Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity

TLDR

Non‑syndromic cleft lip with palate is the most serious sub‑phenotype of non‑syndromic orofacial clefts, the most common craniofacial birth defects in humans. The study aims to identify new NSCLP risk loci and explore genetic heterogeneity between sub‑phenotypes of NSOFC. The authors performed a GWAS of NSCLP using 7,404 cases and 16,059 controls from multiple ethnicities with independent replications. The GWAS identified 41 SNPs in 26 loci, including 14 novel loci, which together explain 10.94 % of NSCLP heritability, reveal genetic heterogeneity across sub‑phenotypes and populations, and substantially expand the known genetic architecture of this common craniofacial malformation.

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.