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 with estimates ranging from 40%-60%. However, top variants detected by large-scale genome-wide association studies (GWAS) explain only a fraction of the total variance in plasma lipid phenotypes and CAD.
Methods and Results—We performed a conditional and joint association analysis using summary-level statistics from two large GWAS meta-analyses: (1) the Global Lipids Genetics Consortium (GLGC) study, and (2) the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis (CARDIoGRAM) study. There were 100,184 individuals from 46 GLGC studies for plasma lipids, and 22,233 cases and 64,762 controls from 14 studies for CAD. We detected a number of loci where multiple independent SNPs were associated with lipid traits within a locus (12 out of 33 loci for high-density lipoprotein cholesterol [HDL-C], 10 of 35 loci for low-density lipoprotein cholesterol [LDL-C], 13 of 44 loci for total cholesterol [TC], and 8 of 28 loci for triglycerides [TG]), reaching genome-wide significance (P<5×10−8), nearly doubling the heritability explained by GWAS (3.6% to 7.6% for HDL-C, 5.0% to 8.8% for LDL-C, 5.5% to 8.8% for TC, and 5.7% to 8.5% for TG). Multiple SNPs were also associated with CAD (3 of 15 loci, 9.6% to 11.4% of increased heritability).
Conclusions—These results demonstrate that a portion of the missing heritability for lipid traits and CAD can be explained by multiple variants at each locus.
- Received November 8, 2013.
- Revision received June 25, 2014.
- Accepted June 27, 2014.