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

Dajiang J. Liu; Gina M. Peloso; Haojie Yu; Adam S. Butterworth; Xiao Wang; Anubha Mahajan; Danish Saleheen; Connor Emdin; Dewan 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. Bis; Michael Boehnke; Eric Boerwinkle; Jette Bork-Jensen; Erwin P. Bottinger; Ivan Brandslund; Morris 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 Dominiczak; Marie Pierre Dubé; Tapani Ebeling; Gudny Eiriksdottir; Toñu Esko; Aliki Eleni Farmaki; Mary F. Feitosa; Marco Ferrario; Jean Ferrieres; Ian Ford; Myriam Fornage; Paul W. Franks; Timothy M. Frayling; Ruth Frikke-Schmidt; Lars G. Fritsche; Philippe Frossard; Valentin Fuster; Santhi K. Ganesh; Wei Gao; Melissa E. Garcia; Christian Gieger; Franco Giulianini; Mark O. Goodarzi; Harald Grallert; Niels Grarup; Leif Groop; Megan L. Grove; Vilmundur Gudnason; Torben Hansen; Tamara B. Harris; Caroline Hayward; Joel N. Hirschhorn; Oddgeir L. Holmen; Jennifer Huffman; Yong Huo; Kristian Hveem; Sehrish Jabeen; Anne U. Jackson; Johanna Jakobsdottir; Marjo Riitta Jarvelin; Gorm B. Jensen; Marit E. Jørgensen; J. Wouter Jukema; Johanne M. Justesen; Pia R. Kamstrup; Stavroula Kanoni; Fredrik Karpe; Frank Kee; Amit V. Khera; Derek Klarin; Heikki A. Koistinen; Jaspal S. Kooner; Charles Kooperberg; Kari Kuulasmaa; Johanna Kuusisto; Markku Laakso; Timo Lakka; Claudia Langenberg; Anne Langsted; Lenore J. Launer; Torsten Lauritzen; David C. MLiewald; Li An Lin; Allan Linneberg; Ruth J.F. Loos; Yingchang Lu; Xiangfeng Lu; Reedik Mägi; Anders Malarstig; Ani Manichaikul; Alisa K. Manning; Pekka Mäntyselkä; Eirini Marouli; Nicholas G.D. Masca; Andrea Maschio; James B. Meigs; Olle Melander; Andres Metspalu; Andrew P. Morris; Alanna C. Morrison; Antonella Mulas; Martina Müller-Nurasyid; Patricia B. Munroe; Matt J. Neville; Sune F. Nielsen; Jonas B. Nielsen; Børge G. Nordestgaard; Jose M. Ordovas; Roxana Mehran; Christoper J. O'Donnell; Marju Orho-Melander; Cliona M. Molony; Pieter Muntendam; Sandosh Padmanabhan; Colin N.A. Palmer; Dorota Pasko; Aniruddh P. Patel; Oluf Pedersen; Markus Perola; Annette Peters; Charlotta Pisinger; Giorgio Pistis; Ozren Polasek; Neil Poulter; Bruce M. Psaty; Daniel J. Rader; Asif Rasheed; Rainer Rauramaa; Dermot F. Reilly; Alex P. Reiner; Frida Renström; Stephen S. Rich; Paul M. Ridker; John D. Rioux; Neil R. Robertson; Dan M. Roden; Jerome I. Rotter; Igor Rudan; Veikko Salomaa; Nilesh J. Samani; Serena Sanna; Naveed Sattar; Ellen M. Schmidt; Robert A. Scott; Peter Sever; Raquel S. Sevilla; Christian M. Shaffer; Xueling Sim; Suthesh Sivapalaratnam; Kerrin S. Small; Albert V. Smith; Blair H. Smith; Sangeetha Somayajula; Lorraine Southam; Timothy D. Spector; Elizabeth K. Speliotes; John M. Starr; Kathleen E. Stirrups; Nathan Stitziel; Konstantin Strauch; Heather M. Stringham; Praveen Surendran; Hayato Tada; Alan R. Tall; Hua Tang; Jean Claude Tardif; Kent D. Taylor; Stella Trompet; Philip S. Tsao; Jaakko Tuomilehto; Anne Tybjaerg-Hansen; Natalie R.Van Zuydam; Anette Varbo; Tibor V. Varga; Jarmo Virtamo; Melanie Waldenberger; Nan Wang; Nick J. Wareham; Helen R. Warren; Peter E. Weeke; Joshua Weinstock; Jennifer Wessel; James G. Wilson; Peter W.F. Wilson; Ming Xu; Hanieh Yaghootkar; Robin Young; Eleftheria Zeggini; He Zhang; Neil S. Zheng; Weihua Zhang; Yan Zhang; Wei Zhou; Yanhua Zhou; Magdalena Zoledziewska; Joanna M.M. Howson; John Danesh; Mark I. McCarthy; Chad A. Cowan; Goncalo Abecasis; Panos Deloukas; Kiran Musunuru; Cristen J. Willer; Sekar Kathiresan

doi:10.1038/ng.3977

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

Dajiang J. Liu, Gina M. Peloso, Haojie Yu, Adam S. Butterworth, Xiao Wang, Anubha Mahajan, Danish Saleheen, Connor Emdin, Dewan 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 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 Dominiczak, Marie Pierre Dubé, Tapani Ebeling, Gudny Eiriksdottir, Toñu Esko, Aliki Eleni Farmaki, Mary F. Feitosa, Marco Ferrario, Jean Ferrieres, Ian Ford, Myriam Fornage, Paul W. Franks, Timothy M. Frayling, Ruth Frikke-Schmidt, Lars G. Fritsche, Philippe Frossard, Valentin Fuster, Santhi K. Ganesh, Wei Gao, Melissa E. Garcia, Christian Gieger, Franco Giulianini, Mark O. Goodarzi, Harald Grallert, Niels Grarup, Leif Groop, Megan L. Grove, Vilmundur Gudnason, Torben Hansen, Tamara B. Harris, Caroline Hayward, Joel N. Hirschhorn, Oddgeir L. Holmen, Jennifer Huffman, Yong Huo, Kristian Hveem, Sehrish Jabeen, Anne U. Jackson, Johanna Jakobsdottir, Marjo Riitta Jarvelin, Gorm B. Jensen, Marit E. Jørgensen, J. Wouter Jukema, Johanne M. Justesen, Pia R. Kamstrup, Stavroula Kanoni, Fredrik Karpe, Frank Kee, Amit V. Khera, Derek Klarin, Heikki A. Koistinen, Jaspal S. Kooner, Charles Kooperberg, Kari Kuulasmaa, Johanna Kuusisto, Markku Laakso, Timo Lakka, Claudia Langenberg, Anne Langsted, Lenore J. Launer, Torsten Lauritzen, David C. MLiewald, Li An Lin, Allan Linneberg, Ruth J.F. Loos, Yingchang Lu, Xiangfeng Lu, Reedik Mägi, Anders Malarstig, Ani Manichaikul, Alisa K. Manning, Pekka Mäntyselkä, Eirini Marouli, Nicholas G.D. Masca, Andrea Maschio, James B. Meigs, Olle Melander, Andres Metspalu, Andrew P. Morris, Alanna C. Morrison, Antonella Mulas, Martina Müller-Nurasyid, Patricia B. Munroe, Matt J. Neville, Sune F. Nielsen, Jonas B. Nielsen, Børge G. Nordestgaard, Jose M. Ordovas, Roxana Mehran, Christoper J. O'Donnell, Marju Orho-Melander, Cliona M. Molony, Pieter Muntendam, Sandosh Padmanabhan, Colin N.A. Palmer, Dorota Pasko, Aniruddh P. Patel, Oluf Pedersen, Markus Perola, Annette Peters, Charlotta Pisinger, Giorgio Pistis, Ozren Polasek, Neil Poulter, Bruce M. Psaty, Daniel J. Rader, Asif Rasheed, Rainer Rauramaa, Dermot F. Reilly, Alex P. Reiner, Frida Renström, Stephen S. Rich, Paul M. Ridker, John D. Rioux, Neil R. Robertson, Dan M. Roden, Jerome I. Rotter, Igor Rudan, Veikko Salomaa, Nilesh J. Samani, Serena Sanna, Naveed Sattar, Ellen M. Schmidt, Robert A. Scott, Peter Sever, Raquel S. Sevilla, Christian M. Shaffer, Xueling Sim, Suthesh Sivapalaratnam, Kerrin S. Small, Albert V. Smith, Blair H. Smith, Sangeetha Somayajula, Lorraine Southam, Timothy D. Spector, Elizabeth K. Speliotes, John M. Starr, Kathleen E. Stirrups, Nathan Stitziel, Konstantin Strauch, Heather M. Stringham, Praveen Surendran, Hayato Tada, Alan R. Tall, Hua Tang, Jean Claude Tardif, Kent D. Taylor, Stella Trompet, Philip S. Tsao, Jaakko Tuomilehto, Anne Tybjaerg-Hansen, Natalie R.Van Zuydam, Anette Varbo, Tibor V. Varga, Jarmo Virtamo, Melanie Waldenberger, Nan Wang, Nick J. Wareham, Helen R. Warren, Peter E. Weeke, Joshua Weinstock, Jennifer Wessel, James G. Wilson, Peter W.F. Wilson, Ming Xu, Hanieh Yaghootkar, Robin Young, Eleftheria Zeggini, He Zhang, Neil S. Zheng, Weihua Zhang, Yan Zhang, Wei Zhou, Yanhua Zhou, Magdalena Zoledziewska, Joanna M.M. Howson, John Danesh, Mark I. McCarthy, Chad A. Cowan, Goncalo Abecasis, Panos Deloukas, Kiran Musunuru, Cristen J. Willer, Sekar Kathiresan

Research output: Contribution to journal › Article › peer-review

415 Scopus citations

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-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.

Original language	English (US)
Pages (from-to)	1758-1766
Number of pages	9
Journal	Nature Genetics
Volume	49
Issue number	12
DOIs	https://doi.org/10.1038/ng.3977
State	Published - Dec 1 2017

All Science Journal Classification (ASJC) codes

Genetics

Access to Document

10.1038/ng.3977

Cite this

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. DI., Arveiler, D., Assimes, T. L., Auer, P. L., Baber, U., Ballantyne, C. M., Bang, L. E., Benn, M., ... Kathiresan, S. (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

@article{2dd2b73f9c484b62b5564b3bba102e0e,

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

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-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.",

author = "Liu, {Dajiang J.} and Peloso, {Gina M.} and Haojie Yu and Butterworth, {Adam S.} and Xiao Wang and Anubha Mahajan and Danish Saleheen and Connor Emdin and Dewan Alam and Alves, {Alexessander Couto} and Philippe Amouyel and Angelantonio, {Emanuele DI} and Dominique Arveiler and Assimes, {Themistocles L.} and Auer, {Paul L.} and Usman Baber and Ballantyne, {Christie M.} and Bang, {Lia E.} and Marianne Benn and Bis, {Joshua C.} and Michael Boehnke and Eric Boerwinkle and Jette Bork-Jensen and Bottinger, {Erwin P.} and Ivan Brandslund and Morris Brown and Fabio Busonero and Caulfield, {Mark J.} and Chambers, {John C.} and Chasman, {Daniel I.} and Chen, {Y. Eugene} and Chen, {Yii Der Ida} and Rajiv Chowdhury and Cramer Christensen and Chu, {Audrey Y.} and Connell, {John M.} and Francesco Cucca and Cupples, {L. Adrienne} and Damrauer, {Scott M.} and Gail Davies and Deary, {Ian J.} and George Dedoussis and Denny, {Joshua C.} and Anna Dominiczak and Dub{\'e}, {Marie Pierre} and Tapani Ebeling and Gudny Eiriksdottir and To{\~n}u Esko and Farmaki, {Aliki Eleni} and Feitosa, {Mary F.} and Marco Ferrario and Jean Ferrieres and Ian Ford and Myriam Fornage and Franks, {Paul W.} and Frayling, {Timothy M.} and Ruth Frikke-Schmidt and Fritsche, {Lars G.} and Philippe Frossard and Valentin Fuster and Ganesh, {Santhi K.} and Wei Gao and Garcia, {Melissa E.} and Christian Gieger and Franco Giulianini and Goodarzi, {Mark O.} and Harald Grallert and Niels Grarup and Leif Groop and Grove, {Megan L.} and Vilmundur Gudnason and Torben Hansen and Harris, {Tamara B.} and Caroline Hayward and Hirschhorn, {Joel N.} and Holmen, {Oddgeir L.} and Jennifer Huffman and Yong Huo and Kristian Hveem and Sehrish Jabeen and Jackson, {Anne U.} and Johanna Jakobsdottir and Jarvelin, {Marjo Riitta} and Jensen, {Gorm B.} and J{\o}rgensen, {Marit E.} and Jukema, {J. Wouter} and Justesen, {Johanne M.} and Kamstrup, {Pia R.} and Stavroula Kanoni and Fredrik Karpe and Frank Kee and Khera, {Amit V.} and Derek Klarin and Koistinen, {Heikki A.} and Kooner, {Jaspal S.} and Charles Kooperberg and Kari Kuulasmaa and Johanna Kuusisto and Markku Laakso and Timo Lakka and Claudia Langenberg and Anne Langsted and Launer, {Lenore J.} and Torsten Lauritzen and MLiewald, {David C.} and Lin, {Li An} and Allan Linneberg and Loos, {Ruth J.F.} and Yingchang Lu and Xiangfeng Lu and Reedik M{\"a}gi and Anders Malarstig and Ani Manichaikul and Manning, {Alisa K.} and Pekka M{\"a}ntyselk{\"a} and Eirini Marouli and Masca, {Nicholas G.D.} and Andrea Maschio and Meigs, {James B.} and Olle Melander and Andres Metspalu and Morris, {Andrew P.} and Morrison, {Alanna C.} and Antonella Mulas and Martina M{\"u}ller-Nurasyid and Munroe, {Patricia B.} and Neville, {Matt J.} and Nielsen, {Sune F.} and Nielsen, {Jonas B.} and Nordestgaard, {B{\o}rge G.} and Ordovas, {Jose M.} and Roxana Mehran and O'Donnell, {Christoper J.} and Marju Orho-Melander and Molony, {Cliona M.} and Pieter Muntendam and Sandosh Padmanabhan and Palmer, {Colin N.A.} and Dorota Pasko and Patel, {Aniruddh P.} and Oluf Pedersen and Markus Perola and Annette Peters and Charlotta Pisinger and Giorgio Pistis and Ozren Polasek and Neil Poulter and Psaty, {Bruce M.} and Rader, {Daniel J.} and Asif Rasheed and Rainer Rauramaa and Reilly, {Dermot F.} and Reiner, {Alex P.} and Frida Renstr{\"o}m and Rich, {Stephen S.} and Ridker, {Paul M.} and Rioux, {John D.} and Robertson, {Neil R.} and Roden, {Dan M.} and Rotter, {Jerome I.} and Igor Rudan and Veikko Salomaa and Samani, {Nilesh J.} and Serena Sanna and Naveed Sattar and Schmidt, {Ellen M.} and Scott, {Robert A.} and Peter Sever and Sevilla, {Raquel S.} and Shaffer, {Christian M.} and Xueling Sim and Suthesh Sivapalaratnam and Small, {Kerrin S.} and Smith, {Albert V.} and Smith, {Blair H.} and Sangeetha Somayajula and Lorraine Southam and Spector, {Timothy D.} and Speliotes, {Elizabeth K.} and Starr, {John M.} and Stirrups, {Kathleen E.} and Nathan Stitziel and Konstantin Strauch and Stringham, {Heather M.} and Praveen Surendran and Hayato Tada and Tall, {Alan R.} and Hua Tang and Tardif, {Jean Claude} and Taylor, {Kent D.} and Stella Trompet and Tsao, {Philip S.} and Jaakko Tuomilehto and Anne Tybjaerg-Hansen and Zuydam, {Natalie R.Van} and Anette Varbo and Varga, {Tibor V.} and Jarmo Virtamo and Melanie Waldenberger and Nan Wang and Wareham, {Nick J.} and Warren, {Helen R.} and Weeke, {Peter E.} and Joshua Weinstock and Jennifer Wessel and Wilson, {James G.} and Wilson, {Peter W.F.} and Ming Xu and Hanieh Yaghootkar and Robin Young and Eleftheria Zeggini and He Zhang and Zheng, {Neil S.} and Weihua Zhang and Yan Zhang and Wei Zhou and Yanhua Zhou and Magdalena Zoledziewska and Howson, {Joanna M.M.} and John Danesh and McCarthy, {Mark I.} and Cowan, {Chad A.} and Goncalo Abecasis and Panos Deloukas and Kiran Musunuru and Willer, {Cristen J.} and Sekar Kathiresan",

note = "Funding Information: of Health. G.M.P. is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health award K01HL125751. A.P.P. is supported by a research fellowship from the Stanley J. Sarnoff Cardiovascular Research Foundation. H. Tada is supported by a grant from the Japanese Circulation Society to study in the United States. The research was supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility and ERC grant 323195; SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC to T.M.F. E.K.S. is supported by NIH grants R01 DK106621 and R01 DK107904, the University of Michigan Biological Sciences Scholars Program, and the University of Michigan Department of Internal Medicine. T.D.S. is supported by an ERC Advanced Principal Investigator award. A.P.M. is supported as a Wellcome Trust Senior Fellow in Basic Biomedical Science (grant no. WT098017). Y.E.C. is supported by HL117491 and HL129778 from the NIH. S.K.G. is supported by HL122684 from the NIH. P.L.A. is supported by NHLBI R21 HL121422-02 from the NIH. C.L., N.J.W., and R.A.S. acknowledge funding from the Medical Research Council, UK (MC_UU_12015/1). J.D. is supported as a British Heart Foundation Professor, European Research Council Senior Investigator, and National Institute for Health Research (NIHR) Senior Investigator. C.J.W. is supported by HL094535 and HL109946 from the NIH. S. Kathiresan is supported by a research scholar award from the Massachusetts General Hospital, the Donovan Family Foundation, and R01 HL127564 and R33 HL120781 from the NIH. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health or the US Department of Health and Human Services. Funding Information: D.J.L. is partially supported by R01HG008983 from the National Human Genome Research Institute of the National Institute of Health, and R21DA040177 and R01DA037904 from the National Institute of Drug Abuse of the National Institute",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/ng.3977",

language = "English (US)",

volume = "49",

pages = "1758--1766",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "12",

}

Liu, DJ, Peloso, GM, Yu, H, Butterworth, AS, Wang, X, Mahajan, A, Saleheen, D, Emdin, C, Alam, D, Alves, AC, Amouyel, P, Angelantonio, EDI, 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, YDI, 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, MP, Ebeling, T, Eiriksdottir, G, Esko, T, Farmaki, AE, 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, MR, 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, Langenberg, C, Langsted, A, Launer, LJ, Lauritzen, T, MLiewald, DC, Lin, LA, Linneberg, A, Loos, RJF, Lu, Y, Lu, X, Mägi, R, Malarstig, 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, SF, Nielsen, JB, 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, Renström, 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, JC, Taylor, KD, Trompet, S, Tsao, PS, Tuomilehto, J, Tybjaerg-Hansen, A, Zuydam, NRV, 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 2017, 'Exome-wide association study of plasma lipids in >300,000 individuals', Nature Genetics, vol. 49, no. 12, pp. 1758-1766. https://doi.org/10.1038/ng.3977

TY - JOUR

T1 - Exome-wide association study of plasma lipids in >300,000 individuals

AU - Liu, Dajiang J.

AU - Peloso, Gina M.

AU - Yu, Haojie

AU - Butterworth, Adam S.

AU - Wang, Xiao

AU - Mahajan, Anubha

AU - Saleheen, Danish

AU - Emdin, Connor

AU - Alam, Dewan

AU - Alves, Alexessander Couto

AU - Amouyel, Philippe

AU - Angelantonio, Emanuele DI

AU - Arveiler, Dominique

AU - Assimes, Themistocles L.

AU - Auer, Paul L.

AU - Baber, Usman

AU - Ballantyne, Christie M.

AU - Bang, Lia E.

AU - Benn, Marianne

AU - Bis, Joshua C.

AU - Boehnke, Michael

AU - Boerwinkle, Eric

AU - Bork-Jensen, Jette

AU - Bottinger, Erwin P.

AU - Brandslund, Ivan

AU - Brown, Morris

AU - Busonero, Fabio

AU - Caulfield, Mark J.

AU - Chambers, John C.

AU - Chasman, Daniel I.

AU - Chen, Y. Eugene

AU - Chen, Yii Der Ida

AU - Chowdhury, Rajiv

AU - Christensen, Cramer

AU - Chu, Audrey Y.

AU - Connell, John M.

AU - Cucca, Francesco

AU - Cupples, L. Adrienne

AU - Damrauer, Scott M.

AU - Davies, Gail

AU - Deary, Ian J.

AU - Dedoussis, George

AU - Denny, Joshua C.

AU - Dominiczak, Anna

AU - Dubé, Marie Pierre

AU - Ebeling, Tapani

AU - Eiriksdottir, Gudny

AU - Esko, Toñu

AU - Farmaki, Aliki Eleni

AU - Feitosa, Mary F.

AU - Ferrario, Marco

AU - Ferrieres, Jean

AU - Ford, Ian

AU - Fornage, Myriam

AU - Franks, Paul W.

AU - Frayling, Timothy M.

AU - Frikke-Schmidt, Ruth

AU - Fritsche, Lars G.

AU - Frossard, Philippe

AU - Fuster, Valentin

AU - Ganesh, Santhi K.

AU - Gao, Wei

AU - Garcia, Melissa E.

AU - Gieger, Christian

AU - Giulianini, Franco

AU - Goodarzi, Mark O.

AU - Grallert, Harald

AU - Grarup, Niels

AU - Groop, Leif

AU - Grove, Megan L.

AU - Gudnason, Vilmundur

AU - Hansen, Torben

AU - Harris, Tamara B.

AU - Hayward, Caroline

AU - Hirschhorn, Joel N.

AU - Holmen, Oddgeir L.

AU - Huffman, Jennifer

AU - Huo, Yong

AU - Hveem, Kristian

AU - Jabeen, Sehrish

AU - Jackson, Anne U.

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N1 - Funding Information: of Health. G.M.P. is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health award K01HL125751. A.P.P. is supported by a research fellowship from the Stanley J. Sarnoff Cardiovascular Research Foundation. H. Tada is supported by a grant from the Japanese Circulation Society to study in the United States. The research was supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility and ERC grant 323195; SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC to T.M.F. E.K.S. is supported by NIH grants R01 DK106621 and R01 DK107904, the University of Michigan Biological Sciences Scholars Program, and the University of Michigan Department of Internal Medicine. T.D.S. is supported by an ERC Advanced Principal Investigator award. A.P.M. is supported as a Wellcome Trust Senior Fellow in Basic Biomedical Science (grant no. WT098017). Y.E.C. is supported by HL117491 and HL129778 from the NIH. S.K.G. is supported by HL122684 from the NIH. P.L.A. is supported by NHLBI R21 HL121422-02 from the NIH. C.L., N.J.W., and R.A.S. acknowledge funding from the Medical Research Council, UK (MC_UU_12015/1). J.D. is supported as a British Heart Foundation Professor, European Research Council Senior Investigator, and National Institute for Health Research (NIHR) Senior Investigator. C.J.W. is supported by HL094535 and HL109946 from the NIH. S. Kathiresan is supported by a research scholar award from the Massachusetts General Hospital, the Donovan Family Foundation, and R01 HL127564 and R33 HL120781 from the NIH. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health or the US Department of Health and Human Services. Funding Information: D.J.L. is partially supported by R01HG008983 from the National Human Genome Research Institute of the National Institute of Health, and R21DA040177 and R01DA037904 from the National Institute of Drug Abuse of the National Institute

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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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U2 - 10.1038/ng.3977

DO - 10.1038/ng.3977

M3 - Article

C2 - 29083408

AN - SCOPUS:85035766416

SN - 1061-4036

VL - 49

SP - 1758

EP - 1766

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

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

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