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

Stavroula Kanoni, Nicholas G. D. Masca, Kathleen E. 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 M. Connell, Anna Dominiczak, Aliki-Eleni FarmakiStephen Franks, Harald Grallert, Jan-Håkan Jansson, Maria Karaleftheri, Sirkka Keinänen-Kiukaanniemi, Angela Matchan, Dorota Pasko, Annette Peters, Neil Poulter, Nigel W. Rayner, Frida Renström, Olov Rolandsson, Maria Sabater-Lleal, Bengt Sennblad, Peter Sever, Denis Shields, Angela Silveira, Alice V. Stanton, Konstantin Strauch, Maciej Tomaszewski, Emmanouil Tsafantakis, Melanie Waldenberger, Alexandra I. F. Blakemore, George Dedoussis, Stefan A. Escher, Jaspal S. Kooner, Mark I. McCarthy, Colin N. A. Palmer, Wellcome Trust Case Control Consortium, Anders Hamsten, Mark J. Caulfield

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Abstract

It has been hypothesised that low frequency (1-5% 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 (6 had MAF < 5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1-5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5-2.5 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.

Original languageEnglish
Pages (from-to)4094-4106
Number of pages13
JournalHuman Molecular Genetics
Volume25
Issue number18
Early online date27 Jul 2016
DOIs
Publication statusPublished - 27 Jul 2016

Keywords

  • ldl cholesterol lipoproteins
  • high density lipoprotein cholesterol
  • genome
  • single nucleotide polymorphism
  • genetics
  • lipids
  • exome

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    Kanoni, S., Masca, N. G. D., Stirrups, K. E., Varga, T. V., Warren, H. R., Scott, R. A., Southam, L., Zhang, W., Yaghootkar, H., Müller-Nurasyid, M., Couto Alves, A., Strawbridge, R. J., Lataniotis, L., Hashim, N. A., Besse, C., Boland, A., Braund, P. S., Connell, J. M., Dominiczak, A., ... Caulfield, M. J. (2016). Analysis with the exome array identifies multiple new independent variants in lipid loci. Human Molecular Genetics, 25(18), 4094-4106. https://doi.org/10.1093/hmg/ddw227