Abstract 10159: A Rare View of Coding Sequence Mutations and Plasma Lipid Levels: Results From an Association Study Including ~82,000 Individuals Genotyped Using the Exome Array
Background: Plasma low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are quantitative, heritable risk factors for coronary heart disease, and genome-wide association screens of common DNA sequence variants have identified many loci associated with plasma lipids. However, common variants incompletely explain the heritability of plasma lipid traits, suggesting the hypothesis that rare coding and splice-site mutations contribute to inter-individual variability of these traits in the population.
Methods: We contributed to the design of a new, rare-variant genotyping array based on the sequences of the protein-coding regions of ~18,500 genes (“the exome”) in >12,000 individuals. This genotyping array (“the Exome Array”) includes approximately 250,000 non-synonymous and splice-site mutations and is estimated to capture nearly all such variation with a >1:1000 allele frequency in the European population. We obtained Exome Array genotype data in >82,000 individuals from 34 studies, which is one of the largest exome datasets to date. Within each study, we tested the association of plasma lipids with individual rare variants. To combine statistical evidence across studies, we performed meta-analysis.
Results: Top results for each trait replicated established associations in the genes APOE, CETP, and APOA5 for LDL-C, HDL-C, and TG, respectively. We identified several new genes associated with plasma lipid levels: ABCA6 and LDL-C (C1359R, frequency = 1:100, effect=+6.3mg/dl, P=2 x 10-11); MAP1A and TG (P2349L, frequency = 2:100, effect=+8.5mg/dl, P=3x10-13); and APOA4 and TG (V13M, frequency = 1:100, effect=+11.7mg/dl, P=3x10-13). In addition, at some genes previously known to affect lipids, we identified new variants: APOC3 and TG (R19Stop, frequency = 4:10,000, effect=-67.2mg/dl, P=2x10-20 and splicesite IVS2+1 G>A, frequency = 2:1000, effect=-68.5mg/dl, P=4x10-66).
Conclusions: Using the Exome Array to genotype rare coding sequence variants, we have discovered several new genes and variants associated with plasma lipids.
- © 2013 by American Heart Association, Inc.