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Hum Mol Genet. 2016 Jun 1;25(11):2331-2341. Epub 2016 Mar 9.

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

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  • 1Department of Molecular and Human Genetics, Department of Pediatrics.
  • 2Department of Molecular and Human Genetics, Center for Statistical Genetics.
  • 3Department of Paediatrics, Children's Hospital, Linz, Austria.
  • 4Department of Molecular and Human Genetics.
  • 5Division of Cardiology, Seattle Children's Hospital, Seattle, WA, USA.
  • 6Pediatric Cardiology, University of Tennessee Health Science Center, Memphis, TN, USA.
  • 7Division of Cardiology, Department of Pediatrics, and.
  • 8Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
  • 9Department of Pediatrics.
  • 10School of Life Sciences, University of Nottingham, Nottingham, UK.
  • 11East Midlands Congenital Heart Centre, Glenfield Hospital, Leicester, UK.
  • 12Radcliffe Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
  • 13Center for Cardiovascular and Pulmonary Research.
  • 14Department of Pediatrics and Center for Cardiovascular and Pulmonary Research, The Heart Center, and.
  • 15Department of Pediatrics and The Heart Center, and.
  • 16Department of Pediatrics and Center for Microbial Pathogenesis, Nationwide Children's Hospital, Columbus, OH, USA.
  • 17College of Medicine, Ohio State University, Columbus, OH, USA.
  • 18Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK and.
  • 19Institute of Cardiovascular Sciences, The University of Manchester, Manchester, UK.
  • 20Department of Molecular and Human Genetics, Department of Pediatrics,
  • 21Department of Pediatrics and Center for Cardiovascular and Pulmonary Research,


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 × 10-8 for rs3746446; imputed Single Nucleotide Polymorphism (SNP) rs6088703 P= 3.01 × 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 × 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 × 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 × 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 ([Formula: see text] 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.

[Available on 2017-06-01]
[PubMed - in process]
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