Exome-wide association study of plasma lipids in >300,000 individuals.
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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.
AuthorsLiu, DJ; Peloso, GM; Yu, H; Butterworth, AS; Wang, X; Mahajan, A; Saleheen, D; Emdin, C; Alam, D; Alves, AC; Amouyel, P; Di Angelantonio, E; Arveiler, D; Assimes, TL; Auer, PL; Baber, U; Ballantyne, CM; Bang, LE; Benn, M; Bis, JC; Boehnke, M; Boerwinkle, E; Bork-Jensen, J; Bottinger, EP; Brandslund, I; Brown, M; Busonero, F; Caulfield, MJ; Chambers, JC; Chasman, DI; Chen, YE; Chen, Y-DI; Chowdhury, R; Christensen, C; Chu, AY; Connell, JM; Cucca, F; Cupples, LA; Damrauer, SM; Davies, G; Deary, IJ; Dedoussis, G; Denny, JC; Dominiczak, A; Dubé, M-P; Ebeling, T; Eiriksdottir, G; Esko, T; Farmaki, A-E; Feitosa, MF; Ferrario, M; Ferrieres, J; Ford, I; Fornage, M; Franks, PW; Frayling, TM; Frikke-Schmidt, R; Fritsche, LG; Frossard, P; Fuster, V; Ganesh, SK; Gao, W; Garcia, ME; Gieger, C; Giulianini, F; Goodarzi, MO; Grallert, H; Grarup, N; Groop, L; Grove, ML; Gudnason, V; Hansen, T; Harris, TB; Hayward, C; Hirschhorn, JN; Holmen, OL; Huffman, J; Huo, Y; Hveem, K; Jabeen, S; Jackson, AU; Jakobsdottir, J; Jarvelin, M-R; Jensen, GB; Jørgensen, ME; Jukema, JW; Justesen, JM; Kamstrup, PR; Kanoni, S; Karpe, F; Kee, F; Khera, AV; Klarin, D; Koistinen, HA; Kooner, JS; Kooperberg, C; Kuulasmaa, K; Kuusisto, J; Laakso, M; Lakka, T; et al.
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