Abstract Human facial shape, while strongly heritable, involves both genetic and structural complexity, necessitating precise phenotyping for accurate assessment. Common phenotyping strategies include simplifying 3D facial features into univariate traits such as anthropometric measurements (e.g., inter-landmark distances), unsupervised dimensionality reductions (e.g., principal component analysis (PCA) and auto-encoder (AE) approaches), and assessing resemblance to particular facial gestalts (e.g., syndromic facial archetypes). This study provides a comparative assessment of these strategies in genome-wide association studies (GWASs) of 3D facial shape. Specifically, we investigated inter-landmark distances, PCA and AE-derived latent dimensions, and facial resemblance to random, extreme, and syndromic gestalts within a GWAS of 8,426 individuals of recent European ancestry. Inter-landmark distances exhibit the highest SNP-based heritability as estimated via LD score regression, followed by AE dimensions. Conversely, resemblance scores to extreme and syndromic facial gestalts display the lowest heritability, in line with expectations. Notably, the aggregation of multiple GWASs on facial resemblance to random gestalts reveals the highest number of independent genetic loci. This novel, easy-to-implement phenotyping approach holds significant promise for capturing genetically relevant morphological traits derived from complex biomedical imaging datasets, and its applications extend beyond faces. Nevertheless, these different phenotyping strategies capture different genetic influences on craniofacial shape. Thus, it remains valuable to explore these strategies individually and in combination to gain a more comprehensive understanding of the genetic factors underlying craniofacial shape and related traits. Author Summary Advancements linking variation in the human genome to phenotypes have rapidly evolved in recent decades and have revealed that most human traits are influenced by genetic variants to at least some degree. While many traits, such as stature, are straightforward to acquire and investigate, the multivariate and multipartite nature of facial shape makes quantification more challenging. In this study, we compared the impact of different facial phenotyping approaches on gene mapping outcomes. Our findings suggest that the choice of facial phenotyping method has an impact on apparent trait heritability and the ability to detect genetic association signals. These results offer valuable insights into the importance of phenotyping in genetic investigations, especially when dealing with highly complex morphological traits.

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