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Large-scale association analysis identifies new risk loci for coronary artery disease

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

Authors: CARDIoGRAMplusC4D Consortium; Deloukas P; Kanoni S; Willenborg C; Farrall M; Assimes TL; Thompson JR; Ingelsson E; Saleheen D; Erdmann J; Goldstein BA; Stirrups K; Konig IR; Cazier JB; Johansson A; Hall AS; Lee JY; Willer CJ; Chambers JC; Esko T; Folkersen L; Goel A; Grundberg E; Havulinna AS; Ho WK; Hopewell JC; Eriksson N; Kleber ME; Kristiansson K; Lundmark P; Lyytikainen LP; Rafelt S; Shungin D; Strawbridge RJ; Thorleifsson G; Tikkanen E; Van Zuydam N; Voight BF; Waite LL; Zhang W; Ziegler A; Absher D; Altshuler D; Balmforth AJ; Barroso I; Braund PS; Burgdorf C; Claudi-Boehm S; Cox D; Dimitriou M; Do R; DIAGRAM Consortium; CARDIOGENICS Consortium; Doney AS; El Mokhtari N; Eriksson P; Fischer K; Fontanillas P; Franco-Cereceda A; Gigante B; Groop L; Gustafsson S; Hager J; Hallmans G; Han BG; Hunt SE; Kang HM; Illig T; Kessler T; Knowles JW; Kolovou G; Kuusisto J; Langenberg C; Langford C; Leander K; Lokki ML; Lundmark A; McCarthy MI; Meisinger C; Melander O; Mihailov E; Maouche S; Morris AD; Muller-Nurasyid M; MuTHER Consortium; Nikus K; Peden JF; Rayner NW; Rasheed A; Rosinger S; Rubin D; Rumpf MP; Schafer A; Sivananthan M; Song C; Stewart AF; Tan ST; Thorgeirsson G; van der Schoot CE; Wagner PJ; Wellcome Trust Case Control Consortium; Wells GA; Wild PS; Yang TP; Amouyel P; Arveiler D; Basart H; Boehnke M; Boerwinkle E; Brambilla P; Cambien F; Cupples AL; de Faire U; Dehghan A; Diemert P; Epstein SE; Evans A; Ferrario MM; Ferrieres J; Gauguier D; Go AS; Goodall AH; Gudnason V; Hazen SL; Holm H; Iribarren C; Jang Y; Kahonen M; Kee F; Kim HS; Klopp N; Koenig W; Kratzer W; Kuulasmaa K; Laakso M; Laaksonen R; Lee JY; Lind L; Ouwehand WH; Parish S; Park JE; Pedersen NL; Peters A; Quertermous T; Rader DJ; Salomaa V; Schadt E; Shah SH; Sinisalo J; Stark K; Stefansson K; Tregouet DA; Virtamo J; Wallentin L; Wareham N; Zimmermann ME; Nieminen MS; Hengstenberg C; Sandhu MS; Pastinen T; Syvanen AC; Hovingh GK; Dedoussis G; Franks PW; Lehtimaki T; Metspalu A; Zalloua PA; Siegbahn A; Schreiber S; Ripatti S; Blankenberg SS; Perola M; Clarke R; Boehm BO; O'Donnell C; Reilly MP; Marz W; Collins R; Kathiresan S; Hamsten A; Kooner JS; Thorsteinsdottir U; Danesh J; Palmer CN; Roberts R; Watkins H; Schunkert H; Samani NJ

Nat Genet. 2013 Jan;45(1):25-33. Epub 2012 Dec 2.

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