Newly identified loci that influence lipid concentrations and risk of coronary artery disease

Abstract

To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.

Figure 1

Summary of genome-wide association scans. The figure summarizes combined genome-wide association scan results in the top 3 panels (plotted as −log₁₀ P value for HDL cholesterol, LDL cholesterol and triglycerides). Loci that were not followed up are in gray. Loci that were followed-up are in green (combined dataset yielded convincing evidence of association, P < 5 × 10⁻⁸), orange (combined dataset yielded promising evidence of association, P < 10⁻⁵), or red (combined dataset did not suggest association, P > 10⁻⁵). The three panels in the bottom row display quantile-quantile plots for test statistics. The red line corresponds to all test statistics, the blue line corresponds to results after excluding statistics at replicated loci (in green, top panel), and the gray area corresponds to the 90% confidence region from a null distribution of P values (generated from 100 simulations).