Abstract
It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.
Highlights
Genome-wide association studies (GWAS) have identified hundreds of mainly common variants that are robustly associated with cardiometabolic traits [1,2,3,4]
In our single-marker meta-analysis of ExomeChip (Illumina) data in 27,312 individuals, we did not find any new variant associated with a lipid trait at either a genome-wide threshold of significance (P
We undertook an association study in 27,312 individuals to test the hypothesis that lowfrequency and rare coding variants contribute to the genetic architecture of the four main lipid traits, total cholesterol (TC), TG, highdensity lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) explaining some of the missing heritability in large-scale genetic studies of common variants [2, 3]
Summary
Genome-wide association studies (GWAS) have identified hundreds of mainly common variants that are robustly associated with cardiometabolic traits [1,2,3,4]. Blood lipid levels have an estimated heritability of 40-70% [9]; variants reaching genome-wide significance explain only ~15% of the heritable fraction for these traits [2, 3]. It has been hypothesised that low frequency (1-5% minor allele frequency (MAF)) and rare (
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