Abstract
Conotruncal heart defects (CTDs) are among the most common and severe groups of congenital heart defects. Despite evidence of an inherited genetic contribution to CTDs, little is known about the specific genes that contribute to the development of CTDs. We performed gene-based genome-wide analyses using microarray-genotyped and imputed common and rare variants data from two large studies of CTDs in the United States. We performed two case-parent trio analyses (N = 640 and 317 trios), using an extension of the family-based multi-marker association test, and two case-control analyses (N = 482 and 406 patients and comparable numbers of controls), using a sequence kernel association test. We also undertook two meta-analyses to combine the results from the analyses that used the same approach (i.e. family-based or case-control). To our knowledge, these analyses are the first reported gene-based, genome-wide association studies of CTDs. Based on our findings, we propose eight CTD candidate genes (ARF5, EIF4E, KPNA1, MAP4K3, MBNL1, NCAPG, NDFUS1 and PSMG3). Four of these genes (ARF5, KPNA1, NDUFS1 and PSMG3) have not been previously associated with normal or abnormal heart development. In addition, our analyses provide additional evidence that genes involved in chromatin-modification and in ribonucleic acid splicing are associated with congenital heart defects.
Highlights
Congenital heart defects (CHDs) are the most common group of birth defects, with a prevalence of approximately 1% in live births [1]
Nationwide, population-based studies conducted in Norway and Denmark indicate that conotruncal heart defects (CTDs) aggregate within families [9, 10] and that affected relatives of patients with a CTD are at a higher relative risk for CTDs (sibling CTD recurrence risk ratio: 9.0, 95% confidence interval (CI) 4.0–20.0) than for other types of CHDs [9]
Heart expression data from E9.5 and E14.5 mouse embryos [18] were available for 15 of the 19 protein-coding genes, of which eight (53%) were in the top quartile of expression at one or both time points (Table 5). We propose these eight genes (ARF5, EIF4E, karyopherin subunit alpha 1 (KPNA1), MAP4K3, MBNL1, NCAPG, NDFUS1, PSMG3) as CTD candidate genes
Summary
Congenital heart defects (CHDs) are the most common group of birth defects, with a prevalence of approximately 1% in live births [1]. There are many different CHD phenotypes, of which approximately one-third involve the cardiac outflow tracts and great arteries [6]–structures that develop from the cardiac neural crest and secondary heart field [7]. This subgroup of CHDs, collectively referred to as conotruncal heart defects (CTDs), includes some of the most severe and costly birth defects [3, 8]. In patients with the 22q11.2 deletion syndrome, the most common cardiac defects are CTDs, but the specific CTD phenotype (e.g. TOF, interrupted aortic arc) varies across patients with this deletion [12]
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