Genetic markers for non-syndromic orofacial clefts in populations of European ancestry: a meta-analysis

Lara Slavec,Ksenija Geršak,Nataša Karas Kuželički,Igor Locatelli

doi:10.1038/s41598-021-02159-5

Lara Slavec, Ksenija Geršak + Show 2 more

Open Access

https://doi.org/10.1038/s41598-021-02159-5

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Abstract

To date, the involvement of various genetic markers in the aetiopathogenesis of non-syndromic orofacial cleft (nsOFC) has been extensively studied. In the present study, we focused on studies performed on populations of European ancestry to systematically review the available literature to define relevant genetic risk factors for nsOFC. Eligible studies were obtained by searching Ovid Medline and Ovid Embase. We gathered the genetic markers from population-based case–control studies on nsOFC, and conducted meta-analysis on the repeatedly reported markers. Whenever possible, we performed stratified analysis based on different nsOFC phenotypes, using allelic, dominant, recessive and overdominant genetic models. Effect sizes were expressed as pooled odds ratios (ORs) with 95% confidence intervals (CIs), and p ≤ 0.05 were considered statistically significant. A total of 84 studies were eligible for this systematic review, with > 700 markers included. Of these, 43 studies were included in the meta-analysis. We analysed 47 genetic variants in 30 genes/loci, which resulted in 226 forest plots. There were statistically significant associations between at least one of the nsOFC phenotypes and 19 genetic variants in 13 genes/loci. These data suggest that IRF6, GRHL3, 8q24, VAX1, TGFA, FOXE1, ABCA4, NOG, GREM1, AXIN2, DVL2, WNT3A and WNT5A have high potential as biomarkers of nsOFC in populations of European descent. Although other meta-analyses that included European samples have been performed on a limited number of genetic variants, this study represents the first meta-analysis of all genetic markers that have been studied in connection with nsOFC in populations of European ancestry.

Highlights

To date, the involvement of various genetic markers in the aetiopathogenesis of non-syndromic orofacial cleft has been extensively studied
Our results suggest significant association between the variant and nsCPO only under overdominant model, but the association did not remain significant after applying Bonferroni correction
Due to the space limitations, we present the data for the genes where there were significant associations with moderate effect sizes, and provide a more detailed description of each gene, with discussion of the involvement of the individual variants in non-syndromic orofacial cleft (nsOFC) in Supplementary Discussion

Summary

Introduction

The involvement of various genetic markers in the aetiopathogenesis of non-syndromic orofacial cleft (nsOFC) has been extensively studied. There were statistically significant associations between at least one of the nsOFC phenotypes and 19 genetic variants in 13 genes/loci These data suggest that IRF6, GRHL3, 8q24, VAX1, TGFA, FOXE1, ABCA4, NOG, GREM1, AXIN2, DVL2, WNT3A and WNT5A have high potential as biomarkers of nsOFC in populations of European descent. Other meta-analyses that included European samples have been performed on a limited number of genetic variants, this study represents the first meta-analysis of all genetic markers that have been studied in connection with nsOFC in populations of European ancestry. Many genetic association studies have been performed to investigate the involvement of such candidate genes in nsOFC10–16. One reason might be that studies have been carried out on different populations or racial groups, and using insufficient sample sizes

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