Genetic interactions in nonsyndromic orofacial clefts in Europe - EUROCRAN study

Peter Mossey, Julian Little, Regine P. Steegers-Theunissen, Anne M. Molloy, Borut Peterlin, William C. Shaw, Candice Johnson, David R. Fitzpatrick, Paola Franceschelli, Michele Rubini (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


Background. Nonsyndromic cleft lip with or without cleft palate (nsCL±P) and cleft palate (nsCP) are caused by a combination of genetic and environmental risk factors. We investigated gene-environment and gene-gene joint effects in a large multi-centre study of case-parent triads.
Methods. nsCL±P or nsCP triads were recruited in 11 European countries between 2001 and 2005. DNA samples were collected from infants, their mothers and fathers, and mothers completed a questionnaire on exposures including smoking and folic acid supplement use during pregnancy. We used log-linear regression to estimate relative risks (RR) and 95% confidence intervals (CI) for associations between nsCL±P or nsCP and variants in MTHFR, MTHFD1, TGFA, SATB2, and MSX1, stratifying by environmental or genetic factors.
Results. We obtained genotype and exposure data for 728 nsCL±P triads and 292 nsCP triads. In male infants, there was no association between the mother’s homozygous MSX1 p(CA) *4/*4 genotype and nsCL±P (RR 0.98, 95% CI 0.63-1.54) but this maternal genotype resulted in a doubling of risk for female infants (RR 2.21, 95% CI 1.13-4.34). There was evidence suggestive of gene-gene joint-effects between MTHFR-TGFA for nsCP but not nsCL±P.
Conclusion. Although we chose the genes and their variants and putative joint-effects based on associations previously reported in the literature, we replicated few associations. These results do not provide evidence supporting associations between these genes and oral clefts in European populations, although gene-environment and gene-gene interactions could play a role in oral cleft etiology.
Original languageEnglish
Pages (from-to)623-630
Number of pages8
JournalCleft Palate-Craniofacial Journal
Issue number6
Early online date20 Dec 2016
Publication statusPublished - Nov 2017


  • cleft lip
  • cleft palate
  • genetics
  • gene-environment interaction
  • gene-gene interaction


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