Analysis with the exome array identifies multiple new independent variants in lipid loci

作者：Kanoni Stavroula; Masca Nicholas G D; Stirrups Kathleen E; Varga Tibor V; Warren Helen R; Scott Robert A; Southam Lorraine; Zhang Weihua; Yaghootkar Hanieh; Mueller Nurasyid Martina; Alves Alexessander Couto; Strawbridge Rona J; Lataniotis Lazaros; Hashim Nikman An; Besse Celine; Boland Anne; Braund Peter S; Connell John M; Dominiczak Anna; Farmaki Aliki Eleni; Franks Stephen; Grallert Harald; Jansson Jan Hakan; Karaleftheri Maria; Keinanen Kiukaanniemi Sirkka

来源：Human Molecular Genetics, 2016, 25(18): 4094-4106.

DOI：10.1093/hmg/ddw227

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.

• 出版日期2016-9-15
• 单位河北医科大学