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

Kanoni, S. et al. (2016) Analysis with the exome array identifies multiple new independent variants in lipid loci. Human Molecular Genetics, 25(18), pp. 4094-4106. (doi:10.1093/hmg/ddw227) (PMID:27466198) (PMCID:PMC5291227)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Dominiczak, Professor Anna and Strawbridge, Dr Rona
Authors: 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., An Hashim, N., Besse, C., Boland, A., Braund, P. S., Connell, J. M., 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, 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.F., Dedoussis, G., Escher, S. A., Kooner, J. S., McCarthy, M. I., Palmer, C. N.A., 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., and Deloukas, P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
Journal Name:Human Molecular Genetics
Publisher:Oxford University Press
ISSN:0964-6906
ISSN (Online):1460-2083
Published Online:27 July 2016
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
174241United Kingdom Collaborative Study to Identify the Major Genes Responsible for Human Essential Hypertension (BRIGHT)John ConnellMedical Research Council (MRC)G9521010SCHOOL OF MEDICINE, DENTISTRY & NURSING
348311The British genetics of hypertension study - application to enhance TDT and control recruitment for fine mapping genes for hypertensionAnna DominiczakBritish Heart Foundation (BHF)PG/02/128 MCPG1A9RRI CARDIOVASCULAR & MEDICAL SCIENCES