TY - JOUR
T1 - Analysis with the exome array identifies multiple new independent variants in lipid loci
AU - Wellcome Trust Case Control Consortium
AU - Kanoni, Stavroula
AU - Masca, Nicholas G.D.
AU - Stirrups, Kathleen E.
AU - Varga, Tibor V.
AU - Warren, Helen R.
AU - Scott, Robert A.
AU - Southam, Lorraine
AU - Zhang, Weihua
AU - Yaghootkar, Hanieh
AU - Müller-Nurasyid, Martina
AU - Alves, Alexessander Couto
AU - Strawbridge, Rona J.
AU - Lataniotis, Lazaros
AU - Hashim, Nikman An
AU - Besse, Céline
AU - Boland, Anne
AU - Braund, Peter S.
AU - Connell, John M.
AU - Dominiczak, Anna
AU - Farmaki, Aliki Eleni
AU - Franks, Stephen
AU - Grallert, Harald
AU - Jansson, Jan Håkan
AU - Karaleftheri, Maria
AU - Keinänen-Kiukaanniemi, Sirkka
AU - Matchan, Angela
AU - Pasko, Dorota
AU - Peters, Annette
AU - Poulter, Neil
AU - Rayner, Nigel W.
AU - Renström, Frida
AU - Rolandsson, Olov
AU - Sabater-Lleal, Maria
AU - Sennblad, Bengt
AU - Sever, Peter
AU - Shields, Denis
AU - Silveira, Angela
AU - Stanton, Alice V.
AU - Strauch, Konstantin
AU - Tomaszewski, Maciej
AU - Tsafantakis, Emmanouil
AU - Waldenberger, Melanie
AU - Blakemore, Alexandra I.F.
AU - Dedoussis, George
AU - Escher, Stefan A.
AU - Kooner, Jaspal S.
AU - McCarthy, Mark I.
AU - Palmer, Colin N.A.
AU - Hamsten, Anders
AU - Zeggini, Eleftheria
N1 - Publisher Copyright:
© The Author 2016. Published by Oxford University Press. All rights reserved.
PY - 2016/9/15
Y1 - 2016/9/15
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85014345453
U2 - 10.1093/hmg/ddw227
DO - 10.1093/hmg/ddw227
M3 - Article
C2 - 27466198
AN - SCOPUS:85014345453
SN - 0964-6906
VL - 25
SP - 4094
EP - 4106
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 18
ER -