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

Vanneste, Michiel, Hoskens, Hanne, Goovaerts, Seppe, Matthews, Harold, Devine, Jay, Aponte, Jose D., Cole, Joanne, Shriver, Mark, Marazita, Mary L., Weinberg, Seth M., Walsh, Susan, Richmond, Stephen ORCID: https://orcid.org/0000-0001-5449-5318, Klein, Ophir D., Spritz, Richard A., Peeters, Hilde, Hallgrímsson, Benedikt and Claes, Peter 2024. Syndrome-informed phenotyping identifies a polygenic background for achondroplasia-like facial variation in the general population. Nature Communications 15 (1) , 10458. 10.1038/s41467-024-54839-1

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Dentistry
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by-nc-nd/4.0/, Type: open-access
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	4 December 2024
Date of Acceptance:	21 November 2024
Last Modified:	04 Dec 2024 12:45
URI:	https://orca.cardiff.ac.uk/id/eprint/174492

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