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

著者: Dajiang J. Liu, Gina M. Peloso, Haojie Yu, Adam S. Butterworth, Xiao Wang, Anubha Mahajan, Danish Saleheen, Connor A. Emdin, Dewan S 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. Böttinger, Ivan Brandslund, Morris J. 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 Connell, Francesco Cucca, L. Adrienne Cupples, Scott M. Damrauer, Gail Davies, Ian J. Deary, George Dedoussis, Joshua C. Denny, Anna F. Dominiczak, Marie‐Pierre Dubé, Tapani Ebeling, Guðný Eiríksdóttir, Tõnu Esko, Aliki‐Eleni Farmaki, Mary F. Feitosa, Maurizio Ferrario, Jean Ferrières, Ian Ford, Myriam Fornage, Paul W. Franks, Timothy M. Frayling, Ruth Frikke‐Schmidt, Lars G. Fritsche, Philippe Frossard, Valentı́n 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 Guðnason, Torben Hansen, Tamara B. Harris, Caroline Hayward, Joel N. Hirschhorn, Oddgeir L. Holmen, Jennifer E. Huffman, Yong Huo, Kristian Hveem, Sehrish Jabeen, Anne Jackson, Jóhanna Jakobsdóttir, Marjo‐Riitta Järvelin, Gorm Boje Jensen, Marit E. Jørgensen, J. Wouter Jukema, Johanne Marie Justesen, Pia R. Kamstrup, Stavroula Kanoni, Fredrik Karpe, Frank Kee, Amit Khera, Derek Klarin, Heikki A. Koistinen, Jaspal S. Kooner, Charles Kooperberg, Kari Kuulasmaa, Johanna Kuusisto, Markku Laakso, Timo A. Lakka, Claudia Langenberg, Anne Langsted, Lenore J. Launer, Torsten Lauritzen, David C. Liewald, Li An Lin, Allan Linneberg, Ruth J. F. Loos, Yingchang Lu, Xiangfeng Lu, Reedik Mägi, Anders Mälarstig, 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, Jonas B. Nielsen, Sune F. Nielsen, Børge G. Nordestgaard, José M. Ordovás, Roxana Mehran, Christoper J. O'Donnell, Marju Orho‐Melander, Cliona Molony, Pieter Muntendam, Sandosh Padmanabhan, Nicholette D. Palmer, Dorota Pasko, Aniruddh P. Patel, Oluf Pedersen, Markus Perola, Annette Peters, Charlotta Pisinger, Giorgio Pistis, Ozren Polašek, 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 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 Stirrups, Nathan O. 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 Tybjærg‐Hansen, Natalie R. van Zuydam, Anette Varbo, Tibor V. Varga, Jarmo Virtamo, Mélanie Waldenberger, Nan Wang, Nicholas J. Wareham, Helen R. Warren, Peter Weeke, Joshua Weinstock, Jennifer Wessel, James G. Wilson, Peter W.F. Wilson, Ming Xu, Hanieh Yaghootkar, Robin Young, Eleftheria Zeggini, He Zhang, NingNing Zheng, Weihua Zhang, Yan Zhang, Wei Zhou, Yanhua Zhou, Magdalena Żołędziewska, Joanna M. M. Howson, John Danesh, Mark I. McCarthy, Chad A. Cowan, Gonçalo R. Abecasis, Panos Deloukas, Yan V. Sun, Cristen J. Willer, Sekar Kathiresan - Figshare (United Kingdom) 2017 被引用: 81

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.