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

Laurence J Howe*, Myoung Keun Lee, Gemma C Sharp, George Davey Smith, Beate St Pourcain, John R Shaffer, Kerstin U Ludwig, Elisabeth Mangold, Mary L Marazita, Eleanor Feingold, Alexei Zhurov, Evie Stergiakouli, Jonathan Sandy, Stephen Richmond, Seth M Weinberg, Gibran Hemani, Sarah J Lewis

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

38 Citations (Scopus)
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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.

Original languageEnglish
Article numbere1007501
Number of pages18
JournalPLoS Genetics
Issue number8
Publication statusPublished - 1 Aug 2018


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