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Get Free AccessIt 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.
Stavroula Kanoni, Nicholas G. D. Masca, Kathleen Stirrups, Tibor V. Varga, Helen R. Warren, Robert A. Scott, Lorraine Southam, Weihua Zhang, Hanieh Yaghootkar, Martina Müller‐Nurasyid, Alexessander Couto Alves, Rona J. Strawbridge, Lazaros Lataniotis, Nikman An Hashim, Céline Besse, Anne Boland, Peter S. Braund, John Connell, Anna F. Dominiczak, Aliki‐Eleni Farmaki, Paul W. Franks, Harald Grallert, Jan‐Håkan Jansson, Maria Karaleftheri, Sirkka Keinänen‐Kiukaanniemi, Angela Matchan, Dorota Pasko, Annette Peters, Neil R Poulter, Nigel W. Rayner, Frida Renström, Olov Rolandsson, Maria Sabater‐Lleal, Bengt Sennblad, Peter Sever, Denis C. Shields, Angela Silveira, Alice Stanton, Konstantin Strauch, Maciej Tomaszewski, Emmanouil Tsafantakis, Mélanie Waldenberger, Alexandra I. F. Blakemore, George Dedoussis, Stefan Andersson Escher, Jaspal S. Kooner, Mark I. McCarthy, Nicholette D. Palmer, Anders Hamsten, Mark J. Caulfield, Timothy M. Frayling, Martin D. Tobin, Paul M Ridker, Eleftheria Zeggini, Christian Gieger, John C. Chambers, Nicholas J. Wareham, Patricia B. Munroe, Paul W. Franks, Nilesh J. Samani, Panos Deloukas (2016). Analysis with the exome array identifies multiple new independent variants in lipid loci. , 25(18), DOI: https://doi.org/10.1093/hmg/ddw227.
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Type
Article
Year
2016
Authors
61
Datasets
0
Total Files
0
Language
en
DOI
https://doi.org/10.1093/hmg/ddw227
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