Identifying genes associated with obstructive congenital heart defects using a family-based genetic random field...

Congenital heart defects (CHDs) are the most common major congenital anomalies and the leading cause of infant mortality attributable to birth defects. Although substantial progress has been made in the identification of single-nucleotide variants associated with CHDs, the genetic etiology of CHDs remains largely unknown. While many studies have focused on common variants, efforts are underway to identify rare variants with heterogeneous effects on CHD development. We applied a family-based genetic random field (FGRF) method to buccal cell DNA specimens collected for the National Birth Defects Prevention Study, including 1,123 case families and 1,481 control families. We and others previously showed that the FGRF method was able to identify rare genetic variants associated with disease outcomes in the presence of disease heterogeneity. In this study, we conducted gene-based association tests for 24,270 genes and identified that SLC44A2 was significantly associated with obstructive CHD risk after Bonferroni adjustment for multiple testing, representing the most robust signal observed in our analyses, while other phase-specific findings require further validation. Our subsequent gene set enrichment analyses supported the likely role of this gene in the biological pathways relevant to CHD development. Our study is complementary to existing genome-wide association studies on CHD risk, providing additional insights into the genetic etiology of these birth defects.