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

ABSTRACT: 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.

SUBMITTER: CARDIoGRAMplusC4D Consortium

PROVIDER: S-EPMC3679547 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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

Deloukas Panos P Kanoni Stavroula S Willenborg Christina C Farrall Martin M Assimes Themistocles L TL Thompson John R JR Ingelsson Erik E Saleheen Danish D Erdmann Jeanette J Goldstein Benjamin A BA Stirrups Kathleen K König Inke R IR Cazier Jean-Baptiste JB Johansson Asa A Hall Alistair S AS Lee Jong-Young JY Willer Cristen J CJ Chambers John C JC Esko Tõnu T Folkersen Lasse L Goel Anuj A Grundberg Elin E Havulinna Aki S AS Ho Weang K WK Hopewell Jemma C JC Eriksson Niclas N Kleber Marcus E ME Kristiansson Kati K Lundmark Per P Lyytikäinen Leo-Pekka LP Rafelt Suzanne S Shungin Dmitry D Strawbridge Rona J RJ Thorleifsson Gudmar G Tikkanen Emmi E Van Zuydam Natalie N Voight Benjamin F BF Waite Lindsay L LL Zhang Weihua W Ziegler Andreas A Absher Devin D Altshuler David D Balmforth Anthony J AJ Barroso Inês I Braund Peter S PS Burgdorf Christof C Claudi-Boehm Simone S Cox David D Dimitriou Maria M Do Ron R Doney Alex S F AS El Mokhtari NourEddine N Eriksson Per P Fischer Krista K Fontanillas Pierre P Franco-Cereceda Anders A Gigante Bruna B Groop Leif L Gustafsson Stefan S Hager Jörg J Hallmans Göran G Han Bok-Ghee BG Hunt Sarah E SE Kang Hyun M HM Illig Thomas T Kessler Thorsten T Knowles Joshua W JW Knowles Joshua W JW Kolovou Genovefa G Kuusisto Johanna J Langenberg Claudia C Langford Cordelia C Leander Karin K Lokki Marja-Liisa ML Lundmark Anders A McCarthy Mark I MI Meisinger Christa C Melander Olle O Mihailov Evelin E Maouche Seraya S Morris Andrew D AD Müller-Nurasyid Martina M Nikus Kjell K Peden John F JF Rayner N William NW Rasheed Asif A Rosinger Silke S Rubin Diana D Rumpf Moritz P MP Schäfer Arne A Sivananthan Mohan M Song Ci C Stewart Alexandre F R AF Tan Sian-Tsung ST Thorgeirsson Gudmundur G van der Schoot C Ellen CE Wagner Peter J PJ Wells George A GA Wild Philipp S PS Yang Tsun-Po TP Amouyel Philippe P Arveiler Dominique D Basart Hanneke H Boehnke Michael M Boerwinkle Eric E Brambilla Paolo P Cambien Francois F Cupples Adrienne L AL de Faire Ulf U Dehghan Abbas A Diemert Patrick P Epstein Stephen E SE Evans Alun A Ferrario Marco M MM Ferrières Jean J Gauguier Dominique D Go Alan S AS Goodall Alison H AH Gudnason Villi V Hazen Stanley L SL Holm Hilma H Iribarren Carlos C Jang Yangsoo Y Kähönen Mika M Kee Frank F Kim Hyo-Soo HS Klopp Norman N Koenig Wolfgang W Kratzer Wolfgang W Kuulasmaa Kari K Laakso Markku M Laaksonen Reijo R Lee Ji-Young JY Lind Lars L Ouwehand Willem H WH Parish Sarah S Park Jeong E JE Pedersen Nancy L NL Peters Annette A Quertermous Thomas T Rader Daniel J DJ Salomaa Veikko V Schadt Eric E Shah Svati H SH Sinisalo Juha J Stark Klaus K Stefansson Kari K Trégouët David-Alexandre DA Virtamo Jarmo J Wallentin Lars L Wareham Nicholas N Zimmermann Martina E ME Nieminen Markku S MS Hengstenberg Christian C Sandhu Manjinder S MS Pastinen Tomi T Syvänen Ann-Christine AC Hovingh G Kees GK Dedoussis George G Franks Paul W PW Lehtimäki Terho T Metspalu Andres A Zalloua Pierre A PA Siegbahn Agneta A Schreiber Stefan S Ripatti Samuli S Blankenberg Stefan S SS Perola Markus M Clarke Robert R Boehm Bernhard O BO O'Donnell Christopher C Reilly Muredach P MP März Winfried W Collins Rory R Kathiresan Sekar S Hamsten Anders A Kooner Jaspal S JS Thorsteinsdottir Unnur U Danesh John J Palmer Colin N A CN Roberts Robert R Watkins Hugh H Schunkert Heribert H Samani Nilesh J NJ

Nature genetics 20121202 1

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 ...[more]

PMID: 23202125

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Project description:Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.

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

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

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