Anorectal atresia is a serious
birth defect of largely unknown etiology but candidate genes have been identified in animal studies and human syndromes. Because alterations in the activity of these genes might lead to
anorectal atresia, we selected 71 common variants predicted to be in
transcription factor binding sites, CpG windows, splice sites, and
miRNA target sites of 25 candidate genes, and tested for their association with
anorectal atresia. The study population comprised 150
anorectal atresia cases and 623 control infants without major malformations. Variants predicted to affect
transcription factor binding, splicing, and DNA methylation in WNT3A, PCSK5, TCF4, MKKS, GLI2, HOXD12, and BMP4 were associated with
anorectal atresia based on a nominal P value < 0.05. The GLI2 and BMP4 variants are reported to be moderately associated with gene expression changes (Spearman's rank correlation coefficients between -0.260 and 0.226). We did not find evidence for interaction between maternal pre-pregnancy
obesity and variants in MKKS, a gene previously associated with
obesity, on the risk of
anorectal atresia. Our results for MKKS support previously suggested associations with
anorectal malformations. Our findings suggest that more research is needed to determine whether altered GLI2 and BMP4 expression is important in
anorectal atresia in humans.