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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.

Author information

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

Abstract

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.

PMID:
26965164
PMCID:
PMC5081047
DOI:
10.1093/hmg/ddw071
[Indexed for MEDLINE]
Free PMC Article

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