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

TitleExome-wide association study of plasma lipids in >300,000 individuals.
Publication TypeJournal Article
Year of Publication2017
AuthorsLiu, 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 AuthorsCharge Diabetes Working Group, EPIC-InterAct Consortium, EPIC-CVD Consortium, GOLD Consortium, VA Million Veteran Program
JournalNat Genet
Date Published2017 Oct 30
ISSN1546-1718
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.

DOI10.1038/ng.3977
Alternate JournalNat. Genet.
PubMed ID29083408
Grant ListR01 DK106621 / DK / NIDDK NIH HHS / United States
R01 HL109946 / HL / NHLBI NIH HHS / United States
R01 HL122684 / HL / NHLBI NIH HHS / United States
R21 DA040177 / DA / NIDA NIH HHS / United States
R01 HL127564 / HL / NHLBI NIH HHS / United States
R01 HL117491 / 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
R01 DA037904 / DA / NIDA NIH HHS / United States
R01 DK107904 / DK / NIDDK NIH HHS / United States
R21 HL121422 / HL / NHLBI NIH HHS / United States