title: Genome-wide association study of maternal and inherited effects on left-sided cardiac malformations.
abstract: Congenital left-sided lesions (LSLs) are serious, heritable malformations of the heart. However, little is known about the genetic causes of LSLs. This study was undertaken to identify common variants acting through the genotype of the affected individual (i.e. case) or the mother (e.g. via an in utero effect) that influence the risk of LSLs. A genome-wide association study (GWAS) was performed using data from 377 LSL case-parent triads, with follow-up studies in an independent sample of 224 triads and analysis of the combined data. Associations with both the case and maternal genotypes were assessed using log-linear analyses under an additive model. An association between LSLs and the case genotype for one intergenic SNP on chromosome 16 achieved genome-wide significance in the combined data (rs8061121, combined P = 4.0 × 10(-9); relative risk to heterozygote: 2.6, 95% CI: 1.9-3.7). In the combined data, there was also suggestive evidence of association between LSLs and the case genotype for a variant in the synaptoporin gene (rs1975649, combined P = 3.4 × 10(-7); relative risk to heterozygote: 1.6, 95% CI: 1.4-2.0) and between LSLs and the maternal genotype for an intergenic SNP on chromosome 10 (rs11008222, combined P = 6.3 × 10(-7); relative risk to heterozygote: 1.6, 95% CI: 1.4-2.0). This is the first GWAS of LSLs to evaluate associations with both the case and maternal genotypes. The results of this study identify three candidate LSL susceptibility loci, including one that appears to be associated with the risk of LSLs via the maternal genotype.
authors.affiliation: Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, TX 77030, USA laura.e.mitchell@uth.tmc.edu.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Mitchell
authors.affiliation: Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, TX 77030, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Agopian
authors.affiliation: Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, TX 77030, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Bhalla
authors.affiliation: The Center for Applied Genomics and.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Glessner
authors.affiliation: The Center for Applied Genomics and.
authors.forename: Cecilia E
authors.initials: CE
authors.lastname: Kim
authors.affiliation: Division of Biostatistics, University of Texas School of Public Health, Houston, TX 77030, USA and.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Swartz
authors.affiliation: The Center for Applied Genomics and Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Division of Cardiology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Goldmuntz
mesh_terms: D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008431:Maternal-Fetal Exchange; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D016708:Synaptophysin / Q000235:genetics*
chemical_list: C504260:SYNPR protein, human; D016708:Synaptophysin