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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.* ; Farmaki, A.-E.* ; Franks, S.* ; Grallert, H. ; Jansson, J.H.* ; Karaleftheri, M.* ; Keinanen-Kiukaanniemi, S.* ; Matchan, A.* ; Pasko, D.* ; Peters, A. ; Poulter, N.* ; Rayner, N.W.* ; Renström, F.* ; Rolandsson, O.* ; Sabater-Lleal, M.* ; Sennblad, B.* ; Sever, P.* ; Shields, D.* ; Silveira, A.* ; Stanton, A.V.* ; Strauch, K. ; Tomaszewski, M.* ; Tsafantakis, E.* ; Waldenberger, M. ; Blakemore, A.I.* ; Dedoussis, G.* ; Escher, S.A.* ; Kooner, J.S.* ; McCarthy, M.I.* ; Palmer, C.N.* ; Hamsten, A.* ; Caulfield, M.J.* ; Frayling, T.M.* ; Tobin, M.D.* ; Jarvelin, M.R.* ; Zeggini, E.* ; Gieger, C. ; Chambers, J.C.* ; Wareham, N.J.* ; Munroe, P.B.* ; Franks, P.W.* ; Samani, N.J.* ; Deloukas, P.*

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

Hum. Mol. Genet. 25, 4094-4106 (2016)
Publ. Version/Full Text Postprint DOI PMC
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Genome-wide Association; Coronary-artery-disease; Low-frequency; Ldl-cholesterol; Blood-lipids; Rare; Heritability; Metaanalysis; Transporter; Traits
Language
Publication Year 2016
HGF-reported in Year 2016
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Journal Human Molecular Genetics
Quellenangaben Volume: 25, Issue: 18, Pages: 4094-4106 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Oxford
Reviewing status Peer reviewed
Institute(s) Institute of Genetic Epidemiology (IGE)
Institute of Epidemiology (EPI)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30202 - Environmental Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-504100-001
G-504091-001
G-504091-002
G-504000-001
G-504091-004
DOI 10.1093/hmg/ddw227
WOS ID WOS:000395806000016
Scopus ID 85014345453
PubMed ID 27466198
Erfassungsdatum 2016-08-02
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