title: A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20.
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 × 10-8for 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 × 10-9for 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 × 10-7for 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.
authors.affiliation: Department of Molecular and Human Genetics, Department of Pediatrics.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Hanchard
authors.affiliation: Department of Molecular and Human Genetics, Department of Pediatrics.
authors.forename: Shanker
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Department of Molecular and Human Genetics, Center for Statistical Genetics.
authors.forename: Kristine
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authors.lastname: Bucasas
authors.affiliation: Department of Paediatrics, Children's Hospital, Linz, Austria.
authors.forename: Dieter
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authors.lastname: Furthner
authors.affiliation: Department of Molecular and Human Genetics.
authors.forename: Susan
authors.initials: S
authors.lastname: Fernbach
authors.affiliation: Department of Molecular and Human Genetics.
authors.forename: Mahshid S
authors.initials: MS
authors.lastname: Azamian
authors.affiliation: Department of Molecular and Human Genetics.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Seattle Children's Hospital, Seattle, WA, USA.
authors.forename: Mark
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authors.lastname: Lewin
authors.affiliation: Pediatric Cardiology, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.affiliation: Division of Cardiology, Department of Pediatrics, and.
authors.forename: Lisa C A
authors.initials: LC
authors.lastname: D'Alessandro
authors.affiliation: Division of Cardiology, Department of Pediatrics, and.
authors.forename: Shaine A
authors.initials: SA
authors.lastname: Morris
authors.affiliation: Division of Cardiology, Department of Pediatrics, and.
authors.forename: William
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authors.lastname: Dreyer
authors.affiliation: Division of Cardiology, Department of Pediatrics, and.
authors.forename: Susan
authors.initials: S
authors.lastname: Denfield
authors.affiliation: Division of Cardiology, Department of Pediatrics, and.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Ayres
authors.affiliation: Division of Cardiology, Department of Pediatrics, and.
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Franklin
authors.affiliation: Division of Cardiology, Department of Pediatrics, and.
authors.forename: Henri
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authors.lastname: Justino
authors.affiliation: Division of Cardiology, Department of Pediatrics, and.
authors.forename: M Regina
authors.initials: MR
authors.lastname: Lantin-Hermoso
authors.affiliation: Division of Cardiology, Department of Pediatrics, and.
authors.forename: Elena C
authors.initials: EC
authors.lastname: Ocampo
authors.affiliation: Division of Cardiology, Department of Pediatrics, and.
authors.forename: Alexia B
authors.initials: AB
authors.lastname: Santos
authors.affiliation: Division of Cardiology, Department of Pediatrics, and.
authors.forename: Dhaval
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authors.lastname: Parekh
authors.affiliation: Division of Cardiology, Department of Pediatrics, and.
authors.forename: Douglas
authors.initials: D
authors.lastname: Moodie
authors.affiliation: Division of Cardiology, Department of Pediatrics, and.
authors.forename: Aamir
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authors.lastname: Jeewa
authors.affiliation: Division of Cardiology, Department of Pediatrics, and.
authors.forename: Emily
authors.initials: E
authors.lastname: Lawrence
authors.affiliation: Division of Cardiology, Department of Pediatrics, and.
authors.forename: Hugh D
authors.initials: HD
authors.lastname: Allen
authors.affiliation: Division of Cardiology, Department of Pediatrics, and.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Penny
authors.affiliation: Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Fraser
authors.affiliation: Department of Molecular and Human Genetics, Department of Pediatrics.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Department of Pediatrics.
authors.forename: Mojisola
authors.initials: M
authors.lastname: Popoola
authors.affiliation: Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Lalita
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authors.lastname: Wadhwa
authors.affiliation: School of Life Sciences, University of Nottingham, Nottingham, UK.
authors.forename: J David
authors.initials: JD
authors.lastname: Brook
authors.affiliation: East Midlands Congenital Heart Centre, Glenfield Hospital, Leicester, UK.
authors.forename: Frances A
authors.initials: FA
authors.lastname: Bu'Lock
authors.affiliation: Radcliffe Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Shoumo
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Department of Molecular and Human Genetics.
authors.forename: Seema R
authors.initials: SR
authors.lastname: Lalani
authors.affiliation: Center for Cardiovascular and Pulmonary Research.
authors.forename: Gloria A
authors.initials: GA
authors.lastname: Zender
authors.affiliation: Department of Pediatrics and Center for Cardiovascular and Pulmonary Research, The Heart Center, and.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Fitzgerald-Butt
authors.affiliation: Department of Pediatrics and The Heart Center, and.
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authors.lastname: Bowman
authors.affiliation: Department of Pediatrics and Center for Microbial Pathogenesis, Nationwide Children's Hospital, Columbus, OH, USA.
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authors.lastname: Corsmeier
authors.affiliation: Department of Pediatrics and Center for Microbial Pathogenesis, Nationwide Children's Hospital, Columbus, OH, USA.
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authors.lastname: White
authors.affiliation: College of Medicine, Ohio State University, Columbus, OH, USA.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Lecerf
authors.affiliation: Department of Molecular and Human Genetics, Department of Pediatrics.
authors.forename: Gladys
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authors.lastname: Zapata
authors.affiliation: Department of Molecular and Human Genetics, Department of Pediatrics.
authors.forename: Patricia
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authors.lastname: Hernandez
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK and.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Goodship
authors.affiliation: Department of Pediatrics and Center for Cardiovascular and Pulmonary Research, The Heart Center, and.
authors.forename: Vidu
authors.initials: V
authors.lastname: Garg
authors.affiliation: Institute of Cardiovascular Sciences, The University of Manchester, Manchester, UK.
authors.forename: Bernard D
authors.initials: BD
authors.lastname: Keavney
authors.affiliation: Department of Molecular and Human Genetics, Center for Statistical Genetics.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK and.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.affiliation: Department of Molecular and Human Genetics, Department of Pediatrics, kim.mcbride@nationwidechildrens.org jbelmont@bcm.edu.
authors.forename: John W
authors.initials: JW
authors.lastname: Belmont
authors.affiliation: Department of Pediatrics and Center for Cardiovascular and Pulmonary Research, kim.mcbride@nationwidechildrens.org jbelmont@bcm.edu.
authors.forename: Kim L
authors.initials: KL
authors.lastname: McBride
mesh_terms: D002874:Chromosome Mapping; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology; D006352:Heart Ventricles / Q000503:physiopathology; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide