Abstract

Objective: To assess the association between common variants in CpG islands (CpG-SNPs) related to the expression of selected genes, and the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in a Chilean sample. Design: A total of 239 Chilean NSCL/P unrelated cases and 524 controls were genotyped using GSA array. Genotypes were imputed from the array, selecting those located within CpG islands coordinates and associated with the expression of genes differentially expressed in human cleft tissues. These selected SNPs were used for association analysis with NSCL/P based on logistic regression. Results: A total of 96 CpG-SNP met the above-mentioned criteria. After multiple comparisons correction (p-value<0.000862), only rs12940418 remains significantly associated with NSCL/P (OR 0.644, 95 % CI 0.496–0.833, p-value=0.000859). Although this variant is located 540 Kb away from the transcription start site of SHMT1, it has evidence of modulating its expression. Conclusions: The most plausible biological explanation for our results is cis/distal regulatory effect of rs12940418 on the expression of SHMT1. This gene encodes an enzyme implicated in folate/one-carbon metabolism, and its variants have been previously associated with NSCL/P in our population. Our results reveal the role of epigenetic mechanisms in birth defects expression such as DNA methylation and small RNAs. © 2025 Elsevier Ltd