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Kanoni, Stavroula; Masca, Nicholas G. D.; Stirrups, Kathleen E.; Varga, Tibor V.; Warren, Helen R.; Scott, Robert A.; Southam, Lorraine; Zhang, Weihua; Yaghootkar, Hanieh; Müller-Nurasyid, Martina; Alves, Alexessander Couto; Strawbridge, Rona J.; Lataniotis, Lazaros; Hashim, Nikman An; Besse, Céline; Boland, Anne; Braund, Peter S.; Connell, John M.; Dominiczak, Anna; Farmaki, Aliki-Eleni; Franks, Stephen; Grallert, Harald; Jansson, Jan-Håkan; Karaleftheri, Maria; Keinänen-Kiukaanniemi, Sirkka; Matchan, Angela; Pasko, Dorota; Peters, Annette; Poulter, Neil; Rayner, Nigel W.; Renström, Frida; Rolandsson, Olov; Sabater-Lleal, Maria; Sennblad, Bengt; Sever, Peter; Shields, Denis; Silveira, Angela; Stanton, Alice V.; Strauch, Konstantin; Tomaszewski, Maciej; Tsafantakis, Emmanouil; Waldenberger, Melanie; Blakemore, Alexandra I. F.; Dedoussis, George; Escher, Stefan A.; Kooner, Jaspal S.; McCarthy, Mark I.; Palmer, Colin N. A.; Hamsten, Anders; Caulfield, Mark J.; Frayling, Timothy M.; Tobin, Martin D.; Jarvelin, Marjo-Riitta; Zeggini, Eleftheria; Gieger, Christian; Chambers, John C.; Wareham, Nick J.; Munroe, Patricia B.; Franks, Paul W.; Samani, Nilesh J.; Deloukas, Panos (2016): Analysis with the exome array identifies multiple new independent variants in lipid loci. In: Human Molecular Genetics, Vol. 25, No. 18: pp. 4094-4106
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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.

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