Fully automatic landmarking of 2D photographs identifies novel genetic loci influencing facial features

We report a genome-wide association study for facial features in > 6,000 Latin Americans. We placed 106 landmarks on 2D frontal photographs using the cloud service platform Face++. After Procrustes superposition, genome-wide association testing was performed for 301 inter-landmark distances. We detected nominally significant association (P-value < 5×10− 8) for 42 genome regions. Of these, 9 regions have been previously reported in GWAS of facial features. In follow-up analyses, we replicated 26 of the 33 novel regions (in East Asians or Europeans). The replicated regions include 1q32.3, 3q21.1, 8p11.21, 10p11.1, and 22q12.1, all comprising strong candidate genes involved in craniofacial development. Furthermore, the 1q32.3 region shows evidence of introgression from archaic humans. These results provide novel biological insights into facial variation and establish that automatic landmarking of standard 2D photographs is a simple and informative approach for the genetic analysis of facial variation, suitable for the rapid analysis of large population samples.- Introduction - Results And Discussion -- Study sample and phenotyping -- Trait/covariate correlation and heritability -- Overview of GWAS results and integration with the literature -- Follow-up of genomic regions newly associated with facial features: Replication in two human cohorts -- Follow-up of genomic regions newly associated with facial features: effects in the mouse -- Genome annotations at associated loci - Conclusion - Methods -- Study subjects -- Genotype data -- Phenotyping -- Statistical genetic analysis -- Interaction of EDAR with other genes -- Expression analysis for significant SNPs -- Detection of archaic introgression near ATF3 and association with facial features -- Annotation of SNPs in FUMA -- Shape GWAS in outbred mic

Automatic landmarking identifies new loci associated with face morphology and implicates Neanderthal introgression in human nasal shape

We report a genome-wide association study of facial features in >6000 Latin Americans based on automatic landmarking of 2D portraits and testing for association with inter-landmark distances. We detected significant associations (P-value <5 × 10−8) at 42 genome regions, nine of which have been previously reported. In follow-up analyses, 26 of the 33 novel regions replicate in East Asians, Europeans, or Africans, and one mouse homologous region influences craniofacial morphology in mice. The novel region in 1q32.3 shows introgression from Neanderthals and we find that the introgressed tract increases nasal height (consistent with the differentiation between Neanderthals and modern humans). Novel regions include candidate genes and genome regulatory elements previously implicated in craniofacial development, and show preferential transcription in cranial neural crest cells. The automated approach used here should simplify the collection of large study samples from across the world, facilitating a cosmopolitan characterization of the genetics of facial features

Statistical Modeling of Craniofacial Shape and Texture

We present a fully-automatic statistical 3D shape modeling approach and apply it to a large dataset of 3D images, the Headspace dataset, thus generating the first public shape-and-texture 3D Morphable Model (3DMM) of the full human head. Our approach is the first to employ a template that adapts to the dataset subject before dense morphing. This is fully automatic and achieved using 2D facial landmarking, projection to 3D shape, and mesh editing. In dense template morphing, we improve on the well-known Coherent Point Drift algorithm, by incorporating iterative data-sampling and alignment. Our evaluations demonstrate that our method has better performance in correspondence accuracy and modeling ability when compared with other competing algorithms. We propose a texture map refinement scheme to build high quality texture maps and texture model. We present several applications that include the first clinical use of craniofacial 3DMMs in the assessment of different types of surgical intervention applied to a craniosynostosis patient group

Three-Dimensional Cephalometric Landmarking and Frankfort Horizontal Plane Construction: Reproducibility of Conventional and Novel Landmarks

In some dentofacial deformity patients, especially patients undergoing surgical orthodontic treatments, Computed Tomography (CT) scans are useful to assess complex asymmetry or to plan orthognathic surgery. This assessment would be made easier for orthodontists and surgeons with a three-dimensional (3D) cephalometric analysis, which would require the localization of landmarks and the construction of reference planes. The objectives of this study were to assess manual landmarking repeatability and reproducibility (R&R) of a set of 3D landmarks and to evaluate R&R of vertical cephalometric measurements using two Frankfort Horizontal (FH) planes as references for horizontal 3D imaging reorientation. Thirty-three landmarks, divided into “conventional”, “foraminal” and “dental”, were manually located twice by three experienced operators on 20 randomly-selected CT scans of orthognathic surgery patients. R&R confidence intervals (CI) of each landmark in the -x, -y and -z directions were computed according to the ISO 5725 standard. These landmarks were then used to construct 2 FH planes: a conventional FH plane (orbitale left, porion right and left) and a newly proposed FH plane (midinternal acoustic foramen, orbitale right and left). R&R of vertical cephalometric measurements were computed using these 2 FH planes as horizontal references for CT reorientation. Landmarks showing a 95% CI of repeatability and/or reproducibility > 2 mm were found exclusively in the “conventional” landmarks group. Vertical measurements showed excellent R&R (95% CI < 1 mm) with either FH plane as horizontal reference. However, the 2 FH planes were not found to be parallel (absolute angular difference of 2.41°, SD 1.27°). Overall, “dental” and “foraminal” landmarks were more reliable than the “conventional” landmarks. Despite the poor reliability of the landmarks orbitale and porion, the construction of the conventional FH plane provided a reliable horizontal reference for 3D craniofacial CT scan reorientation

A landmark-free morphometrics pipeline for high-resolution phenotyping: application to a mouse model of Down syndrome

Characterising phenotypes often requires quantification of anatomical shape. Quantitative shape comparison (morphometrics) traditionally uses manually located landmarks and is limited by landmark number and operator accuracy. Here, we apply a landmark-free method to characterise the craniofacial skeletal phenotype of the Dp1Tyb mouse model of Down syndrome and a population of the Diversity Outbred (DO) mouse model, comparing it with a landmark-based approach. We identified cranial dysmorphologies in Dp1Tyb mice, especially smaller size and brachycephaly (front-back shortening), homologous to the human phenotype. Shape variation in the DO mice was partly attributable to allometry (size-dependent shape variation) and sexual dimorphism. The landmark-free method performed as well as, or better than, the landmark-based method but was less labour-intensive, required less user training and, uniquely, enabled fine mapping of local differences as planar expansion or shrinkage. Its higher resolution pinpointed reductions in interior mid-snout structures and occipital bones in both the models that were not otherwise apparent. We propose that this landmark-free pipeline could make morphometrics widely accessible beyond its traditional niches in zoology and palaeontology, especially in characterising developmental mutant phenotypes

Novel genetic loci affecting facial shape variation in humans

The human face represents a combined set of highly heritable phenotypes, but knowledge on its genetic architecture remains limited, despite the relevance for various fields. A series of genome-wide association studies on 78 facial shape phenotypes quantified from 3-dimensional facial images of 10,115 Europeans identified 24 genetic loci reaching study-wide suggestive association (p-8), among which 17 were previously unreported. A follow-up multi-ethnic study in additional 7,917 individuals confirmed 10 loci including 6 unreported ones (padjusted-3). A global map of derived polygenic face scores assembled facial features in major continental groups consistent with anthropological knowledge. Analyses of epigenomic datasets from cranial neural crest cells revealed abundant cis-regulatory activities at the face-associated genetic loci. Luciferase reporter assays in neural crest progenitor cells highlighted enhancer activities of several face-associated DNA variants. These results substantially advance our understanding of the genetic basis underlying human facial variation and provide candidates for future in-vivo functional studies