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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 27 312 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.

Original publication

DOI

10.1093/hmg/ddw227

Type

Journal article

Journal

Hum Mol Genet

Publication Date

15/09/2016

Volume

25

Pages

4094 - 4106

Keywords

Adolescent, Adult, Aged, Child, Cholesterol, HDL, Cholesterol, LDL, European Continental Ancestry Group, Exome, Gene Frequency, Genome-Wide Association Study, Humans, Lipid Metabolism, Lipids, Middle Aged, Polymorphism, Single Nucleotide, Triglycerides