Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate

Terri H. Beaty, Ingo Ruczinski, Jeffrey C. Murray, Mary L. Marazita, Ronald G. Munger, Jacqueline B. Hetmanski, Tanda Murray, Richard J. Redett, M. Daniele Fallin, Kung Yee Liang, Tao Wu, Poorav J. Patel, Sheng Chih Jin, Tian Xiao Zhang, Holger Schwender, Yah Huei Wu-Chou, Philip K. Chen, Samuel S. Chong, Felicia Cheah, Vincent YeowXiaoqian Ye, Hong Wang, Shangzhi Huang, Ethylin W. Jabs, Bing Shi, Allen J. Wilcox, Rolv T. Lie, Sun Ha Jee, Kaare Christensen, Kimberley F. Doheny, Elizabeth W. Pugh, Hua Ling, Alan F. Scott

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

Nonsyndromic cleft palate (CP) is a common birth defect with a complex and heterogeneous etiology involving both genetic and environmental risk factors. We conducted a genome-wide association study (GWAS) using 550 case-parent trios, ascertained through a CP case collected in an international consortium. Family-based association tests of single nucleotide polymorphisms (SNP) and three common maternal exposures (maternal smoking, alcohol consumption, and multivitamin supplementation) were used in a combined 2 df test for gene (G) and gene-environment (G × E) interaction simultaneously, plus a separate 1 df test for G × E interaction alone. Conditional logistic regression models were used to estimate effects on risk to exposed and unexposed children. While no SNP achieved genome-wide significance when considered alone, markers in several genes attained or approached genome-wide significance when G × E interaction was included. Among these, MLLT3 and SMC2 on chromosome 9 showed multiple SNPs resulting in an increased risk if the mother consumed alcohol during the peri-conceptual period (3 months prior to conception through the first trimester). TBK1 on chr. 12 and ZNF236 on chr. 18 showed multiple SNPs associated with higher risk of CP in the presence of maternal smoking. Additional evidence of reduced risk due to G × E interaction in the presence of multivitamin supplementation was observed for SNPs in BAALC on chr. 8. These results emphasize the need to consider G × E interaction when searching for genes influencing risk to complex and heterogeneous disorders, such as nonsyndromic CP.

Original languageEnglish
Pages (from-to)469-478
Number of pages10
JournalGenetic Epidemiology
Volume35
Issue number6
DOIs
Publication statusPublished - Sep 1 2011
Externally publishedYes

Keywords

  • Cleft palate
  • Gene-environment interaction
  • Genome wide association studies

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)

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  • Cite this

    Beaty, T. H., Ruczinski, I., Murray, J. C., Marazita, M. L., Munger, R. G., Hetmanski, J. B., Murray, T., Redett, R. J., Fallin, M. D., Liang, K. Y., Wu, T., Patel, P. J., Jin, S. C., Zhang, T. X., Schwender, H., Wu-Chou, Y. H., Chen, P. K., Chong, S. S., Cheah, F., ... Scott, A. F. (2011). Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate. Genetic Epidemiology, 35(6), 469-478. https://doi.org/10.1002/gepi.20595