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

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.; Angelantonio, E.D.; 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.; MLiewald, D.C.; 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, S.F.; Nielsen, J.B.; 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.; Zuydam, N.R.V.; 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, Hanieh; 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.; Kathiresan, S.

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

journal contribution

posted on 2024-07-25, 15:48 authored by D.J. Liu, G.M. Peloso, H. Yu, A.S. Butterworth, X. Wang, A. Mahajan, D. Saleheen, C. Emdin, D. Alam, A.C. Alves, P. Amouyel, E.D. Angelantonio, D. Arveiler, T.L. Assimes, P.L. Auer, U. Baber, C.M. Ballantyne, L.E. Bang, M. Benn, J.C. Bis, M. Boehnke, E. Boerwinkle, J. Bork-Jensen, E.P. Bottinger, I. Brandslund, M. Brown, F. Busonero, M.J. Caulfield, J.C. Chambers, D.I. Chasman, Y.E. Chen, Y.-D.I. Chen, R. Chowdhury, C. Christensen, A.Y. Chu, J.M. Connell, F. Cucca, L.A. Cupples, S.M. Damrauer, G. Davies, I.J. Deary, G. Dedoussis, J.C. Denny, A. Dominiczak, M.-P. Dubé, T. Ebeling, G. Eiriksdottir, T. Esko, A.-E. Farmaki, M.F. Feitosa, M. Ferrario, J. Ferrieres, I. Ford, M. Fornage, P.W. Franks, T.M. Frayling, R. Frikke-Schmidt, L.G. Fritsche, P. Frossard, V. Fuster, S.K. Ganesh, W. Gao, M.E. Garcia, C. Gieger, F. Giulianini, M.O. Goodarzi, H. Grallert, N. Grarup, L. Groop, M.L. Grove, V. Gudnason, T. Hansen, T.B. Harris, C. Hayward, J.N. Hirschhorn, O.L. Holmen, J. Huffman, Y. Huo, K. Hveem, S. Jabeen, A.U. Jackson, J. Jakobsdottir, M.-R. Jarvelin, G.B. Jensen, M.E. Jørgensen, J.W. Jukema, J.M. Justesen, P.R. Kamstrup, S. Kanoni, F. Karpe, F. Kee, A.V. Khera, D. Klarin, H.A. Koistinen, J.S. Kooner, C. Kooperberg, K. Kuulasmaa, J. Kuusisto, M. Laakso, T. Lakka, C. Langenberg, A. Langsted, L.J. Launer, T. Lauritzen, D.C. MLiewald, L.A. Lin, A. Linneberg, R.J.F. Loos, Y. Lu, X. Lu, R. Mägi, A. Malarstig, A. Manichaikul, A.K. Manning, P. Mäntyselkä, E. Marouli, N.G.D. Masca, A. Maschio, J.B. Meigs, O. Melander, A. Metspalu, A.P. Morris, A.C. Morrison, A. Mulas, M. Müller-Nurasyid, P.B. Munroe, M.J. Neville, S.F. Nielsen, J.B. Nielsen, B.G. Nordestgaard, J.M. Ordovas, R. Mehran, C.J. O'Donnell, M. Orho-Melander, C.M. Molony, P. Muntendam, S. Padmanabhan, C.N.A. Palmer, D. Pasko, A.P. Patel, O. Pedersen, M. Perola, A. Peters, C. Pisinger, G. Pistis, O. Polasek, N. Poulter, B.M. Psaty, D.J. Rader, A. Rasheed, R. Rauramaa, D.F. Reilly, A.P. Reiner, F. Renström, S.S. Rich, P.M. Ridker, J.D. Rioux, N.R. Robertson, D.M. Roden, J.I. Rotter, I. Rudan, V. Salomaa, N.J. Samani, S. Sanna, N. Sattar, E.M. Schmidt, R.A. Scott, P. Sever, R.S. Sevilla, C.M. Shaffer, X. Sim, S. Sivapalaratnam, K.S. Small, A.V. Smith, B.H. Smith, S. Somayajula, L. Southam, T.D. Spector, E.K. Speliotes, J.M. Starr, K.E. Stirrups, N. Stitziel, K. Strauch, H.M. Stringham, P. Surendran, H. Tada, A.R. Tall, H. Tang, J.-C. Tardif, K.D. Taylor, S. Trompet, P.S. Tsao, J. Tuomilehto, A. Tybjaerg-Hansen, N.R.V. Zuydam, A. Varbo, T.V. Varga, J. Virtamo, M. Waldenberger, N. Wang, N.J. Wareham, H.R. Warren, P.E. Weeke, J. Weinstock, J. Wessel, J.G. Wilson, P.W.F. Wilson, M. Xu, Hanieh YaghootkarHanieh Yaghootkar, R. Young, E. Zeggini, H. Zhang, N.S. Zheng, W. Zhang, Y. Zhang, W. Zhou, Y. Zhou, M. Zoledziewska, J.M.M. Howson, J. Danesh, M.I. McCarthy, C.A. Cowan, G. Abecasis, P. Deloukas, K. Musunuru, C.J. Willer, S. Kathiresan

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-densitylipoprotein 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 TGrich 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.

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School affiliated with

School of Chemistry (Research Outputs)

Publication Title

Nature Genetics

Volume

49

Issue

12

Pages/Article Number

1758-1766

Publisher

Nature Publishing Group

External DOI

https://www.doi.org/10.1038/ng.3977

ISSN

10614036

Date Accepted

2017-09-26

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

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