Syndrome-informed phenotyping identifies a polygenic background for achondroplasia-like facial variation in the general population

Abstract

Human craniofacial shape is highly variable yet highly heritable with genetic variants interacting through multiple layers of development. Here, we hypothesize that Mendelian phenotypes represent the extremes of a phenotypic spectrum and, using achondroplasia as an example, we introduce a syndrome-informed phenotyping approach to identify genomic loci associated with achondroplasia-like facial variation in the normal population. We 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 revealed a polygenic basis for normal facial variation along an achondroplasia-specific shape axis, identifying genes primarily involved in skeletal development. Jointly modeling these genes in two independent control samples showed 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 new insights into the genetic intersection of complex traits and Mendelian disorders.

Mapping genes for human face shape: exploration of univariate phenotyping strategies

“…While eventually achieving a comparable GWAS discovery rate to PCA, this convergence primarily resulted from the inclusion of more extreme facial examples, which were progressively less extreme. Nevertheless, while resemblance scores derived from syndromic and extreme facial examples may not yield the greatest number of loci in GWAS, studies [22–24] have demonstrated that a targeted facial phenotyping resulted in GWAS loci that displayed a stronger link with disease etiology versus non-targeted phenotyping approaches. Therefore, facial traits derived from genetic conditions may facilitate the discovery of disease-related genes and pathways in future investigations.…”

“…Furthermore, to investigate both typical-range and disease-associated variation in facial morphology, some studies employed a phenotyping method supervised by genetic conditions characterized by distinct facial features. Examples include resemblance scores to the facial archetype associated with Achondroplasia [22] and Pierre Robin Sequence [23] as well as resemblance scores to the distinctive facial endophenotype in unaffected family members of individuals with non-syndromic cleft lip [24]. The general idea of this approach is to directly measure the facial features that result from subtle variations within the same physiological pathways, which when disrupted result in distinct (sub-)clinical facial characteristics.…”

“…For instance, it is feasible to extract facial characteristics expected to exhibit high heritability, such as facial traits shared among siblings [21]. Another illustration is GWASs conducted using resemblance scores guided by patient facial archetype associated with Achondroplasia [22] or Pierre Robin Sequence [23]. Similarly, resemblance scores to the distinctive facial endophenotype in unaffected relatives of individuals with non-syndromic cleft lip was successfully used in GWAS, which helped to further elucidate the genetic susceptibility to non-syndromic cleft lip [24].…”