Via PLOS genetics
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Abstract
Inter-individual variation in facial shape is one of the most noticeable
phenotypes in humans, and it is clearly under genetic regulation;
however, almost nothing is known about the genetic basis of normal human
facial morphology. We therefore conducted a genome-wide association
study for facial shape phenotypes in multiple discovery and replication
cohorts, considering almost ten thousand individuals of European descent
from several countries. Phenotyping of facial shape features was based
on landmark data obtained from three-dimensional head magnetic resonance
images (MRIs) and two-dimensional portrait images. We identified five
independent genetic loci associated with different facial phenotypes,
suggesting the involvement of five candidate genes—PRDM16, PAX3, TP63, C5orf50, and COL17A1—in
the determination of the human face. Three of them have been implicated
previously in vertebrate craniofacial development and disease, and the
remaining two genes potentially represent novel players in the molecular
networks governing facial development. Our finding at PAX3
influencing the position of the nasion replicates a recent GWAS of
facial features. In addition to the reported GWA findings, we
established links between common DNA variants previously associated with
NSCL/P at 2p21, 8q24, 13q31, and 17q22 and normal facial-shape
variations based on a candidate gene approach. Overall our study implies
that DNA variants in genes essential for craniofacial development
contribute with relatively small effect size to the spectrum of normal
variation in human facial morphology. This observation has important
consequences for future studies aiming to identify more genes involved
in the human facial morphology, as well as for potential applications of
DNA prediction of facial shape such as in future forensic applications.
Introduction
The morphogenesis and
patterning of the face is one of the most complex events in mammalian
embryogenesis. Signaling cascades initiated from both facial and
neighboring tissues mediate transcriptional networks that act to direct
fundamental cellular processes such as migration, proliferation,
differentiation and controlled cell death. The complexity of human
facial development is reflected in the high incidence of congenital
craniofacial anomalies, and almost certainly underlies the vast spectrum
of subtle variation that characterizes facial appearance in the human
population.
Facial appearance has
a strong genetic component; monozygotic (MZ) twins look more similar
than dizygotic (DZ) twins or unrelated individuals. The heritability of
craniofacial morphology is as high as 0.8 in twins and families [1], [2], [3]. Some craniofacial traits, such as facial height and position of the lower jaw, appear to be more heritable than others [1], [2], [3].
The general morphology of craniofacial bones is largely genetically
determined and partly attributable to environmental factors [4]–[11]. Although genes have been mapped for various rare craniofacial syndromes largely inherited in Mendelian form [12],
the genetic basis of normal variation in human facial shape is still
poorly understood. An appreciation of the genetic basis of facial shape
variation has far reaching implications for understanding the etiology
of facial pathologies, the origin of major sensory organ systems, and
even the evolution of vertebrates [13], [14].
In addition, it is feasible to speculate that once the majority of
genetic determinants of facial morphology are understood, predicting
facial appearance from DNA found at a crime scene will become useful as
investigative tool in forensic case work [15]. Some externally visible human characteristics, such as eye color [16]–[18] and hair color [19], can already be inferred from a DNA sample with practically useful accuracies.
In a recent candidate
gene study carried out in two independent European population samples,
we investigated a potential association between risk alleles for
non-syndromic cleft lip with or without cleft palate (NSCL/P) and nose
width and facial width in the normal population [20].
Two NSCL/P associated single nucleotide polymorphisms (SNPs) showed
association with different facial phenotypes in different populations.
However, facial landmarks derived from 3-Dimensional (3D) magnetic
resonance images (MRI) in one population and 2-Dimensional (2D) portrait
images in the other population were not completely comparable, posing a
challenge for combining phenotype data. In the present study, we focus
on the MRI-based approach for capturing facial morphology since previous
facial imaging studies by some of us have demonstrated that MRI-derived
soft tissue landmarks represent a reliable data source [21], [22].
In geometric
morphometrics, there are different ways to deal with the confounders of
position and orientation of the landmark configurations, such as (1)
superimposition [23], [24] that places the landmarks into a consensus reference frame; (2) deformation [25]–[27], where shape differences are described in terms of deformation fields of one object onto another; and (3) linear distances [28], [29],
where Euclidean distances between landmarks instead of their
coordinates are measured. Rationality and efficacy of these approaches
have been reviewed and compared elsewhere [30]–[32].
We briefly compared these methods in the context of our genome-wide
association study (GWAS) (see Methods section) and applied them when
appropriate.
We extracted facial
landmarks from 3D head MRI in 5,388 individuals of European origin from
Netherlands, Australia, and Germany, and used partial Procrustes
superimposition (PS) [24], [30], [33]
to superimpose different sets of facial landmarks onto a consensus 3D
Euclidean space. We derived 48 facial shape features from the
superimposed landmarks and estimated their heritability in 79 MZ and 90
DZ Australian twin pairs. Subsequently, we conducted a series of GWAS
separately for these facial shape dimensions, and attempted to replicate
the identified associations in 568 Canadians of European (French)
ancestry with similar 3D head MRI phenotypes and additionally sought
supporting evidence in further 1,530 individuals from the UK and 2,337
from Australia for whom facial phenotypes were derived from 2D portrait
images.
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