAS) could explain only a fraction of the total variance in these phenotypes, raising the challenge for “missing heritability” to which multiple variants at a loci may contribute. Recently, a conditional and joint association analysis tool using summary-level statistics has been developed.
Methods and Results: We performed a conditional and joint association analysis using GWAS summary-level statistics from two large consortiums: (1). the Global Lipids Genetics Consortium (GLGC) study, and (2). the CAD from the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis (CARDIoGRAM) study. These studies included up to 100,184 individuals from 46 studies for lipids, and 22,233 cases and 64,762 controls from 14 studies for CAD, respectively. We detected a number of loci which represent multiple associated independent SNPs with lipid traits within a locus (12 at 33 loci for high-density lipoprotein cholesterol [HDL-C], 10 at 35 loci for low-density lipoprotein cholesterol [LDL-C], 13 at 44 loci for total cholesterol [TC], and 8 at 28 loci for triglycerides [TG]) with genome-wide significance (p < 5x10-8), nearly doubling the heritability explained by the previous GWAS results (3.6% to 7.6% for HDL-C, 4.9% to 8.8% for LDL-C, 5.4% to 8.8% for TC, and 5.7% to 8.5% for TG). Multiple SNPs were also associated with CAD (3 at 15 loci, 9.6% to 11.4% of increased heritability). Among them, 9 SNPs in the CETP locus could explain as much as 2.6% of variance explained in HDL-C, 9 SNPs in the APOE locus explained 2.1% of that in LDL-C, 6 SNPs in the APOE locus explained 1.1% of that in TC, 7 SNPs in the LPL locus explained 1.7% in that of TG, and 2 SNPs in the CDKN2A/CDKN2B locus explained 2.8% of that in CAD trait. The prediction analysis validated our results.
Conclusions: A portion of the missing heritability for lipid traits and CAD could be explained by joint effects from multiple variants at each locus. There should be multiple causal variants within a single locus, providing deeper understanding for various complex heritable traits.
- © 2013 by American Heart Association, Inc.