Background Maternal and inherited (i.e., case) genetic factors likely contribute to the etiology of congenital heart defects, but it is unclear whether individual common variants confer a large risk. Methods and Results To evaluate the relationship between individual common maternal/inherited genotypes and risk for heart defects, we conducted genome-wide association studies (GWAS) in five cohorts. Three cohorts were recruited at the Children’s Hospital of Philadelphia: 670 conotruncal heart defect (CTD) case-parent trios; 317 left ventricular obstructive tract defect (LVOTD) case-parent trios; and 406 CTD cases and 2,976 pediatric controls. Two cohorts were recruited through the Pediatric Cardiac Genomics Consortium: 355 CTD trios and 192 LVOTD trios. We also conducted meta-analyses using the GWAS results from the CTD cohorts, the LVOTD cohorts and from the combined CTD and LVOTD cohorts. In the individual GWAS, several genome-wide significant associations (p≤5×10−8) were observed. In our meta-analyses, one genome-wide significant association was detected: the case genotype for rs72820264, an intra-genetic SNP associated with LVOTDs (p=2.1×10−8). Conclusions We identified one novel candidate region associated with LVOTDs and report on several additional regions with suggestive evidence for association with CTD and/or LVOTD. These studies were constrained by the relatively small samples sizes and thus have limited power to detect small to moderate associations. Approaches that minimize the multiple testing burden (e.g. gene- or pathway-based) may, therefore, be required to uncover common variants contributing to the risk of these relatively rare conditions.
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