Facial Shape Variation in Humans

The human face is a highly variable feature. Facial shape variation is seen between and within multiple populations. However, the source of this variation is mostly unknown. Furthermore, phenotypic variation is observed within syndromes that display a unique craniofacial phenotype. Because of this inherent variation, facial shape has a large clinical important and diagnostic significance. To explore facial shape variation, I have conducted several studies that examine the role of morphological integration in producing coordinated shape changes in the face. In these studies, I hypothesized that the size of the face and skull are correlated with facial shape; and that dysmorphic patients will display different morphological relationships between parts of the face, when compared to controls. These hypotheses were tested in several groups; namely healthy controls, patients with non-syndromic cleft lip and/or palate, and patients with ectodermal dysplasia. While these conditions have different etiologies, genetics, inheritance, mechanism of development, and resultant facial shape, using both of these patient groups has allowed me to explore these hypotheses in starkly different phenotypic groups. My studies have shown that the allometric factors of facial shape variation are complex and overlapping. Size represents a relatively small proportion of facial shape variation in humans. Furthermore, different classifications of cleft phenotypes are crucial when deciphering covariance structure in cleft individuals. Collectively, these studies have furthered the knowledge of complex craniofacial phenotypes, and have extended the knowledge on how allometry affects human facial shapes

Human Facial Shape and Size Heritability and Genetic Correlations

The human face is an array of variable physical features that together make each of us unique and distinguishable. Striking familial facial similarities underscore a genetic component, but little is known of the genes that underlie facial shape differences. Numerous studies have estimated facial shape heritability using various methods. Here, we used advanced three-dimensional imaging technology and quantitative human genetics analysis to estimate narrow-sense heritability, heritability explained by common genetic variation, and pairwise genetic correlations of 38 measures of facial shape and size in normal African Bantu children from Tanzania. Specifically, we fit a linear mixed model of genetic relatedness between close and distant relatives to jointly estimate variance components that correspond to heritability explained by genome-wide common genetic variation and variance explained by uncaptured genetic variation, the sum representing total narrow-sense heritability. Our significant estimates for narrow-sense heritability of specific facial traits range from 28 to 67%, with horizontal measures being slightly more heritable than vertical or depth measures. Furthermore, for over half of facial traits, >90% of narrow-sense heritability can be explained by common genetic variation. We also find high absolute genetic correlation between most traits, indicating large overlap in underlying genetic loci. Not surprisingly, traits measured in the same physical orientation (i.e., both horizontal or both vertical) have high positive genetic correlations, whereas traits in opposite orientations have high negative correlations. The complex genetic architecture of facial shape informs our understanding of the intricate relationships among different facial features as well as overall facial development

Human Facial Shape and Size Heritability and Genetic Correlations

The human face is an array of variable physical features that together make each of us unique and distinguishable. Striking familial facial similarities underscore a genetic component, but little is known of the genes that underlie facial shape differences. Numerous studies have estimated facial shape heritability using various methods. Here, we used advanced three-dimensional imaging technology and quantitative human genetics analysis to estimate narrow-sense heritability, heritability explained by common genetic variation, and pairwise genetic correlations of 38 measures of facial shape and size in normal African Bantu children from Tanzania. Specifically, we fit a linear mixed model of genetic relatedness between close and distant relatives to jointly estimate variance components that correspond to heritability explained by genome-wide common genetic variation and variance explained by uncaptured genetic variation, the sum representing total narrow-sense heritability. Our significant estimates for narrow-sense heritability of specific facial traits range from 28 to 67%, with horizontal measures being slightly more heritable than vertical or depth measures. Furthermore, for over half of facial traits, >90% of narrow-sense heritability can be explained by common genetic variation. We also find high absolute genetic correlation between most traits, indicating large overlap in underlying genetic loci. Not surprisingly, traits measured in the same physical orientation (i.e., both horizontal or both vertical) have high positive genetic correlations, whereas traits in opposite orientations have high negative correlations. The complex genetic architecture of facial shape informs our understanding of the intricate relationships among different facial features as well as overall facial development

Genomewide Association Study of African Children Identifies Association of <i>SCHIP1</i> and <i>PDE8A</i> with Facial Size and Shape

<div><p>The human face is a complex assemblage of highly variable yet clearly heritable anatomic structures that together make each of us unique, distinguishable, and recognizable. Relatively little is known about the genetic underpinnings of normal human facial variation. To address this, we carried out a large genomewide association study and two independent replication studies of Bantu African children and adolescents from Mwanza, Tanzania, a region that is both genetically and environmentally relatively homogeneous. We tested for genetic association of facial shape and size phenotypes derived from 3D imaging and automated landmarking of standard facial morphometric points. SNPs within genes <i>SCHIP1</i> and <i>PDE8A</i> were associated with measures of facial size in both the GWAS and replication cohorts and passed a stringent genomewide significance threshold adjusted for multiple testing of 34 correlated traits. For both <i>SCHIP1</i> and <i>PDE8A</i>, we demonstrated clear expression in the developing mouse face by both whole-mount <i>in situ</i> hybridization and RNA-seq, supporting their involvement in facial morphogenesis. Ten additional loci demonstrated suggestive association with various measures of facial shape. Our findings, which differ from those in previous studies of European-derived whites, augment understanding of the genetic basis of normal facial development, and provide insights relevant to both human disease and forensics.</p></div

<i>SCHIP1</i> locus associated with centroid size.

<p><b>(A)</b> Regional association plot of centroid size at the <i>SCHIP1</i> locus. Association data are shown using GWAS P-values with the meta-analysis P-value for the lead SNP, rs79909949. The LD pattern is based on the 1000 Genomes Project 2012 African reference and GRCh37/hg19. The estimated recombination rate (cM/Mb) is from HapMap samples. <b>(B)</b> Relative facial size at the upper and lower 95% confidence intervals for centroid size after adjusting for sex and age.</p

GWAS, replication, and meta-analysis results of replicated association signals.

<p>GWAS, replication, and meta-analysis results of replicated association signals.</p

Expression of <i>Schip1</i> and <i>Pde8a</i> during mouse embryonic development.

<p>Whole-mount <i>in situ</i> hybridization of <b>(A-D)</b> <i>Schip1</i> and <b>(E-H)</b> <i>Pde8a</i> expression in mouse embryos from E9.5 to E12.5. ba1, first branchial arch (future mandible); ba2, second branchial arch; fb, forebrain; fn, frontonasal process; fl, forelimb; hb, hindbrain; hl, hindlimb; ln, lateronasal process; mb, midbrain; md, mandible; mn, medionasal process; mx, maxilla; ov, otic vesicle.</p

Facial size and shape phenotypes tested for genetic association.

<p>Facial size and shape phenotypes tested for genetic association.</p

3D Facial scan with annotated landmarks.

<p>3D facial mesh obtained for each study individual with study landmarks obtained from automatic landmarking overlaid and labeled.</p