Kanoni S, Masca NG, Stirrups KE, Varga TV, Warren HR, Scott RA, Southam L, Zhang W, Yaghootkar H, Müller-Nurasyid M, Couto Alves A, Strawbridge RJ, Lataniotis L, An Hashim N, Besse C, Boland A, Braund PS, Connell JM, Dominiczak A, Farmaki AE, Franks S, Grallert H, Jansson JH, Karaleftheri M, Keinänen-Kiukaanniemi S, Matchan A, Pasko D, Peters A, Poulter N, Rayner NW, Renström F, Rolandsson O, Sabater-Lleal M, Sennblad B, Sever P, Shields D, Silveira A, Stanton AV, Strauch K, Tomaszewski M, Tsafantakis E, Waldenberger M, Blakemore AI, Dedoussis G, Escher SA, Kooner JS, McCarthy MI, Palmer CN, Wellcome Trust Case Control Consortium , Hamsten A, Caulfield MJ, Frayling TM, Tobin MD, Jarvelin MR, Zeggini E, Gieger C, Chambers JC, Wareham NJ, Munroe PB, Franks PW, Samani NJ, Deloukas P
Hum. Mol. Genet. 25 (18) 4094-4106 [2016-09-15; online 2016-07-27]
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.