Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology

There is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used polygenic risk scores (PRS) to test for genetic overlap between nsCL/P and seven biologically relevant facial phenotypes. Where evidence was found of genetic overlap, we used bidirectional Mendelian randomization (MR) to test the hypothesis that genetic liability to nsCL/P is causally related to implicated facial phenotypes. Across 5,804 individuals of European ancestry from two studies, we found strong evidence, using PRS, of genetic overlap between nsCL/P and philtrum width; a 1 S.D. increase in nsCL/P PRS was associated with a 0.10 mm decrease in philtrum width (95% C.I. 0.054, 0.146; P = 2x10-5). Follow-up MR analyses supported a causal relationship; genetic variants for nsCL/P homogeneously cause decreased philtrum width. In addition to the primary analysis, we also identified two novel risk loci for philtrum width at 5q22.2 and 7p15.2 in our Genome-wide Association Study (GWAS) of 6,136 individuals. Our results support a liability threshold model of inheritance for nsCL/P, related to abnormalities in development of the philtrum.Author summary: Non-syndromic cleft lip/palate (nsCL/P) is a birth defect, primarily affecting the upper lip and hard palate. Individuals with nsCL/P and their unaffected family members sometimes present with other minor craniofacial anomalies and may have differences in facial morphology compared to the general population. Here, we investigate the shared genetic relationship between nsCL/P and facial morphology in a sample of around 6,000 Europeans from two different studies. We demonstrate that genetic risk factors for nsCL/P are associated with decreased philtrum width in unaffected individuals from the general population and that the relationship is likely causal. This finding is important because it demonstrates that nsCL/P, which is often treated as a dichotomous trait, may have a continuous dimension and offers insight into potential biological mechanisms that result in nsCL/P.