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


AUTHORS

Liu DJ , Peloso GM , Yu H , Butterworth AS , Wang X , Mahajan A , Saleheen D , Emdin C , Alam D , Alves AC , Amouyel P , Di Angelantonio E , Arveiler D , Assimes TL , Auer PL , Baber U , Ballantyne CM , Bang LE , Benn M , Bis JC , Boehnke M , Boerwinkle E , Bork-Jensen J , Bottinger EP , Brandslund I , Brown M , Busonero F , Caulfield MJ , Chambers JC , Chasman DI , Chen YE , Chen YI , Chowdhury R , Christensen C , Chu AY , Connell JM , Cucca F , Cupples LA , Damrauer SM , Davies G , Deary IJ , Dedoussis G , Denny JC , Dominiczak A , Dubé MP , Ebeling T , Eiriksdottir G , Esko T , Farmaki AE , Feitosa MF , Ferrario M , Ferrieres J , Ford I , Fornage M , Franks PW , Frayling TM , Frikke-Schmidt R , Fritsche LG , Frossard P , Fuster V , Ganesh SK , Gao W , Garcia ME , Gieger C , Giulianini F , Goodarzi MO , Grallert H , Grarup N , Groop L , Grove ML , Gudnason V , Hansen T , Harris TB , Hayward C , Hirschhorn JN , Holmen OL , Huffman J , Huo Y , Hveem K , Jabeen S , Jackson AU , Jakobsdottir J , Jarvelin MR , Jensen GB , Jørgensen ME , Jukema JW , Justesen JM , Kamstrup PR , Kanoni S , Karpe F , Kee F , Khera AV , Klarin D , Koistinen HA , Kooner JS , Kooperberg C , Kuulasmaa K , Kuusisto J , Laakso M , Lakka T , Langenberg C , Langsted A , Launer LJ , Lauritzen T , Liewald DCM , Lin LA , Linneberg A , Loos RJF , Lu Y , Lu X , Mägi R , Malarstig A , Manichaikul A , Manning AK , Mäntyselkä P , Marouli E , Masca NGD , Maschio A , Meigs JB , Melander O , Metspalu A , Morris AP , Morrison AC , Mulas A , Müller-Nurasyid M , Munroe PB , Neville MJ , Nielsen JB , Nielsen SF , Nordestgaard BG , Ordovas JM , Mehran R , O'Donnell CJ , Orho-Melander M , Molony CM , Muntendam P , Padmanabhan S , Palmer CNA , Pasko D , Patel AP , Pedersen O , Perola M , Peters A , Pisinger C , Pistis G , Polasek O , Poulter N , Psaty BM , Rader DJ , Rasheed A , Rauramaa R , Reilly DF , Reiner AP , Renström F , Rich SS , Ridker PM , Rioux JD , Robertson NR , Roden DM , Rotter JI , Rudan I , Salomaa V , Samani NJ , Sanna S , Sattar N , Schmidt EM , Scott RA , Sever P , Sevilla RS , Shaffer CM , Sim X , Sivapalaratnam S , Small KS , Smith AV , Smith BH , Somayajula S , Southam L , Spector TD , Speliotes EK , Starr JM , Stirrups KE , Stitziel N , Strauch K , Stringham HM , Surendran P , Tada H , Tall AR , Tang H , Tardif JC , Taylor KD , Trompet S , Tsao PS , Tuomilehto J , Tybjaerg-Hansen A , van Zuydam NR , Varbo A , Varga TV , Virtamo J , Waldenberger M , Wang N , Wareham NJ , Warren HR , Weeke PE , Weinstock J , Wessel J , Wilson JG , Wilson PWF , Xu M , Yaghootkar H , Young R , Zeggini E , Zhang H , Zheng NS , Zhang W , Zhang Y , Zhou W , Zhou Y , Zoledziewska M , , , , , , Howson JMM , Danesh J , McCarthy MI , Cowan CA , Abecasis G , Deloukas P , Musunuru K , Willer CJ , Kathiresan S , . Nature genetics. 2017 10 30; ().

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.


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.