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

• Published in: Nature genetics Vol. 49; no. 12; pp. 1758 - 1766
• Main Authors: Peloso, Gina M, Wang, Xiao, Alam, Dewan, Arveiler, Dominique, Ballantyne, Christie M, Bis, Joshua C, Boerwinkle, Eric, Bork-Jensen, Jette, Brandslund, Ivan, Busonero, Fabio, Caulfield, Mark J, Chasman, Daniel I, Chen, Yii-Der Ida, Christensen, Cramer, Cucca, Francesco, Cupples, L Adrienne, Davies, Gail, Deary, Ian J, Dubé, Marie-Pierre, Ford, Ian, Fornage, Myriam, Fuster, Valentin, Ganesh, Santhi K, Giulianini, Franco, Grarup, Niels, Groop, Leif, Hansen, Torben, Harris, Tamara B, Hayward, Caroline, Hveem, Kristian, Jabeen, Sehrish, Jackson, Anne U, Jensen, Gorm B, Jørgensen, Marit E, Kamstrup, Pia R, Kanoni, Stavroula, Khera, Amit V, Koistinen, Heikki A, Kooperberg, Charles, Kuusisto, Johanna, Laakso, Markku, Langsted, Anne, Linneberg, Allan, Loos, Ruth J F, Lu, Yingchang, Malarstig, Anders, Manichaikul, Ani, Manning, Alisa K, Marouli, Eirini, Maschio, Andrea, Melander, Olle, Morrison, Alanna C, Mulas, Antonella, Neville, Matt J, Nielsen, Jonas B, Nordestgaard, Børge G, Mehran, Roxana, O'Donnell, Christoper J, Molony, Cliona M, Palmer, Colin N A, Pasko, Dorota, Peters, Annette, Pisinger, Charlotta, Polasek, Ozren, Poulter, Neil, Psaty, Bruce M, Rasheed, Asif, Reiner, Alex P, Robertson, Neil R, Rudan, Igor, Salomaa, Veikko, Sanna, Serena, Schmidt, Ellen M, Sever, Peter, Sevilla, Raquel S, Smith, Blair H, Speliotes, Elizabeth K, Stirrups, Kathleen E, Stitziel, Nathan, Surendran, Praveen, Tall, Alan R, Tsao, Philip S, van Zuydam, Natalie R, Varbo, Anette, Waldenberger, Melanie, Wareham, Nick J, Weeke, Peter E, Wessel, Jennifer, Wilson, James G, Wilson, Peter W F, Yaghootkar, Hanieh, Young, Robin, Zeggini, Eleftheria, Zhang, Weihua, Zhou, Wei, Howson, Joanna M M, McCarthy, Mark I, Cowan, Chad A, Deloukas, Panos, Kathiresan, Sekar
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2017; Nature Publishing Group
• Subjects: 45/43; 631/208/205/2138; 692/699/75; Age; Agriculture; Alleles; Animal Genetics and Genomics; Biomedicine; Blood lipids; Cancer Research; Cardiovascular disease; Cholesterol; Consortia; Coronary artery; Coronary artery disease; Coronary Artery Disease - blood; Coronary Artery Disease - genetics; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; Exome - genetics; Gene Function; Genetic aspects; Genetic Association Studies - methods; Genetic Predisposition to Disease - genetics; Genetic Variation; Genome-wide association studies; Genomes; Genotype; Genotypes; Genotyping; Heart diseases; High density lipoprotein; Human Genetics; Humans; Identification and classification; Janus kinase 2; letter; Lipids; Lipids - blood; Lipolysis; Lipoproteins; Liver; Loci; Low density lipoprotein; Macular degeneration; Macular Degeneration - blood; Macular Degeneration - genetics; Medicin och hälsovetenskap; Methods; Phenotype; Plasma; Quality control; Risk; Risk Factors; Studies; Thalassemia; Triglycerides
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.3977

Exome-wide genetic analysis on >300,000 individuals identifies associations with plasma lipid traits. Loci significantly associated with cholesterol and triglycerides are examined together to determine the effects of alleles on type 2 diabetes and coronary artery disease risk. 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.