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, Tõnu 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 M Liewald, 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, Jonas B Nielsen, Sune F 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 journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)1758–1766
JournalNature Genetics
Volume49
Issue number12
Early online date30 Oct 2017
DOIs
Publication statusPublished - Dec 2017

Keywords

  • cardiovascular diseases
  • genome wide association studies

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