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.
| Original language | English |
|---|---|
| Pages (from-to) | 822-824 |
| Number of pages | 3 |
| Journal | Nature Genetics |
| Volume | 45 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Jul 2013 |
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In: Nature Genetics, Vol. 45, No. 7, 07.2013, p. 822-824.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16
AU - Cordell, Heather J.
AU - Bentham, Jamie
AU - Topf, Ana
AU - Zelenika, Diana
AU - Heath, Simon
AU - Mamasoula, Chrysovalanto
AU - Cosgrove, Catherine
AU - Blue, Gillian
AU - Granados-Riveron, Javier
AU - Setchfield, Kerry
AU - Thornborough, Chris
AU - Breckpot, Jeroen
AU - Soemedi, Rachel
AU - Martin, Ruairidh
AU - Rahman, Thahira J.
AU - Hall, Darroch
AU - Van Engelen, Klaartje
AU - Moorman, Antoon F.M.
AU - Zwinderman, Aelko H.
AU - Barnett, Phil
AU - Koopmann, Tamara T.
AU - Adriaens, Michiel E.
AU - Varro, Andras
AU - George, Alfred L.
AU - Dos Remedios, Christobal
AU - Bishopric, Nanette H.
AU - Bezzina, Connie R.
AU - O'Sullivan, John
AU - Gewillig, Marc
AU - Bu'Lock, Frances A.
AU - Winlaw, David
AU - Bhattacharya, Shoumo
AU - Devriendt, Koen
AU - Brook, J. David
AU - Mulder, Barbara J.M.
AU - Mital, Seema
AU - Postma, Alex V.
AU - Lathrop, G. Mark
AU - Farrall, Martin
AU - Goodship, Judith A.
AU - Keavney, Bernard D.
N1 - Funding Information: 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. Copyright: Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2013/7
Y1 - 2013/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84879687374&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/ng.2637
DO - https://doi.org/10.1038/ng.2637
M3 - Article
C2 - 23708191
SN - 1061-4036
VL - 45
SP - 822
EP - 824
JO - Nature Genetics
JF - Nature Genetics
IS - 7
ER -