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

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

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

Facial size and shape phenotypes tested for genetic association.

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

<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

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

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

World Health Organization 2007 reference BMI Z-scores for the Tanzanian study population.

<p>Histogram of Tanzanian Z-scores calculated from WHO 2007 reference data by age and sex with WHO cutoffs for thinness and overweight classifications.</p

<i>SCHIP1</i> locus associated with PC4.

<p><b>(A)</b> Regional association plot of PC4 at the <i>SCHIP1</i> locus. Association data are shown using GWAS P-values. The most associated SNP rs368386044 could not be displayed in the LocusZoom plot, but is in complete linkage disequilibrium with rs9868698. See <b><a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006174#pgen.1006174.g003" target="_blank">Fig 3</a></b>legend for details. <b>(B)</b> Morphs showing the range of shape variation along PC4. The heatmap depicts the regions of the face that vary the most between the min and max morphs. Red shows the regions that project most beyond the mean mesh at the positive extreme while yellow is intermediate in that direction. Blue shows the areas that project most inwards from the mean mesh while light blue shows a lesser degree of inwards projection. Green shows those regions that align most closely to the mean mesh.</p