Dataset Information

Genetic determination of human facial morphology: links between cleft-lips and normal variation.

ABSTRACT: Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with non-syndromic cleft lip with or without cleft palate (NSCL/P), and other previous studies showed distinctly differing facial distance measurements when comparing unaffected relatives of NSCL/P patients with normal controls. Here, we test the hypothesis that genetic loci involved in NSCL/P also influence normal variation in facial morphology. We tested 11 SNPs from 10 genomic regions previously showing replicated evidence of association with NSCL/P for association with normal variation of nose width and bizygomatic distance in two cohorts from Germany (N=529) and the Netherlands (N=2497). The two most significant associations found were between nose width and SNP rs1258763 near the GREM1 gene in the German cohort (P=6 × 10(-4)), and between bizygomatic distance and SNP rs987525 at 8q24.21 near the CCDC26 gene (P=0.017) in the Dutch sample. A genetic prediction model explained 2% of phenotype variation in nose width in the German and 0.5% of bizygomatic distance variation in the Dutch cohort. Although preliminary, our data provide a first link between genetic loci involved in a pathological facial trait such as NSCL/P and variation of normal facial morphology. Moreover, we present a first approach for understanding the genetic basis of human facial appearance, a highly intriguing trait with implications on clinical practice, clinical genetics, forensic intelligence, social interactions and personal identity.

SUBMITTER: Boehringer S

PROVIDER: S-EPMC3198142 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Genetic determination of human facial morphology: links between cleft-lips and normal variation.

Boehringer Stefan S van der Lijn Fedde F Liu Fan F Liu Fan F Günther Manuel M Sinigerova Stella S Nowak Stefanie S Ludwig Kerstin U KU Herberz Ruth R Klein Stefan S Hofman Albert A Uitterlinden Andre G AG Niessen Wiro J WJ Breteler Monique M B MM van der Lugt Aad A Würtz Rolf P RP Nöthen Markus M MM Horsthemke Bernhard B Wieczorek Dagmar D Mangold Elisabeth E Kayser Manfred M

European journal of human genetics : EJHG 20110622 11

Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with non-syndromic cleft lip with or without cleft palate (NSCL/P), and other previous studies showed distinctly differing facial distance measurements when comparing unaffected relatives of NSCL/P patients with normal controls. Here, we test the hypothesis that genetic loci involved in NSCL/P also influence normal variation in facial morphology. We tested 11 SNPs from 10 genomic regions prev ...[more]

PMID: 21694738

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Project description:IntroductionThe regular collection of 3-dimensional (3D) imaging data is critical to the development and implementation of accurate predictive models of facial skeletal growth. However, repeated exposure to x-ray-based modalities such as cone-beam computed tomography has unknown risks that outweigh many potential benefits, especially in pediatric patients. One solution is to make inferences about the facial skeleton from external 3D surface morphology captured using safe nonionizing imaging modalities alone. However, the degree to which external 3D facial shape is an accurate proxy of skeletal morphology has not been previously quantified. As a first step in validating this approach, we tested the hypothesis that population-level variation in the 3D shape of the face and skeleton significantly covaries.MethodsWe retrospectively analyzed 3D surface and skeletal morphology from a previously collected cross-sectional cone-beam computed tomography database of nonsurgical orthodontics patients and used geometric morphometrics and multivariate statistics to test the hypothesis that shape variation in external face and internal skeleton covaries.ResultsExternal facial morphology is highly predictive of variation in internal skeletal shape ([Rv] = 0.56, P <0.0001; partial least squares [PLS] 1-13 = 98.7% covariance, P <0.001) and asymmetry (Rv = 0.34, P <0.0001; PLS 1-5 = 90.2% covariance, P <0.001), whereas age-related (r(2) = 0.84, P <0.001) and size-related (r(2) = 0.67, P <0.001) shape variation was also highly correlated.ConclusionsSurface morphology is a reliable source of proxy data for the characterization of skeletal shape variation and thus is particularly valuable in research designs where reducing potential long-term risks associated with radiologic imaging methods is warranted. We propose that longitudinal surface morphology from early childhood through late adolescence can be a valuable source of data that will facilitate the development of personalized craniodental and treatment plans and reduce exposure levels to as low as reasonably achievable.

Project description:The purpose of this project is to identify genes associated with normal human quantitative facial variation. The motivation for this project stems from the fact that very little is known about how variation in specific genes relates to the diversity of facial forms commonly observed in humans. Viable candidates for these morphogenes originate from a number of sources: tissue expression studies, animal models with targeted or spontaneous mutations, and genetic syndromes with craniofacial manifestations. Importantly, understanding the genetic basis for normal facial variation also has important implications for health-related research. For example, this work has the potential to shed light on the factors influencing liability to common craniofacial anomalies such as orofacial clefts. There is now ample evidence that certain facial features (e.g., increased midfacial retrusion) characterize individuals genetically at-risk for orofacial clefts (e.g., biological relatives of affected cases). While these predisposing facial features are statistically over-represented in at-risk groups, they are also common in the general population. Since many of the current candidate genes for clefting are thought to play a critical role in facial morphogenesis, variation in these genes may also underlie normal variation in these facial features. These candidate genes, however, probably represent only a small fraction of the total number of loci influencing normal human facial variation. Phenotypes for this project were obtained from over 3000 healthy Caucasian subjects recruited through three separate studies. The majority of the subjects were recruited as part of the 3D Facial Norms Project, which is described in extensive detail here: (<a href="https://www.facebase.org/facial_norms/notes" target="_blank">https://www.facebase.org/facial_norms/notes</a>). The provided dbGaP phenotypes include a series of anthropometric craniofacial measurements (linear distances) primarily derived from 3D photographic facial surface scans (see previous hyperlink). The specific genotyping requested is described elsewhere in this document. Our analysis team is pursuing a variety of different analytic approaches to derive genetically informative phenotypes, including various shape-based morphometric methods. For those interested in pursuing more advanced phenotypic approaches, the original 3D surface scans and additional phenotypic traits are available to researchers through the FaceBase Consortium. This dataset has the potential to facilitate the discovery of new genetic loci with an important role in both normal and abnormal facial development. It may also serve as a dataset to test hypotheses regarding specific SNP associations (e.g. as a replication dataset) or as part of a larger meta-analysis.

Dataset Information

Genetic determination of human facial morphology: links between cleft-lips and normal variation.

Publications

Genetic determination of human facial morphology: links between cleft-lips and normal variation.

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