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

Journal Paper/Review - Oct 30, 2017

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Liu D, Peloso G, Yu H, Butterworth A, Wang X, Mahajan A, Saleheen D, Emdin C, Alam D, Alves A, Amouyel P, Di Angelantonio E, Arveiler D, Assimes T, Auer P, Baber U, Ballantyne C, Bang L, Benn M, Bis J, Boehnke M, Boerwinkle E, Bork-Jensen J, Bottinger E, Brandslund I, Brown M, Busonero F, Caulfield M, Chambers J, Chasman D, Chen Y, Chen Y, Chowdhury R, Christensen C, Chu A, Connell J, Cucca F, Cupples L, Damrauer S, Davies G, Deary I, Dedoussis G, Denny J, Dominiczak A, Dubé M, Ebeling T, Eiriksdottir G, Esko T, Farmaki A, Feitosa M, Ferrario M, Ferrieres J, Ford I, Fornage M, Franks P, Frayling T, Frikke-Schmidt R, Fritsche L, Frossard P, Fuster V, Ganesh S, Gao W, Garcia M, Gieger C, Giulianini F, Goodarzi M, Grallert H, Grarup N, Groop L, Grove M, Gudnason V, Hansen T, Harris T, Hayward C, Hirschhorn J, Holmen O, Huffman J, Huo Y, Hveem K, Jabeen S, Jackson A, Jakobsdottir J, Jarvelin M, Jensen G, Jørgensen M, Jukema J, Justesen J, Kamstrup P, Kanoni S, Karpe F, Kee F, Khera A, Klarin D, Koistinen H, Kooner J, Kooperberg C, Kuulasmaa K, Kuusisto J, Laakso M, Lakka T, Langenberg C, Langsted A, Launer L, Lauritzen T, Liewald D, Lin L, Linneberg A, Loos R, Lu Y, Lu X, Mägi R, Malarstig A, Manichaikul A, Manning A, Mäntyselkä P, Marouli E, Masca N, Maschio A, Meigs J, Melander O, Metspalu A, Morris A, Morrison A, Mulas A, Müller-Nurasyid M, Munroe P, Neville M, Nielsen J, Nielsen S, Nordestgaard B, Ordovas J, Mehran R, O'Donnell C, Orho-Melander M, Molony C, Muntendam P, Padmanabhan S, Palmer C, Pasko D, Patel A, Pedersen O, Perola M, Peters A, Pisinger C, Pistis G, Polasek O, Poulter N, Psaty B, Rader D, Rasheed A, Rauramaa R, Reilly D, Reiner A, Renström F, Rich S, Ridker P, Rioux J, Robertson N, Roden D, Rotter J, Rudan I, Salomaa V, Samani N, Sanna S, Sattar N, Schmidt E, Scott R, Sever P, Sevilla R, Shaffer C, Sim X, Sivapalaratnam S, Small K, Smith A, Smith B, Somayajula S, Southam L, Spector T, Speliotes E, Starr J, Stirrups K, Stitziel N, Strauch K, Stringham H, Surendran P, Tada H, Tall A, Tang H, Tardif J, Taylor K, Trompet S, Tsao P, Tuomilehto J, Tybjaerg-Hansen A, van Zuydam N, Varbo A, Varga T, Virtamo J, Waldenberger M, Wang N, Wareham N, Warren H, Weeke P, Weinstock J, Wessel J, Wilson J, Wilson P, Xu M, Yaghootkar H, Young R, Zeggini E, Zhang H, Zheng N, Zhang W, Zhang Y, Zhou W, Zhou Y, Zoledziewska M, Howson J, Danesh J, McCarthy M, Cowan C, Abecasis G, Deloukas P, Musunuru K, Willer C, Kathiresan S. Exome-wide association study of plasma lipids in >300,000 individuals. Nat Genet 2017; 49:1758-1766.
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Journal Paper/Review (English)
Journal
Nat Genet 2017; 49
Publication Date
Oct 30, 2017
Issn Print
Issn Electronic
1546-1718
Pages
1758-1766
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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.