Dissecting the Polygenic and Multifactorial Basis of Craniofacial Development and Orofacial Anomalies

Craniofacial genetics and genetic epidemiology represent rapidly evolving fields at the intersection of human morphology, complex trait genetics, and multidisciplinary analytic strategies. Recent research has highlighted the intricate polygenic foundation underpinning craniofacial shape and the multifactorial etiology of orofacial clefts (OFC), one of the most prevalent congenital anomalies globally. Traditional studies limited to candidate gene associations or single-locus analyses have given way to comprehensive, multidimensional approaches that incorporate genome-wide association studies (GWAS), rare variant analyses, high-dimensional phenotyping, and novel statistical frameworks. Despite significant advances, such as identifying major loci like 1q32.2, 8q24, and 17p13.1 in OFC, and employing deep phenotyping in facial morphology, key questions persist about the full architecture and interaction of genetic factors, the functional pathways involved (e.g., glutathione synthesis, drug detoxification), and the relationship between complex traits and Mendelian disorders. Current gaps in the field include the challenge of detecting rare variant effects, understanding gene-gene and gene-environment interactions, and leveraging multidimensional phenotypic data to its fullest potential. This Research Topic aims to integrate cutting-edge statistical genetics, multidimensional phenotyping, and historical methodological insights to advance our understanding of the genetic foundations of both craniofacial variation and orofacial clefts. The main objectives are to elucidate the polygenic and multifactorial basis of craniofacial development, delineate shared and distinct genetic pathways between normal morphological variation and craniofacial anomalies, and foster innovative analytic methods for comprehensive data interrogation. Specific questions include how common and rare variants interact to mold craniofacial structure, which biological pathways mediate these effects, and how advances in genetic epidemiology can inform predictions, prevention, and personalized health interventions. The scope of this Research Topic encompasses research and reviews that deepen our knowledge of craniofacial trait genetics and orofacial cleft etiology through integrative multi-method approaches. It encourages submissions utilizing large-scale genomic data, advanced phenotyping modalities (including 3D facial imaging), and sophisticated statistical or computational techniques, but excludes studies restricted to single-gene or unidimensional models alone. To gather further insights into these interrelated domains, we welcome articles addressing, but not limited to, the following themes: - Polygenic risk scores and the discovery of novel genetic loci for craniofacial traits - Genome-wide and rare variant association studies in craniofacial development and OFC High-dimensional and multivariate phenotyping, including 3D facial morphology - Statistical genetics methodologies (e.g., linear mixed models, TWAS, conditional FDR) in craniofacial and orofacial cleft research -Mechanistic insights into biological pathways such as glutathione synthesis and drug detoxification - Historical and methodological reviews on the evolution of genetic studies in this field - The intersection of complex trait genetics with Mendelian craniofacial disorders - Predictive modeling and translational genomics for human health and disease prevention Topic editors: Goo Jun, Lord Jephthah Joojo Gowans Source: https://www.frontiersin.org/research-topics/79183/dissecting-the-polygenic-and-multifactorial-basis-of-craniofacial-development-and-orofacial-anomalies