Anorectal atresia and variants at predicted regulatory sites in candidate genes

Tonia C Carter; Denise M Kay; Marilyn L Browne; Aiyi Liu; Paul A Romitti; Devon Kuehn; Mary R Conley; Michele Caggana; Charlotte M Druschel; Lawrence C Brody; James L Mills

doi:10.1111/j.1469-1809.2012.00734.x

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Anorectal atresia and variants at predicted regulatory sites in candidate genes

Journal article

Peer reviewed

Anorectal atresia and variants at predicted regulatory sites in candidate genes

Tonia C Carter, Denise M Kay, Marilyn L Browne, Aiyi Liu, Paul A Romitti, Devon Kuehn, Mary R Conley, Michele Caggana, Charlotte M Druschel, Lawrence C Brody, …

Annals of human genetics, Vol.77(1), pp.31-46

01/2013

DOI: 10.1111/j.1469-1809.2012.00734.x

PMCID: PMC3535506

PMID: 23127126

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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.

Genetic Association Studies

Humans

Male

Anorectal Malformations

Case-Control Studies

Genetic Variation

Young Adult

Maternal Age

Anus, Imperforate - genetics

Genes, Regulator

Adult

Female

Polymorphism, Single Nucleotide

Infant, Newborn

Details

Title: Subtitle: Anorectal atresia and variants at predicted regulatory sites in candidate genes
Creators: Tonia C Carter - 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
Denise M Kay
Marilyn L Browne
Aiyi Liu
Paul A Romitti
Devon Kuehn
Mary R Conley
Michele Caggana
Charlotte M Druschel
Lawrence C Brody
James L Mills
Resource Type: Journal article
Publication Details: Annals of human genetics, Vol.77(1), pp.31-46
DOI: 10.1111/j.1469-1809.2012.00734.x
PMID: 23127126
PMCID: PMC3535506
NLM abbreviation: Ann Hum Genet
ISSN: 0003-4800
eISSN: 1469-1809
Publisher: England
Grant note: HHSN267200703431C / PHS HHS P30 ES005605 / NIEHS NIH HHS N01-DK-7-3431 / NIDDK NIH HHS ZIA HD008792-03 / Intramural NIH HHS
Language: English
Date published: 01/2013
Academic Unit: Epidemiology; Biostatistics
Record Identifier: 9983995174902771

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