Exome-wide association study of plasma lipids in >300,000 individuals

Liu, D. J. et al. (2017) Exome-wide association study of plasma lipids in >300,000 individuals. Nature Genetics, 49, pp. 1758-1766. (doi:10.1038/ng.3977) (PMID:29083408)

Liu, D. J. et al. (2017) Exome-wide association study of plasma lipids in >300,000 individuals. Nature Genetics, 49, pp. 1758-1766. (doi:10.1038/ng.3977) (PMID:29083408)

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Abstract

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ford, Professor Ian and Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna and Young, Dr Robin and Sattar, Professor Naveed
Authors: Liu, D. J., Peloso, G. M., Yu, H., Butterworth, A. S., Wang, X., Mahajan, A., Saleheen, D., Emdin, C., Alam, D., Alves, A. C., Amouyel, P., Di Angelantonio, E., Arveiler, D., Assimes, T. L., Auer, P. L., Baber, U., Ballantyne, C. M., Bang, L. E., Benn, M., Bis, J. C., Boehnke, M., Boerwinkle, E., Bork-Jensen, J., Bottinger, E. P., Brandslund, I., Brown, M., Busonero, F., Caulfield, M. J., Chambers, J. C., Chasman, D. I., Chen, Y. E., Chen, Y.-D. I., Chowdhury, R., Christensen, C., Chu, A. Y., Connell, J. M., Cucca, F., Cupples, L. A., Damrauer, S. M., Davies, G., Deary, I. J., Dedoussis, G., Denny, J. C., Dominiczak, A., Dubé, M.-P., Ebeling, T., Eiriksdottir, G., Esko, T., Farmaki, A.-E., Feitosa, M. F., Ferrario, M., Ferrieres, J., Ford, I., Fornage, M., Franks, P. W., Frayling, T. M., Frikke-Schmidt, R., Fritsche, L. G., Frossard, P., Fuster, V., Ganesh, S. K., Gao, W., Garcia, M. E., Gieger, C., Giulianini, F., Goodarzi, M. O., Grallert, H., Grarup, N., Groop, L., Grove, M. L., Gudnason, V., Hansen, T., Harris, T. B., Hayward, C., Hirschhorn, J. N., Holmen, O. L., Huffman, J., Huo, Y., Hveem, K., Jabeen, S., Jackson, A. U., Jakobsdottir, J., Jarvelin, M.-R., Jensen, G. B., Jørgensen, M. E., Jukema, J. W., Justesen, J. M., Kamstrup, P. R., Kanoni, S., Karpe, F., Kee, F., Khera, A. V., Klarin, D., Koistinen, H. A., Kooner, J. S., Kooperberg, C., Kuulasmaa, K., Kuusisto, J., Laakso, M., Lakka, T., Langenberg, C., Langsted, A., Launer, L. J., Lauritzen, T., Liewald, D. C. M., Lin, L. A., Linneberg, A., Loos, R. J. F., Lu, Y., Lu, X., Mägi, R., Malarstig, A., Manichaikul, A., Manning, A. K., Mäntyselkä, P., Marouli, E., Masca, N. G. D., Maschio, A., Meigs, J. B., Melander, O., Metspalu, A., Morris, A. P., Morrison, A. C., Mulas, A., Müller-Nurasyid, M., Munroe, P. B., Neville, M. J., Nielsen, J. B., Nielsen, S. F., Nordestgaard, B. G., Ordovas, J. M., Mehran, R., O'Donnell, C. J., Orho-Melander, M., Molony, C. M., Muntendam, P., Padmanabhan, S., Palmer, C. N. A., Pasko, D., Patel, A. P.., Pedersen, O., Perola, M., Peters, A., Pisinger, C., Pistis, G., Polasek, O., Poulter, N., Psaty, B. M., Rader, D. J., Rasheed, A., Rauramaa, R., Reilly, D. F., Reiner, A. P., Renström, F., Rich, S. S., Ridker, P. M., Rioux, J. D., Robertson, N. R., Roden, D. M., Rotter, J. I., Rudan, I., Salomaa, V., Samani, N. J., Sanna, S., Sattar, N., Schmidt, E. M., Scott, R. A., Sever, P., Sevilla, R. S., Shaffer, C. M., Sim, X., Sivapalaratnam, S., Small, K. S., Smith, A. V., Smith, B. H., Somayajula, S., Southam, L., Spector, T. D., Speliotes, E. K., Starr, J. M., Stirrups, K. E., Stitziel, N., Strauch, K., Stringham, H. M., Surendran, P., Tada, H., Tall, A. R., Tang, H., Tardif, J.-C., Taylor, K. D., Trompet, S., Tsao, P. S., Tuomilehto, J., Tybjaerg-Hansen, A., van Zuydam, N. R., Varbo, A., Varga, T. V., Virtamo, J., Waldenberger, M., Wang, N., Wareham, N. J., Warren, H. R., Weeke, P. E., Weinstock, J., Wessel, J., Wilson, J. G., Wilson, P. W. F., Xu, M., Yaghootkar, H., Young, R., Zeggini, E., Zhang, H., Zheng, N. S., Zhang, W., Zhang, Y., Zhou, W., Zhou, Y., Zoledziewska, M., Howson, J. M. M., Danesh, J., McCarthy, M. I., Cowan, C. A., Abecasis, G., Deloukas, P., Musunuru, K., Willer, C. J., and Kathiresan, S.
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 > Robertson Centre
Journal Name:Nature Genetics
Publisher:Nature Publishing Group
ISSN:1061-4036
ISSN (Online):1546-1718
Published Online:30 October 2017
Copyright Holders:Copyright © 2017 Nature Publications
First Published:First published in Nature Genetics 49:1758–1766
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
690421Glasgow Molecular Pathology (GMP) NodeKarin OienMedical Research Council (MRC)MR/N005813/1ICS - EXPERIMENTAL THERAPEUTICS