Maternal and Parent-of-Origin Gene-Environment Effects on the Etiology of Orofacial Clefting

Abstract

Background/Objectives: We investigated maternal and parent-of-origin (PoO) gene-environment interaction effects on the risk of nonsyndromic orofacial clefts for two maternal environmental factors: periconceptional smoking and folic acid supplementation. Methods: Genome-wide single nucleotide polymorphisms (SNPs) genotypes and TopMed-imputed genotypes were obtained for case-parent triads from the EUROCRAN and ITALCLEFT studies. Candidate regions were selected around target SNPs from a previous genome-wide association study, resulting in 12 (726 SNPs) and 11 regions (730 SNPs) for maternal and PoO effects, respectively. Log-linear models were used to analyze 404 case-parent triads and 40 case-parent dyads. p-values were combined across regions. Results: None of the interactions reached statistical significance after correction for the number of regions tested. Nominally significant (pooled p-values < 0.05) interactions pointed to regions in or close to genes LRRC7 (maternal gene-folate interaction), NCKAP5 (PoO-smoking interaction), and IFT43 and GPATCH2L (PoO-folate interaction). Conclusions: Our results suggested that the genetic effects in or around these genes were heightened under periconceptional exposure to tobacco or no folic acid supplementation. The involvement of these genes in orofacial cleft development, in conjunction with environmental exposures, should be further studied.

Keywords: case-parent triads; gene–environment interaction; maternal genetic effects; orofacial clefts; parent-of-origin genetic effects.

Figure 1

(a) Wald test for the interaction between maternal genetic effects and smoking; (b) Wald test for the interaction between maternal genetic effects and folic acid supplementation. Colors represent linkage disequilibrium (LD) structure in the region measured by r² with the most significant SNP. SNP p-values are shown as diamond shapes, where filled shapes indicate imputed SNPs and open shapes indicate genotyped SNPs. Pooled empirical Fisher and Cauchy p-values are shown as open black triangles and circles. The black, green, and orange dashed lines indicate, respectively, the 0.05 significance level, the significance level for the pooled p-value Bonferroni-corrected for the number of regions tested, and the significance level Bonferroni corrected for the total number of SNPs tested across all regions.

Figure 2

(a) Wald test for the interaction between parent-of-origin genetic effects and smoking; (b) Wald test for the interaction between parent-of-origin genetic effects and folic acid supplementation. Colors represent linkage disequilibrium (LD) structure in the region measured by r² with the most significant SNP. SNP p-values are shown as diamond shapes, where filled shapes indicate imputed SNPs and open shapes indicate genotyped SNPs. Pooled empirical Fisher and Cauchy p-values are shown as open black triangles and circles. The black, green, and orange dashed lines indicate, respectively, the 0.05 significance level, the significance level for the pooled p-value Bonferroni corrected for the number of regions tested, and the significance level Bonferroni corrected for the total number of SNPs tested across all regions.