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 numerous 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 general population. We compare 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.

Fig. 1. Sample characteristics of the achondroplasia (ACH) and control dataset.

a Age and sex distribution, (b) Average facial shapes. Source data are provided as a Source Data file.

Fig. 2. Achondroplasia-informed phenotyping.

a Achondroplasia (ACH) trait axis spanning the ACH and control mean shapes. Morphs on the left and right sides of the axis represent the extremes of the phenotypic spectrum. Controls (ID_1-3) can be scored along the axis by measuring the angle between their individual vectors and the ACH trait vector. The facial variation of the three control individuals is visualized as a heatmap. Red areas on the facial shape correspond to a local outward deviation from the control mean shape, blue indicates inward deviation. b Distribution of the facial trait scores for the full face (segment 1) for both the ACH (in green) and control (in beige) datasets. Values smaller than 1 indicate more ACH-like; values greater than 1 indicate less ACH-like. The mean facial shape of the 5 lowest and highest-scoring individuals is shown for both ACH and control samples. c Manhattan plot of genome-wide associations. For each SNP, the lowest p-value (Canonical correlation analysis, right-tailed chi-square) across all 41 significant facial segments is plotted. The full horizontal line represents the genome-wide significance threshold (p = 5e-8). Candidate genes are annotated to each genome-wide significant locus (n = 19). Source data are provided as a Source Data file.

Fig. 3. GO enrichment analysis.

Relative fold enrichment of Gene Ontology (GO) biological processes enriched in the Achondroplasia (ACH) GWAS (diamonds) compared to different background sets. Terms with at least one gene in the background (circles) are shown for additional context. a ACH-informed GWAS versus uninformed GWAS of typical facial variation by White et al. . b ACH-informed GWAS versus all genes previously identified through GWAS of facial shape. Node size corresponds to the number of genes mapped to each process. P-values were estimated using a right-tailed hypergeometric test, alpha levels were adjusted to a 5% false discovery rate (FDR) using an adapted Benjamini-Hochberg procedure. Source data are provided as a Source Data file.

Fig. 4. Multivariate genotype-phenotype mapping of mouse and human craniofacial shape.

Genetic marker loadings for the multivariate genotype-phenotype mapping (MGP) of the GWAS candidate genes onto (a) mouse craniofacial shape and (c) human cranial vault shape. In (a), the relative contributions of the different founder genotypes of the Diversity Outbred mice are shown. In (c), the loadings per principal component are indicated. Genes are ordered by their relative contribution to the associated shape effects shown in (b) and (d), respectively. The top row shows the mean craniofacial shape colored according to the difference between the upper and lower extremes of the MGP shape axis. Red areas indicate a local inward deviation, and blue indicates an outward deviation. The middle row shows the upper extreme of the MGP shape axis. The bottom row shows the lower extreme of the same shape axis. Source data are provided as a Source Data file.