Detecting Gene-Environment Interaction for Maternal Exposures Using Case-Parent Trios Ascertained Through a Case With Non-Syndromic Orofacial Cleft.

Two large studies of case-parent trios ascertained through a proband with
a non-syndromic orofacial cleft (OFC, which includes cleft lip and palate,
cleft lip alone, or cleft palate alone) were used to test for possible
gene-environment (G × E) interaction between genome-wide markers (both
observed and imputed) and self-reported maternal exposure to smoking,
alcohol consumption, and multivitamin supplementation during pregnancy. The
parent studies were as follows: GENEVA, which included 1,939 case-parent
trios recruited largely through treatment centers in Europe, the United
States, and Asia, and 1,443 case-parent trios from the Pittsburgh Orofacial
Cleft Study (POFC) also ascertained through a proband with an OFC including
three major racial/ethnic groups (European, Asian, and Latin American).
Exposure rates to these environmental risk factors (maternal smoking,
alcohol consumption, and multivitamin supplementation) varied across
studies and among racial/ethnic groups, creating substantial differences in
power to detect G × E interaction, but the trio design should minimize
spurious results due to population stratification. The GENEVA and POFC
studies were analyzed separately, and a meta-analysis was conducted across
both studies to test for G × E interaction using the 2 df test of gene and
G × E interaction and the 1 df test for G × E interaction alone. The 2 df
test confirmed effects for several recognized risk genes, suggesting modest
G × E effects. This analysis did reveal suggestive evidence for G × Vitamin
interaction for CASP9 on 1p36 located about 3 Mb from PAX7, a recognized risk gene. Several regions gave suggestive evidence of G × E
interaction in the 1 df test. For example, for G × Smoking interaction, the
1 df test suggested markers in MUSK on 9q31.3 from meta-analysis. Markers near SLCO3A1 also showed suggestive evidence in the 1 df test for G × Alcohol
interaction, and rs41117 near RETREG1 (a.k.a. FAM134B) also gave suggestive significance in the meta-analysis of the 1 df test
for G × Vitamin interaction. While it remains quite difficult to obtain
definitive evidence for G × E interaction in genome-wide studies, perhaps
due to small effect sizes of individual genes combined with low exposure
rates, this analysis of two large case-parent trio studies argues for
considering possible G × E interaction in any comprehensive study of
complex and heterogeneous disorders such as OFC.