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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

Nature Genetics volume 45, pages 822–824 (2013)Cite this article

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Abstract

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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References

  1. Tennant, P.W., Pearce, M.S., Bythell, M. & Rankin, J. 20-year survival of children born with congenital anomalies: a population-based study. Lancet 375, 649–656 (2010).

    Article  Google Scholar 

  2. Soemedi, R. et al. Contribution of global rare copy-number variants to the risk of sporadic congenital heart disease. Am. J. Hum. Genet. 91, 489–501 (2012).

    Article  CAS  Google Scholar 

  3. Pruim, R.J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).

    Article  CAS  Google Scholar 

  4. Webb, G. & Gatzoulis, M.A. Atrial septal defects in the adult: recent progress and overview. Circulation 114, 1645–1653 (2006).

    Article  Google Scholar 

  5. Campbell, M. Natural history of atrial septal defect. Br. Heart J. 32, 820–826 (1970).

    Article  CAS  Google Scholar 

  6. Iinuma, T. et al. Role of syntaxin 18 in the organization of endoplasmic reticulum subdomains. J. Cell Sci. 122, 1680–1690 (2009).

    Article  CAS  Google Scholar 

  7. Boogerd, K.J. et al. Msx1 and Msx2 are functional interacting partners of T-box factors in the regulation of Connexin43. Cardiovasc. Res. 78, 485–493 (2008).

    Article  CAS  Google Scholar 

  8. Li, Q.Y. et al. Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat. Genet. 15, 21–29 (1997).

    Article  Google Scholar 

  9. Chen, Y.H., Ishii, M., Sucov, H.M. & Maxson, R.E. Jr. Msx1 and Msx2 are required for endothelial-mesenchymal transformation of the atrioventricular cushions and patterning of the atrioventricular myocardium. BMC Dev. Biol. 8, 75 (2008).

    Article  CAS  Google Scholar 

  10. Ishii, M. et al. Combined deficiencies of Msx1 and Msx2 cause impaired patterning and survival of the cranial neural crest. Development 132, 4937–4950 (2005).

    Article  CAS  Google Scholar 

  11. Jumlongras, D. et al. A nonsense mutation in MSX1 causes Witkop syndrome. Am. J. Hum. Genet. 69, 67–74 (2001).

    Article  CAS  Google Scholar 

  12. van den Boogaard, M.J., Dorland, M., Beemer, F.A. & van Amstel, H.K. MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. Nat. Genet. 24, 342–343 (2000).

    Article  CAS  Google Scholar 

  13. Vastardis, H., Karimbux, N., Guthua, S.W., Seidman, J.G. & Seidman, C.E. A human MSX1 homeodomain missense mutation causes selective tooth agenesis. Nat. Genet. 13, 417–421 (1996).

    Article  CAS  Google Scholar 

  14. Goodship, J.A. et al. A common variant in the PTPN11 gene contributes to the risk of tetralogy of Fallot. Circ. Cardiovasc. Genet. 5, 287–292 (2012).

    Article  CAS  Google Scholar 

  15. Greenway, S.C. et al. De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nat. Genet. 41, 931–935 (2009).

    Article  CAS  Google Scholar 

  16. Soemedi, R. et al. Phenotype-specific effect of chromosome 1q21.1 rearrangements and GJA5 duplications in 2436 congenital heart disease patients and 6760 controls. Hum. Mol. Genet. 21, 1513–1520 (2012).

    Article  CAS  Google Scholar 

  17. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  18. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).

    Article  CAS  Google Scholar 

  19. Barrett, J.C. et al. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat. Genet. 41, 1330–1334 (2009).

    Article  CAS  Google Scholar 

  20. Mells, G.F. et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat. Genet. 43, 329–332 (2011).

    Article  CAS  Google Scholar 

  21. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  Google Scholar 

  22. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

    Article  CAS  Google Scholar 

  23. Abecasis, G.R. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

    Article  Google Scholar 

  24. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  25. Moorman, A.F., Houweling, A.C., de Boer, P.A. & Christoffels, V.M. Sensitive nonradioactive detection of mRNA in tissue sections: novel application of the whole-mount in situ hybridization protocol. J. Histochem. Cytochem. 49, 1–8 (2001).

    Article  CAS  Google Scholar 

  26. Dunning, M.J., Smith, M.L., Ritchie, M.E. & Tavare, S. beadarray: R classes and methods for Illumina bead-based data. Bioinformatics 23, 2183–2184 (2007).

    Article  CAS  Google Scholar 

  27. Kauffmann, A., Gentleman, R. & Huber, W. arrayQualityMetrics—a bioconductor package for quality assessment of microarray data. Bioinformatics 25, 415–416 (2009).

    Article  CAS  Google Scholar 

  28. Shi, W., Oshlack, A. & Smyth, G.K. Optimizing the noise versus bias trade-off for Illumina whole genome expression BeadChips. Nucleic Acids Res. 38, e204 (2010).

    Article  Google Scholar 

  29. Aulchenko, Y.S., Ripke, S., Isaacs, A. & van Duijn, C.M. GenABEL: an R library for genome-wide association analysis. Bioinformatics 23, 1294–1296 (2007).

    Article  CAS  Google Scholar 

  30. Scott, L.J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Author notes

  1. Javier Granados-Riveron

    Present address: Present address: Department of Genetics, Genomics and Bioinformatics, Hospital Infantil de México Federico Gómez, Mexico City, Mexico.,

  2. Heather J Cordell and Jamie Bentham: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK

    Heather J Cordell, Ana Topf, Chrysovalanto Mamasoula, Rachel Soemedi, Ruairidh Martin, Thahira J Rahman, Darroch Hall, Judith A Goodship & Bernard D Keavney

  2. Department of Cardiovascular Medicine, University of Oxford, Oxford, UK

    Jamie Bentham, Catherine Cosgrove, Shoumo Bhattacharya & Martin Farrall

  3. Commisariat à l'Energie Atomique (CEA), Institut Genomique, Centre National de Genotypage, Evry, France

    Diana Zelenika, Simon Heath & G Mark Lathrop

  4. Fondation Jean Dausset, Centre d'Etude du Polymorphisme Humain, Paris, France

    Diana Zelenika & G Mark Lathrop

  5. Centro Nacional de Análisis Genómico, Barcelona, Spain

    Simon Heath

  6. The Children's Hospital at Westmead, Westmead, New South Wales, Australia

    Gillian Blue & David Winlaw

  7. Institute of Genetics, University of Nottingham, Nottingham, UK

    Javier Granados-Riveron, Kerry Setchfield & J David Brook

  8. East Midlands Congenital Heart Centre, University Hospitals of Leicester National Health Service (NHS) Trust, Leicester, UK

    Chris Thornborough & Frances A Bu'Lock

  9. Center for Human Genetics, University of Leuven, Leuven, Belgium

    Jeroen Breckpot & Koen Devriendt

  10. Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands

    Klaartje van Engelen

  11. Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands

    Antoon F M Moorman, Phil Barnett & Alex V Postma

  12. Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, The Netherlands

    Aelko H Zwinderman

  13. Department of Clinical and Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands

    Tamara T Koopmann, Michiel E Adriaens & Connie R Bezzina

  14. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary

    Andras Varro

  15. Department of Medicine, Division of Genetic Medicine, Vanderbilt University, Nashville, Tennessee, USA

    Alfred L George Jr

  16. Department of Anatomy, Muscle Research Unit, Bosch Institute, The University of Sydney, Sydney, New South Wales, Australia

    Christobal dos Remedios

  17. Department of Medicine, Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida, USA

    Nanette H Bishopric

  18. Newcastle Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK

    John O'Sullivan

  19. Pediatric Cardiology, University of Leuven, Leuven, Belgium

    Marc Gewillig

  20. Heart Center, Academic Medical Center, Amsterdam, The Netherlands

    Barbara J M Mulder

  21. Hospital for Sick Children, Toronto, Ontario, Canada

    Seema Mital

  22. Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK

    Bernard D Keavney

Authors
  1. Heather J Cordell
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  2. Jamie Bentham
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  3. Ana Topf
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  8. Gillian Blue
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  24. Alfred L George Jr
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  26. Nanette H Bishopric
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  27. Connie R Bezzina
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  28. John O'Sullivan
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  29. Marc Gewillig
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  30. Frances A Bu'Lock
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  31. David Winlaw
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  32. Shoumo Bhattacharya
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  33. Koen Devriendt
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  34. J David Brook
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  35. Barbara J M Mulder
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  36. Seema Mital
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  37. Alex V Postma
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  38. G Mark Lathrop
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  39. Martin Farrall
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  40. Judith A Goodship
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Contributions

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.

Corresponding authors

Correspondence to Judith A Goodship or Bernard D Keavney.

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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). https://doi.org/10.1038/ng.2637

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