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Title: Analysis with the exome array identifies multiple new independent variants in lipid loci.
Authors: Kanoni, S
Masca, NGD
Stirrups, KE
Varga, TV
Warren, HR
Scott, RA
Southam, L
Zhang, W
Yaghootkar, H
Müller-Nurasyid, M
Couto Alves, A
Strawbridge, RJ
Lataniotis, L
An Hashim, N
Besse, C
Boland, A
Braund, PS
Connell, JM
Dominiczak, A
Farmaki, A-E
Franks, S
Grallert, H
Jansson, J-H
Karaleftheri, M
Keinänen-Kiukaanniemi, S
Matchan, A
Pasko, D
Peters, A
Poulter, N
Rayner, NW
Renström, F
Rolandsson, O
Sabater-Lleal, M
Sennblad, B
Sever, P
Shields, D
Silveira, A
Stanton, AV
Strauch, K
Tomaszewski, M
Tsafantakis, E
Waldenberger, M
Blakemore, AIF
Dedoussis, G
Escher, SA
Kooner, JS
McCarthy, MI
Palmer, CNA
Wellcome Trust Case Control Consortium
Hamsten, A
Caulfield, MJ
Frayling, TM
Tobin, MD
Jarvelin, M-R
Zeggini, E
Gieger, C
Chambers, JC
Wareham, NJ
Munroe, PB
Franks, PW
Samani, NJ
Deloukas, P
First Published: 27-Jul-2016
Publisher: Oxford University Press (OUP)
Citation: Human Molecular Genetics, 2016, 25 (18), pp. 4094-4106
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.
DOI Link: 10.1093/hmg/ddw227
eISSN: 1460-2083
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2016, Oxford University Press (OUP). Deposited with reference to the publisher’s open access archiving policy. (
Description: Supplementary Material is available at HMG online.
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

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