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

Publication

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

Journal Paper/Review - Jul 27, 2016

Deloukas Panos, Escher Stefan A, Dedoussis George, Blakemore Alexandra I F, Waldenberger Melanie, Tsafantakis Emmanouil, Tomaszewski Maciej, Strauch Konstantin, Stanton Alice V, Silveira Angela, Shields Denis, Sever Peter, Sennblad Bengt, Sabater-Lleal Maria, Kooner Jaspal S, McCarthy Mark I, Palmer Colin N A, Samani Nilesh J, Franks Paul W, Munroe Patricia B, Wareham Nick J, Chambers John C, Gieger Christian, Zeggini Eleftheria, Jarvelin Marjo-Riitta, Tobin Martin D, Frayling Timothy M, Caulfield Mark J, Hamsten Anders, Rolandsson Olov, Renström Frida, An Hashim Nikman, Lataniotis Lazaros, Strawbridge Rona J, Couto Alves Alexessander, Müller-Nurasyid Martina, Yaghootkar Hanieh, Zhang Weihua, Southam Lorraine, Scott Robert A, Warren Helen R, Varga Tibor V, Stirrups Kathleen E, Masca Nicholas G D, Besse Céline, Boland Anne, Braund Peter S, Rayner Nigel W, Poulter Neil, Peters Annette, Pasko Dorota, Matchan Angela, Keinänen-Kiukaanniemi Sirkka, Karaleftheri Maria, Jansson Jan-Håkan, Grallert Harald, Franks Stephen, Farmaki Aliki-Eleni, Dominiczak Anna, Connell John M, Kanoni Stavroula

Citation

Deloukas P, Escher S, Dedoussis G, Blakemore A, Waldenberger M, Tsafantakis E, Tomaszewski M, Strauch K, Stanton A, Silveira A, Shields D, Sever P, Sennblad B, Sabater-Lleal M, Kooner J, McCarthy M, Palmer C, Samani N, Franks P, Munroe P, Wareham N, Chambers J, Gieger C, Zeggini E, Jarvelin M, Tobin M, Frayling T, Caulfield M, Hamsten A, Rolandsson O, Renström F, An Hashim N, Lataniotis L, Strawbridge R, Couto Alves A, Müller-Nurasyid M, Yaghootkar H, Zhang W, Southam L, Scott R, Warren H, Varga T, Stirrups K, Masca N, Besse C, Boland A, Braund P, Rayner N, Poulter N, Peters A, Pasko D, Matchan A, Keinänen-Kiukaanniemi S, Karaleftheri M, Jansson J, Grallert H, Franks S, Farmaki A, Dominiczak A, Connell J, Kanoni S. Analysis with the exome array identifies multiple new independent variants in lipid loci. Hum Mol Genet 2016; 25:4094-4106.

Type

Journal Paper/Review (English)

Journal

Hum Mol Genet 2016; 25

Publication Date

Jul 27, 2016

Issn Electronic

1460-2083

Pages

4094-4106

Brief description/objective

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.