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

Michiel Vanneste, Hanne Hoskens, Seppe Goovaerts, Harold Matthews, Jay Devine, Jose D. Aponte, Joanne Cole, Mark Shriver, Mary L. Marazita, Seth M. Weinberg, Susan Walsh, Stephen Richmond, Ophir D. Klein, Richard A. Spritz, Hilde Peeters (), Benedikt Hallgrímsson () and Peter Claes ()
Additional contact information
Michiel Vanneste: KU Leuven
Hanne Hoskens: University of Calgary
Seppe Goovaerts: KU Leuven
Harold Matthews: KU Leuven
Jay Devine: University Hospitals Leuven
Jose D. Aponte: University of Calgary
Joanne Cole: University of Colorado School of Medicine
Mark Shriver: Pennsylvania State University
Mary L. Marazita: University of Pittsburgh
Seth M. Weinberg: University of Pittsburgh
Susan Walsh: Indiana University Purdue University Indianapolis
Stephen Richmond: Cardiff University
Ophir D. Klein: Cedars-Sinai Guerin Children’s
Richard A. Spritz: University of Colorado School of Medicine
Hilde Peeters: KU Leuven
Benedikt Hallgrímsson: University of Calgary
Peter Claes: KU Leuven

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-54839-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54839-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-54839-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().