Abstract
Non-syndromic cleft lip with or without cleft palate (nsCL/P) ranks among the most common human congenital malformations, and has a multifactorial background in which both exogenous and genetic risk factors act in concert. The present report describes a genome-wide association study (GWAS) involving a total of 285 nsCL/P patients and 1212 controls from the Netherlands and Belgium. Twenty of the 40 previously reported nsC/LP susceptibility loci were replicated, which underlined the validity of this sample. SNV-based analysis of the data identified an as yet unreported suggestive locus at chromosome 16p12.1 (p-value of the lead SNV: 4.17 × 10−7). This association was replicated in two of three patient/control replication series (Central European and Yemeni). Gene analysis of the GWAS data prioritized SH3PXD2A at chromosome 10q24.33 as a candidate gene for nsCL/P. To date, support for this gene as a cleft gene has been restricted to data from zebrafish and a knockout mouse model. The present GWAS was the first to implicate SH3PXD2A in non-syndromic cleft formation in humans. In summary, although performed in a relatively small sample, the present GWAS generated novel insights into nsCL/P etiology.
Highlights
Orofacial clefting represents the second most common congenital malformation in humans, after various forms of heart defects all combined [1]
Many key genetic findings in nsCL/P have resulted from another powerful tool of the genomics era, i.e., the genome-wide association study (GWAS) and follow-up analysis approach
The gene-set analysis implemented in FUMAGWAS revealed twelve gene ontology (GO) gene sets with an adjusted p-value < 0.05 (Table S2)
Summary
Orofacial clefting represents the second most common congenital malformation in humans, after various forms of heart defects all combined [1]. Many key genetic findings in nsCL/P have resulted from another powerful tool of the genomics era, i.e., the genome-wide association study (GWAS) and follow-up analysis approach. To date, this approach has identified a total of 38 common risk loci for nsCL/P [8,9,10,11,12,13,14,15,16,17,18,19,20]. At the time of writing, a total 40 common nsCL/P risk loci are known These account for only a modest proportion of the genetic variance of nsCL/P, e.g., up to 30% of the narrow-sense heritability in the European population [19]. Genetic marker data were aggregated to the level of whole genes or biological processing to test the joint association of all markers in the gene with the phenotype of interest, thereby increasing statistical power
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