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, Klein Ophir D, Spritz Richard A, Peeters Hilde, Hallgrímsson Benedikt, Claes Peter
Department of Human Genetics, KU Leuven, Leuven, Belgium.
Department of Cell Biology & Anatomy, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Nat Commun. 2024 Dec 2;15(1):10458. doi: 10.1038/s41467-024-54839-1.
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.
人类颅面形状具有高度变异性，但又具有高度遗传性，众多基因变异通过多层发育相互作用。在此，我们假设孟德尔表型代表了表型谱的极端情况，并以软骨发育不全为例，引入一种基于综合征的表型分析方法，以识别普通人群中与软骨发育不全样面部变异相关的基因组位点。我们比较了43例软骨发育不全患者和8246名对照者的三维面部扫描结果，以计算软骨发育不全样面部评分。对对照评分进行多变量全基因组关联研究（GWAS），揭示了沿软骨发育不全特异性形状轴面部变异的多基因基础，确定了主要参与骨骼发育的基因。在人类和小鼠这两个独立的对照样本中对这些基因进行联合建模，显示颅面效应接近典型的软骨发育不全表型。这些发现表明，复杂遗传变异和孟德尔遗传变异作用于相同的由发育决定的面部变异轴，为复杂性状和孟德尔疾病的遗传交叉提供了见解。
