Journal Article

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

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

2018

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adolescent / Adult / Bioinformatics / Biology / Biology and Life Sciences / Child / Child, Preschool / Cleft lip / Cleft Lip - genetics / Cleft lip/palate / Cleft palate / Cleft Palate - genetics / Councils / Dentistry / Epidemiology / Face / Funding / Genetic analysis / Genetic aspects / Genetic Association Studies / Genetic diversity / Genetic Predisposition to Disease / Genetic variance / Genetics / Genome-wide association studies / Genomes / Genotyping Techniques / Health sciences / Humans / Lip - abnormalities / Longitudinal Studies / Medical research / Medicine and Health Sciences / Meta-analysis / Morphology / Morphology (Biology) / Multifactorial Inheritance / Phenotype / Phenotypes / Physical Sciences / Physiological aspects / Polygenic inheritance / Polymorphism, Single Nucleotide / Population / Public health / Racial Groups - genetics / Research and Analysis Methods / Single-nucleotide polymorphism / Supervision / Young Adult