title: Anorectal atresia and variants at predicted regulatory sites in candidate genes.
abstract: 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.
authors.affiliation: Division of Epidemiology, Statistics, and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda 20892, MD, USA.
authors.forename: Tonia C
authors.initials: TC
authors.lastname: Carter
authors.forename: Denise M
authors.initials: DM
authors.lastname: Kay
authors.forename: Marilyn L
authors.initials: ML
authors.lastname: Browne
authors.forename: Aiyi
authors.initials: A
authors.lastname: Liu
authors.forename: Paul A
authors.initials: PA
authors.lastname: Romitti
authors.forename: Devon
authors.initials: D
authors.lastname: Kuehn
authors.forename: Mary R
authors.initials: MR
authors.lastname: Conley
authors.forename: Michele
authors.initials: M
authors.lastname: Caggana
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Druschel
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Brody
authors.forename: James L
authors.initials: JL
authors.lastname: Mills
mesh_terms: D000328:Adult; D000071056:Anorectal Malformations; D001006:Anus, Imperforate / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005809:Genes, Regulator; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008423:Maternal Age; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult