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

Dajiang J. Liu, Gina M. Peloso, Haojie Yu, Adam S. Butterworth, Xiao-Yu Wang, Anubha Mahajan, Danish Saleheen, Connor Emdin, Dewan S. Alam, Alexessander Couto Alves, Philippe Amouyel, Emanuele Di Angelantonio, Dominique Arveiler, Themistocles L. Assimes, Paul L. Auer, Usman Baber, Christie M. Ballantyne, Lia E. Bang, Marianne Benn, Joshua C. BisMichael Boehnke, Eric Boerwinkle, Jette Bork-Jensen, Erwin P. Bottinger, Ivan Brandslund, Morris J. Brown, Fabio Busonero, Mark J. Caulfield, John C. Chambers, Daniel I. Chasman, Y Eugene Chen, Yii-Der Ida Chen, Rajiv Chowdhury, Cramer Christensen, Audrey Y. Chu, John M. Connell, Francesco Cucca, L. Adrienne Cupples, Scott M Damrauer, Gail Davies, Ian J. Deary, George Dedoussis, Joshua C. Denny, Anna F. Dominiczak, Marie Pierre Dubé, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Colin N. A. Palmer, Blair H. Smith, Charge Diabetes Working Group, The EPIC-InterAct Consortium, EPIC-CVD Consortium, GOLD Consortium, VA Million Veteran Program

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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.

Original languageEnglish
Pages (from-to)1758-1766
Number of pages9
JournalNature Genetics
Volume49
Issue number12
Early online date30 Oct 2017
DOIs
Publication statusPublished - 30 Oct 2017

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    Liu, D. J., Peloso, G. M., Yu, H., Butterworth, A. S., Wang, X-Y., Mahajan, A., Saleheen, D., Emdin, C., Alam, D. S., 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., ... Charge Diabetes Working Group, The EPIC-InterAct Consortium, EPIC-CVD Consortium, GOLD Consortium, VA Million Veteran Program (2017). Exome-wide association study of plasma lipids in >300,000 individuals. Nature Genetics, 49(12), 1758-1766. https://doi.org/10.1038/ng.3977