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A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20

Lookup NU author(s): Professor Judith Goodship, Professor Heather Cordell


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Congenital heart defects involving left-sided lesions (LSLs) are relatively common birth defects with substantial morbidity and mortality. Previous studies have suggested a high heritability with a complex genetic architecture, such that only a few LSL loci have been identified. We performed a genome-wide case-control association study to address the role of common variants using a discovery cohort of 778 cases and 2756 controls. We identified a genome-wide significant association mapping to a 200 kb region on chromosome 20q11 [P= 1.72 x 10(-8) for rs3746446; imputed Single Nucleotide Polymorphism (SNP) rs6088703 P= 3.01 x 10(-9), odds ratio (OR)= 1.6 for both]. This result was supported by transmission disequilibrium analyses using a subset of 541 case families (lowest P in region= 4.51 x 10(-5), OR= 1.5). Replication in a cohort of 367 LSL cases and 5159 controls showed nominal association (P= 0.03 for rs3746446) resulting in P= 9.49 x 10(-9) for rs3746446 upon meta-analysis of the combined cohorts. In addition, a group of seven SNPs on chromosome 1q21.3 met threshold for suggestive association (lowest P= 9.35 x 10(-7) for rs12045807). Both regions include genes involved in cardiac development-MYH7B/miR499A on chromosome 20 and CTSK, CTSS and ARNT on chromosome 1. Genome-wide heritability analysis using case-control genotyped SNPs suggested that the mean heritability of LSLs attributable to common variants is moderately high h range= 0.26-0.34) and consistent with previous assertions. These results provide evidence for the role of common variation in LSLs, proffer new genes as potential biological candidates, and give further insight to the complex genetic architecture of congenital heart disease.

Publication metadata

Author(s): Hanchard NA, Swaminathan S, Bucasas K, Furthner D, Fernbach S, Azamian MS, Wang XQ, Lewin M, Towbin JA, D'Alessandro LCA, Morris SA, Dreyer W, Denfield S, Ayres NA, Franklin WJ, Justino H, Lantin-Hermoso MR, Ocampo EC, Santos AB, Parekh D, Moodie D, Jeewa A, Lawrence E, Allen HD, Penny DJ, Fraser CD, Lupski JR, Popoola M, Wadhwa L, Brook JD, Bu'Lock FA, Bhattacharya S, Lalani SR, Zender GA, Fitzgerald-Butt SM, Bowman J, Corsmeier D, White P, Lecerf K, Zapata G, Hernandez P, Goodship JA, Garg V, Keavney BD, Leal SM, Cordell HJ, Belmont JW, McBride KL

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2016

Volume: 25

Issue: 11

Pages: 2331-2341

Print publication date: 01/06/2016

Online publication date: 09/03/2016

Acceptance date: 26/02/2016

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddw071


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Funder referenceFunder name
British Heart Foundation
European Union
Heart Research UK
1R21 HL106549-01National Institutes of Health (NIH)
1U54 HD083092National Institutes of Health (NIH)
2013096Doris Duke Charitable Foundation
5RO1 HD039056National Institutes of Health (NIH)
5RO1 HL090506National Institutes of Health (NIH)
5RO1 HL091771National Institutes of Health (NIH)
5 R01 HL109758National Institutes of Health (NIH)
U54HG006542US National Human Genome Research Institute (NHGRI)/National Heart Blood Lung Institute (NHLBI)