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Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16


We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P = 9.5 × 10−7) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 × 10−5; odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19–1.65; combined P = 2.6 × 10−10). Genotype accounted for 9% of the population-attributable risk of ASD.

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Figure 1: LocusZoom plot of the region associated with ASD on chromosome 4p16.

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Our principal acknowledgment is of the individuals with CHD, their families and the healthy individuals who participated in the research. We acknowledge the contributions of C. de Gier-de Vries, L.M. Sneddon, M. Westerveld, C.Q. Simmons, T. Zhang, R. Hussein and V. Otero. This study was funded by the Wellcome Trust (grants BH100708 and 087436), the British Heart Foundation (BHF), the European Union Framework Programme 7 CHeartED Programme (HEALTH-F2-2008-223040), the SickKids Labatt Family Heart Centre Biobank (to S.M.), the Netherlands Heart Foundation (NHS2010B175 to T.T.K. and C.R.B.), Heart Research UK, the US National Institutes of Health (HL068880 to A.L.G.) and the Agence Nationale de la Recherche (ANR) Labex project Medical Genomics (to G.M.L.). M.F. acknowledges support from the Wellcome Trust core award (090532/Z/09/Z) and BHF Centre of Research Excellence in Oxford. S.B. and B.D.K. hold BHF Personal Chairs. This study makes use of data generated by the WTCCC2, funded by the Wellcome Trust under award 085475. Access to genotype data from the TwinsUK cohort was kindly provided by the Department of Twin Research and Genetic Epidemiology at King's College London. TwinsUK is funded by the Wellcome Trust and the European Community's Seventh Framework Programme (FP7/2007-2013) and also receives support from the UK Department of Health via a National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London. TwinsUK SNP genotyping was performed by the Wellcome Trust Sanger Institute and the National Eye Institute via the US National Institutes of Health/Center for Integrated Disease Research.

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Authors and Affiliations



H.J.C., J. Bentham, S.B., J.D.B., G.M.L., M.F., J.A.G. and B.D.K. conceived of and designed the study. J. Bentham, M.F. and B.D.K. secured funding for the GWAS. J. Bentham, A.T., C.C., G.B., J.G.-R., K.S., C.T., J. Breckpot, J.O., M.G., F.A.B., D.W., K.D., J.A.G. and B.D.K. supervised and/or coordinated discovery sample collection. A.T., G.B., J.G.-R., K.S., K.v.E., A.F.M.M., A.H.Z., F.A.B., D.W., B.J.M.M., S.M., A.V.P., J.A.G. and B.D.K. supervised and/or coordinated the replication sample collection. A.V., A.L.G., C.d.R., N.H.B. and C.R.B. supervised and/or coordinated human tissue sample collection. J. Bentham, R.M., T.R., D.H., A.T., D.Z., S.H., J.G.-R., K.S., R.S., T.T.K., P.B., C.R.B., G.M.L., J.A.G. and B.D.K. performed or supervised laboratory work. H.J.C., C.M., M.E.A. and M.F. performed statistical analyses. H.J.C., J. Breckpot, J.A.G. and B.D.K. wrote the first draft. All authors commented critically on and revised the draft.

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Correspondence to Judith A Goodship or Bernard D Keavney.

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The authors declare no competing financial interests.

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Supplementary Tables 1–4, Supplementary Figures 1–12 (PDF 17329 kb)

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Cordell, H., Bentham, J., Topf, A. et al. Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16. Nat Genet 45, 822–824 (2013).

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