Kanoni Analysis with the exome array identifies multiple new independent variants in lipid loci 2016 Accepted.pdf (235.33 kB)
Analysis with the exome array identifies multiple new independent variants in lipid loci.
journal contribution
posted on 2019-06-12, 08:59 authored by S Kanoni, NGD Masca, KE Stirrups, TV Varga, HR Warren, RA Scott, L Southam, W Zhang, H Yaghootkar, M Müller-Nurasyid, A Couto Alves, RJ Strawbridge, L Lataniotis, N An Hashim, C Besse, A Boland, PS Braund, JM Connell, A Dominiczak, A-E Farmaki, S Franks, H Grallert, J-H Jansson, M Karaleftheri, S Keinänen-Kiukaanniemi, A Matchan, D Pasko, A Peters, N Poulter, NW Rayner, F Renström, O Rolandsson, M Sabater-Lleal, B Sennblad, P Sever, D Shields, A Silveira, AV Stanton, K Strauch, M Tomaszewski, E Tsafantakis, M Waldenberger, AIF Blakemore, G Dedoussis, SA Escher, JS Kooner, MI McCarthy, CNA Palmer, Wellcome Trust Case Control Consortium, A Hamsten, MJ Caulfield, TM Frayling, MD Tobin, M-R Jarvelin, E Zeggini, C Gieger, JC Chambers, NJ Wareham, PB Munroe, PW Franks, NJ Samani, P DeloukasIt 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.
Funding
1958BC was funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. This work forms part of the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Unit which is supported and funded by the National Institute for Health Research. PD is supported by British Heart Foundation grant RG/14/5/30893. ASCOT was supported by Pfizer, New York, NY, USA, Servier Research Group, Paris, France and by Leo Laboratories, Copenhagen, Denmark. BRIGHT was supported by the Medical Research Council of Great Britain (grant number G9521010D), the British Heart Foundation (grant number PG/02/128) and the Wellcome Trust Strategic Awards 083948A and 085475. AFD was supported by the British Heart Foundation (grant numbers RG/07/005/23633, SP/08/005/25115); and by the European Union Ingenious HyperCare Consortium: Integrated Genomics, Clinical Research, and Care in Hypertension (grant number LSHM-C7-2006-037093). DIABNORD was funded by Novo Nordisk, the Swedish Research Council, Påhlssons Foundation, the Swedish Heart Lung Foundation, and the Skåne Regional Health Authority (all to PWF). The EFSOCH study was supported by South West NHS Research and Development, Exeter NHS Research and Development, the Darlington Trust, and the Peninsula NIHR Clinical Research Facility at the University of Exeter. Timothy Frayling is supported by the European Research Council grant: SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC. EPIC and EPIC-Norfolk is supported by the Medical Research Council programme grants (G0401527, G1000143) and Cancer Research UK programme grant (C864/A8257). The Fenland Study is funded by the Medical Research Council (MC_U106179471). FIA3 was supported in part by a grant from the Swedish Heart-Lung Foundation (grant no. 2020389 to PW Franks). GLACIER was funded by Novo Nordisk, the Swedish Research Council, Påhlssons Foundation, the Swedish Heart Lung Foundation, and the Skåne Regional Heal
History
Citation
Human Molecular Genetics, 2016, 25 (18), pp. 4094-4106Author affiliation
/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular SciencesVersion
- AM (Accepted Manuscript)
Published in
Human Molecular GeneticsPublisher
Oxford University Press (OUP)eissn
1460-2083Acceptance date
2016-07-08Copyright date
2016Available date
2019-06-12Publisher DOI
Publisher version
https://academic.oup.com/hmg/article/25/18/4094/2525839Notes
Supplementary Material is available at HMG online.Language
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