| Title | Exome-wide association study of plasma lipids in >300,000 individuals. |
| Publication Type | Journal Article |
| Year of Publication | 2017 |
| Authors | Liu, DJ, Peloso, GM, Yu, H, Butterworth, AS, Wang, X, Mahajan, A, Saleheen, D, Emdin, C, Alam, D, Alves, ACouto, 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, Y Chen, E, Chen, Y-DIda, Chowdhury, iv, R, Christensen, C, Chu, AY, Connell, JM, Cucca, F, L Cupples, A, Damrauer, SM, Davies, G, Deary, IJ, Dedoussis, G, Denny, JC, Dominiczak, A, Dube, 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, J Jukema, W, 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, Langenberg, C, Langsted, A, Launer, LJ, Lauritzen, T, Liewald, DCM, Lin, LAn, Linneberg, A, Loos, RJF, Lu, Y, Lu, X, Mägi, R, Mälarstig, A, Manichaikul, A, Manning, AK, Mäntyselkä, P, Marouli, E, Masca, NGD, Maschio, A, Meigs, JB, Melander, O, Metspalu, A, Morris, AP, Morrison, AC, Mulas, A, Müller-Nurasyid, M, Munroe, PB, Neville, MJ, Nielsen, JB, Nielsen, SF, Nordestgaard, BG, Ordovas, JM, Mehran, R, O'Donnell, CJ, Orho-Melander, M, Molony, CM, Muntendam, P, Padmanabhan, S, Palmer, CNA, Pasko, D, Patel, AP, Pedersen, O, Perola, M, Peters, A, Pisinger, C, Pistis, G, Polasek, O, Poulter, N, Psaty, BM, Rader, DJ, Rasheed, A, Rauramaa, R, Reilly, DF, Reiner, AP, Renstrom, F, Rich, SS, Ridker, PM, Rioux, JD, Robertson, NR, Roden, DM, Rotter, JI, Rudan, I, Salomaa, V, Samani, NJ, Sanna, S, Sattar, N, Schmidt, EM, Scott, RA, Sever, P, Sevilla, RS, Shaffer, CM, Sim, X, Sivapalaratnam, S, Small, KS, Smith, AV, Smith, BH, Somayajula, S, Southam, L, Spector, TD, Speliotes, EK, Starr, JM, Stirrups, KE, Stitziel, N, Strauch, K, Stringham, HM, Surendran, P, Tada, H, Tall, AR, Tang, H, Tardif, J-C, Taylor, KD, Trompet, S, Tsao, PS, Tuomilehto, J, Tybjaerg-Hansen, A, Van Zuydam, NR, Varbo, A, Varga, TV, Virtamo, J, Waldenberger, M, Wang, N, Wareham, NJ, Warren, HR, Weeke, PE, Weinstock, J, Wessel, J, Wilson, JG, Wilson, PWF, Xu, M, Yaghootkar, H, Young, R, Zeggini, E, Zhang, H, Zheng, NS, Zhang, W, Zhang, Y, Zhou, W, Zhou, Y, Zoledziewska, M, Howson, JMM, Danesh, J, McCarthy, MI, Cowan, CA, Abecasis, G, Deloukas, P, Musunuru, K, Willer, CJ, Kathiresan, S |
| Corporate Authors | Charge Diabetes Working Group, EPIC-InterAct Consortium, EPIC-CVD Consortium, GOLD Consortium, VA Million Veteran Program |
| Journal | Nat Genet |
| Volume | 49 |
| Issue | 12 |
| Pagination | 1758-1766 |
| Date Published | 2017 Dec |
| ISSN | 1546-1718 |
| Keywords | Coronary Artery Disease, Diabetes Mellitus, Type 2, Exome, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Lipids, Macular Degeneration, Phenotype, Risk Factors |
| 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. |
| DOI | 10.1038/ng.3977 |
| Alternate Journal | Nat Genet |
| PubMed ID | 29083408 |
| PubMed Central ID | PMC5709146 |
| Grant List | KL2 TR001100 / TR / NCATS NIH HHS / United States R01 HL117491 / HL / NHLBI NIH HHS / United States S10 OD018522 / OD / NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States U01 DK062370 / DK / NIDDK NIH HHS / United States MR/P02811X/1 / MRC_ / Medical Research Council / United Kingdom R21 HL121422 / HL / NHLBI NIH HHS / United States R01 DK106621 / DK / NIDDK NIH HHS / United States R01 HL120393 / HL / NHLBI NIH HHS / United States R01 HL109946 / HL / NHLBI NIH HHS / United States MR/L003120/1 / MRC_ / Medical Research Council / United Kingdom RG/13/13/30194 / BHF_ / British Heart Foundation / United Kingdom R01 HL122684 / HL / NHLBI NIH HHS / United States MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom R21 DA040177 / DA / NIDA NIH HHS / United States U01 HL120393 / HL / NHLBI NIH HHS / United States MC_EX_MR/M009203/1 / MRC_ / Medical Research Council / United Kingdom MR/K006584/1 / MRC_ / Medical Research Council / United Kingdom R01 HL118567 / HL / NHLBI NIH HHS / United States T32 HG000040 / HG / NHGRI NIH HHS / United States R01 HL127564 / HL / NHLBI NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States R01 HL129778 / HL / NHLBI NIH HHS / United States K99 HL094535 / HL / NHLBI NIH HHS / United States K01 HL125751 / HL / NHLBI NIH HHS / United States R01 HG008983 / HG / NHGRI NIH HHS / United States MR/N005813/1 / MRC_ / Medical Research Council / United Kingdom G0600237 / MRC_ / Medical Research Council / United Kingdom K24 DK080140 / DK / NIDDK NIH HHS / United States RG/08/014/24067 / BHF_ / British Heart Foundation / United Kingdom RG/14/5/30893 / BHF_ / British Heart Foundation / United Kingdom MC_PC_U127561128 / MRC_ / Medical Research Council / United Kingdom R00 HL094535 / HL / NHLBI NIH HHS / United States P30 DK020541 / DK / NIDDK NIH HHS / United States G9521010 / MRC_ / Medical Research Council / United Kingdom UM1 CA182913 / CA / NCI NIH HHS / United States MR/M009203/1 / MRC_ / Medical Research Council / United Kingdom U01 DK078616 / DK / NIDDK NIH HHS / United States R01 DA037904 / DA / NIDA NIH HHS / United States G0601261 / MRC_ / Medical Research Council / United Kingdom R01 DK107904 / DK / NIDDK NIH HHS / United States P30 DK020572 / DK / NIDDK NIH HHS / United States S10 OD020069 / OD / NIH HHS / United States / WT_ / Wellcome Trust / United Kingdom RG/16/4/32218 / BHF_ / British Heart Foundation / United Kingdom UL1 TR001881 / TR / NCATS NIH HHS / United States MR/P013880/1 / MRC_ / Medical Research Council / United Kingdom U54 GM115428 / GM / NIGMS NIH HHS / United States CH/12/2/29428 / BHF_ / British Heart Foundation / United Kingdom MC_PC_14089 / MRC_ / Medical Research Council / United Kingdom MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom |
Exome-wide association study of plasma lipids in >300,000 individuals.
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