title: Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate.
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.
authors: School of Public Health, Johns Hopkins University, 615 N. Wolfe St., Baltimore, Maryland, USA. tbeaty@jhsph.edu
authors: Terri H
authors: TH
authors: Beaty
authors: Ingo
authors: I
authors: Ruczinski
authors: Jeffrey C
authors: JC
authors: Murray
authors: Mary L
authors: ML
authors: Marazita
authors: Ronald G
authors: RG
authors: Munger
authors: Jacqueline B
authors: JB
authors: Hetmanski
authors: Tanda
authors: T
authors: Murray
authors: Richard J
authors: RJ
authors: Redett
authors: M Daniele
authors: MD
authors: Fallin
authors: Kung Yee
authors: KY
authors: Liang
authors: Tao
authors: T
authors: Wu
authors: Poorav J
authors: PJ
authors: Patel
authors: Sheng-Chih
authors: SC
authors: Jin
authors: Tian Xiao
authors: TX
authors: Zhang
authors: Holger
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authors: Schwender
authors: Yah Huei
authors: YH
authors: Wu-Chou
authors: Philip K
authors: PK
authors: Chen
authors: Samuel S
authors: SS
authors: Chong
authors: Felicia
authors: F
authors: Cheah
authors: Vincent
authors: V
authors: Yeow
authors: Xiaoqian
authors: X
authors: Ye
authors: Hong
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authors: Wang
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authors: Jabs
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authors: Sun Ha
authors: SH
authors: Jee
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authors: Christensen
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authors: KF
authors: Doheny
authors: Elizabeth W
authors: EW
authors: Pugh
authors: Hua
authors: H
authors: Ling
authors: Alan F
authors: AF
authors: Scott
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