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 > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Health & 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 |
| Related URLs: |
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