In this study, researchers use syndrome-informed phenotyping to identify a polygenic background for achondroplasia-like facial variation in the general population.
The authors of this study hypothesize that Mendelian phenotypes represent the extremes of a phenotypic spectrum. Using achondroplasia as an example, they introduce a syndrome-informed phenotyping approach to identify genomic loci associated with achondroplasia-like facial variation in the general population. The researchers compared three-dimensional facial scans from 43 individuals with achondroplasia and 8246 controls to calculate achondroplasia-like facial scores. Multivariate GWAS of the control scores reveals a polygenic basis for facial variation along an achondroplasia-specific shape axis, identifying genes primarily involved in skeletal development. Jointly modeling these genes in two independent control samples, both human and mouse, shows craniofacial effects approximating the characteristic achondroplasia phenotype. These findings suggest that both complex and Mendelian genetic variation act on the same developmentally determined axes of facial variation, providing insights into the genetic intersection of complex traits and Mendelian disorders. Human craniofacial shape is highly variable yet highly heritable with numerous genetic variants interacting through multiple layers of development. (Published Abstract Provided)