| Literature DB >> 27466198 |
Stavroula Kanoni1, Nicholas G D Masca2,3, Kathleen E Stirrups1,4, Tibor V Varga5,6,7, Helen R Warren8,9, Robert A Scott10, Lorraine Southam4,11, Weihua Zhang12,13, Hanieh Yaghootkar14, Martina Müller-Nurasyid15,16,17,18, Alexessander Couto Alves19, Rona J Strawbridge20, Lazaros Lataniotis1, Nikman An Hashim21, Céline Besse22, Anne Boland22, Peter S Braund2,3, John M Connell23, Anna Dominiczak24, Aliki-Eleni Farmaki25, Stephen Franks26, Harald Grallert27,28,29, Jan-Håkan Jansson30, Maria Karaleftheri31, Sirkka Keinänen-Kiukaanniemi32, Angela Matchan4, Dorota Pasko14, Annette Peters18,28, Neil Poulter33, Nigel W Rayner4,11,34, Frida Renström7,35, Olov Rolandsson36, Maria Sabater-Lleal20, Bengt Sennblad20,37, Peter Sever33, Denis Shields38, Angela Silveira20, Alice V Stanton39, Konstantin Strauch16,17, Maciej Tomaszewski2,3, Emmanouil Tsafantakis40, Melanie Waldenberger27,28, Alexandra I F Blakemore21,41, George Dedoussis25, Stefan A Escher7, Jaspal S Kooner13,42,43, Mark I McCarthy11,34,44, Colin N A Palmer23, Anders Hamsten20, Mark J Caulfield1,9, Timothy M Frayling14, Martin D Tobin45, Marjo-Riitta Jarvelin19,32,46,47,48, Eleftheria Zeggini4, Christian Gieger27,28,29, John C Chambers12,13,42, Nick J Wareham8, Patricia B Munroe1,9, Paul W Franks7,49,50, Nilesh J Samani51,3, Panos Deloukas52,53.
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 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.Entities:
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Year: 2016 PMID： 27466198 PMCID： PMC5291227 DOI： 10.1093/hmg/ddw227
Source DB: PubMed Journal: Hum Mol Genet ISSN： 0964-6906 Impact factor: 6.150