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

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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 & 207 others 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

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 languageEnglish
JournalNature Genetics
Volume49
Issue number12
Pages (from-to)1758-1766
Number of pages9
ISSN1061-4036
DOIs
Publication statusPublished - 1 Dec 2017

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