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

Publication

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

Journal Paper/Review - Oct 30, 2017

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

Citation

Sim X, Ridker P, Rich S, Renström F, Reiner A, Reilly D, Rauramaa R, Rasheed A, Rader D, Psaty B, Poulter N, Polasek O, Pistis G, Rioux J, Robertson N, Shaffer C, Sevilla R, Sever P, Scott R, Schmidt E, Sattar N, Sanna S, Samani N, Salomaa V, Rudan I, Rotter J, Roden D, Pisinger C, Peters A, Perola M, Neville M, Munroe P, Müller-Nurasyid M, Mulas A, Morrison A, Morris A, Metspalu A, Melander O, Meigs J, Maschio A, Masca N, Marouli E, Nielsen J, Nielsen S, Pedersen O, Patel A, Pasko D, Palmer C, Padmanabhan S, Muntendam P, Molony C, Orho-Melander M, O'Donnell C, Mehran R, Ordovas J, Nordestgaard B, Mäntyselkä P, Kathiresan S, Zheng N, Zhang H, Zeggini E, Young R, Yaghootkar H, Xu M, Wilson P, Wilson J, Wessel J, Weinstock J, Weeke P, Warren H, Zhang W, Zhang Y, Willer C, Musunuru K, Deloukas P, Abecasis G, Cowan C, McCarthy M, Danesh J, Howson J, Zoledziewska M, Zhou Y, Zhou W, Wareham N, Wang N, Waldenberger M, Stringham H, Strauch K, Stitziel N, Stirrups K, Starr J, Speliotes E, Spector T, Southam L, Somayajula S, Smith B, Smith A, Small K, Surendran P, Tada H, Virtamo J, Varga T, Varbo A, van Zuydam N, Tybjaerg-Hansen A, Tuomilehto J, Tsao P, Trompet S, Taylor K, Tardif J, Tang H, Tall A, Sivapalaratnam S, Frikke-Schmidt R, Dedoussis G, Deary I, Davies G, Damrauer S, Cupples L, Cucca F, Connell J, Chu A, Christensen C, Chowdhury R, Chen Y, Chen Y, Denny J, Dominiczak A, Frayling T, Franks P, Fornage M, Ford I, Ferrieres J, Ferrario M, Feitosa M, Farmaki A, Esko T, Eiriksdottir G, Ebeling T, Dubé M, Chasman D, Chambers J, Caulfield M, Arveiler D, Di Angelantonio E, Amouyel P, Alves A, Alam D, Emdin C, Saleheen D, Mahajan A, Wang X, Butterworth A, Yu H, Peloso G, Assimes T, Auer P, Busonero F, Brown M, Brandslund I, Bottinger E, Bork-Jensen J, Boerwinkle E, Boehnke M, Bis J, Benn M, Bang L, Ballantyne C, Baber U, Liu D, Manning A, Laakso M, Kuusisto J, Kuulasmaa K, Kooperberg C, Kooner J, Koistinen H, Klarin D, Khera A, Kee F, Karpe F, Kanoni S, Kamstrup P, Lakka T, Langenberg C, Manichaikul A, Malarstig A, Mägi R, Lu X, Lu Y, Loos R, Linneberg A, Lin L, Liewald D, Lauritzen T, Launer L, Langsted A, Justesen J, Jukema J, Jørgensen M, Grove M, Groop L, Grarup N, Grallert H, Goodarzi M, Giulianini F, Gieger C, Garcia M, Gao W, Ganesh S, Fuster V, Frossard P, Gudnason V, Hansen T, Jensen G, Jarvelin M, Jakobsdottir J, Jackson A, Jabeen S, Hveem K, Huo Y, Huffman J, Holmen O, Hirschhorn J, Hayward C, Harris T, Fritsche L. Exome-wide association study of plasma lipids in >300,000 individuals. Nat Genet 2017; 49:1758-1766.

Type

Journal Paper/Review (English)

Journal

Nat Genet 2017; 49

Publication Date

Oct 30, 2017

Issn Electronic

1546-1718

Pages

1758-1766

Brief description/objective

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.