Abstract
Non-syndromic cleft lip with palate (NSCLP) is the most serious sub-phenotype of non-syndromic orofacial clefts (NSOFC), which are the most common craniofacial birth defects in humans. Here we conduct a GWAS of NSCLP with multiple independent replications, totalling 7,404 NSOFC cases and 16,059 controls from several ethnicities, to identify new NSCLP risk loci, and explore the genetic heterogeneity between sub-phenotypes of NSOFC. We identify 41 SNPs within 26 loci that achieve genome-wide significance, 14 of which are novel (RAD54B, TMEM19, KRT18, WNT9B, GSC/DICER1, PTCH1, RPS26, OFCC1/TFAP2A, TAF1B, FGF10, MSX1, LINC00640, FGFR1 and SPRY1). These 26 loci collectively account for 10.94% of the heritability for NSCLP in Chinese population. We find evidence of genetic heterogeneity between the sub-phenotypes of NSOFC and among different populations. This study substantially increases the number of genetic susceptibility loci for NSCLP and provides important insights into the genetic aetiology of this common craniofacial malformation.
Highlights
Non-syndromic cleft lip with palate (NSCLP) is the most serious sub-phenotype of nonsyndromic orofacial clefts (NSOFC), which are the most common craniofacial birth defects in humans
Only one genome-wide association study (GWAS) of non-syndromic CL with or without CP (NSCL/P) was conducted in a Chinese population[15] and the heritability in the risk of NSOFC remains unexplained in China, especially for the three distinct sub-groups of NSCLP, non-syndromic CL only (NSCLO) and non-syndromic CPO (NSCPO) in both Chinese and European populations
803,202 single-nucleotide polymorphisms (SNPs) (call rate495% and minor allele frequency (MAF)41%) in 2,033 NSCLP cases and 4,051 controls of Chinese ancestry were used in the GWAS discovery analysis (Fig. 1 and Supplementary Table 1)
Summary
Non-syndromic cleft lip with palate (NSCLP) is the most serious sub-phenotype of nonsyndromic orofacial clefts (NSOFC), which are the most common craniofacial birth defects in humans. We conduct a GWAS of NSCLP with multiple independent replications, totalling 7,404 NSOFC cases and 16,059 controls from several ethnicities, to identify new NSCLP risk loci, and explore the genetic heterogeneity between sub-phenotypes of NSOFC. We identify 41 SNPs within 26 loci that achieve genome-wide significance, 14 of which are novel (RAD54B, TMEM19, KRT18, WNT9B, GSC/DICER1, PTCH1, RPS26, OFCC1/TFAP2A, TAF1B, FGF10, MSX1, LINC00640, FGFR1 and SPRY1) These 26 loci collectively account for 10.94% of the heritability for NSCLP in Chinese population. NSOFC is further classified into non-syndromic cleft lip with palate (NSCLP), non-syndromic CL only (NSCLO) and non-syndromic CPO (NSCPO), based on the anatomical morphology[4] As they share common epidemiological patterns and occur during the same embryological period, NSCLP and NSCLO are often grouped together as non-syndromic CL with or without CP (NSCL/P), differing only in severity[5]. Evidence of genetic heterogeneity is observed between the three sub-phenotypes of NSOFC and among different populations
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