TY - JOUR
T1 - Maternal and Parent-of-Origin Gene–Environment Effects on the Etiology of Orofacial Clefting
AU - Rasevic, Nikola
AU - Bastasic, Joseph
AU - Rubini, Michele
AU - Rakesh, Mohan R.
AU - Burkett, Kelly M.
AU - Ray, Debashree
AU - Mossey, Peter A.
AU - Peterlin, Borut
AU - Khan, Mohammad Faisal J.
AU - Ravaei, Amin
AU - Autelitano, Luca
AU - Meazzini, Maria C.
AU - Little, Julian
AU - Roy-Gagnon, Marie Hélène
N1 - Publisher Copyright:
© 2025 by the authors.
PY - 2025/2/4
Y1 - 2025/2/4
N2 - 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.
AB - 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.
KW - case-parent triads
KW - gene–environment interaction
KW - maternal genetic effects
KW - orofacial clefts
KW - parent-of-origin genetic effects
UR - http://www.scopus.com/inward/record.url?scp=85218903247&partnerID=8YFLogxK
U2 - 10.3390/genes16020195
DO - 10.3390/genes16020195
M3 - Article
C2 - 40004524
AN - SCOPUS:85218903247
SN - 2073-4425
VL - 16
JO - Genes
JF - Genes
IS - 2
M1 - 195
ER -