Article

Human Facial Shape and Size Heritability and Genetic Correlations

Abstract and Figures

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 3D 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 genomewide 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% - 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.
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|INVESTIGATION
Human Facial Shape and Size Heritability and
Genetic Correlations
Joanne B. Cole,* Mange Manyama,
Jacinda R. Larson,
,§
Denise K. Liberton,
,§
Tracey M. Ferrara,*
Sheri L. Riccardi,* Mao Li,** Washington Mio,** Ophir D. Klein,
††,‡‡,§§
Stephanie A. Santorico,*
,
***
Benedikt Hallgrímsson,
,§
and Richard A. Spritz*
,†††,1
*Human Medical Genetics and Genomics Program, and †††Department of Pediatrics, University of Colorado School of Medicine,
Aurora, Colorado 80045, Department of Anatomy, Catholic University of Health and Allied Sciences, Mwanza, TZ-18, Tanzania,
Department of Anatomy and Cell Biology, and §McCaig Institute for Bone and Joint Health, Alberta Childrens Hospital Research
Institute, Cumming School of Medicine, University of Calgary, T2N 1N4, Canada, **Department of Mathematics, Florida State
University, Tallahassee, Florida 32304, ††Department of Orofacial Sciences, ‡‡Department of Pediatrics, and §§Program in
Craniofacial Biology, University of California, San Francisco, California 94143, and ***Department of Mathematical and Statistical
Science, University of Colorado Denver, Colorado 80202
ABSTRACT 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.
Specically, we t 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 signicant estimates for narrow-sense heritability of specic
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 nd 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.
KEYWORDS heritability; facial shape; facial size; morphometrics; complex traits
HUMAN appearance is comprised of a remarkably variable
set of physical traits. Of all externally visible character-
istics, facial appearance is both the most morphologically
variable and the most distinctive and recognizable. Facial
appearance involves a major genetic component, with each
of the many structural features that dene facial shape and
appearance themselves likely determined by a multiplicity of
genes, with environmental variables such as nutrition and
environmental toxins, exerting increasing inuence over time
(Fitzgerald et al. 2010). Nevertheless, the striking similarity
of facial appearance within families, often across many gen-
erations, suggests that certain key genes exert particularly
large effects on facial shape and appearance.
Facial shape is measured in various ways, including specic
linear measurements between dened morphological points
as well as complex quantitative measurements of the entire
face. Previous estimates of the heritability of facial shape
distances and angles were principally derived by direct mea-
surements between common facial morphometric landmarks
on human faces, cephalograms, and skulls. These estimates
Copyright © 2017 by the Genetics Society of America
doi: 10.1534/genetics.116.193185
Manuscript received June 27, 2016; accepted for publication December 8, 2016;
published Early Online December 14, 2016.
Supplemental material is available online at www.genetics.org/lookup/suppl/doi:10.
1534/genetics.116.193185/-/DC1.
1
Corresponding author: University of Colorado School of Medicine, Anschutz Medical
Campus, Rm. 3100, Mail-stop 8300, 12800 East 19th Ave., Aurora, CO 80045.
E-mail: richard.spritz@ucdenver.edu
Genetics, Vol. 205, 967978 February 2017 967
vary widely; in general, facial height dimensions tend to be
more heritable than width (Manfredi et al. 1997; Carson
2006; Amini and Borzabadi-Farahani 2009; AlKhudhairi
and AlKode 2010), in contrast with the rest of the skull,
for which heritability of width tends to be greater than for
height (Martínez-Abadías et al. 2009a,b, 2012).
The genetic architecture of facial shape variation has been
studied more extensively in mice than in humans. In the mouse,
measures of craniofacial morphology are highly heritable (Leamy
1977; Klingenberg and Leamy 2001; Klingenberg et al. 2001;
Percival et al. 2016). Further, the mouse skull is highly inte-
grated in terms of phenotypic and genetic correlations (Leamy
1977; Cheverud 1982). Genetic and environmental correlations
also tend to be similar, likely due to their basis in similar de-
velopmental connections among traits (Cheverud 1982).
Morphological assessment of facial variation has typically
required manual landmarking, an approach that is slow, labor
intensive, and error prone; complicating its application to large-
scale studies as well as comparisonsacrossmultiplestudies.Asan
advance toward standardized, replicable phenotyping of human
facial traits, we combined advanced three-dimensional (3D)
imaging technology with a novel automated landmarking
method (Li et al. 2016) to derive precise, detailed, and informa-
tive facial phenotypes from 29 standard facial morphometric
landmarks (Supplemental Material, Table S1) (Bookstein 1997).
Our study, based on Bantu children from Tanzania, avoids
facial shape variation that occurs later in life due to injury,
weight gain, and disease. Moreover,these African children are
very lean, with minimal variation related to facial adiposity,
and furthermore have signicant occult relatedness, provid-
ing the opportunity to formally analyze the heritability of
facial shape phenotypes in this population.
To assess heritability, we analyzed genotypes of .15 million
common SNPs with minor allele frequencies .1% using
Genome-wide Complex Trait Analysis (GCTA) (Yang et al.
2010, 2011). We estimated narrow-sense heritability (h
2
);
heritability explained by common genetic variation (h
2
g
); and
pairwise genetic correlations of 38 facial phenotypes, incorpo-
rating close family structures into a joint linear mixed model
with two variance components, one representing the genetic
relatedness between close relatives and the other representing
the genetic relatedness between all individuals in the study
(Zaitlen et al. 2013). The phenotypic variance was then parti-
tioned into variance explained by common genetic variation,
variance explained by close genetic relationships but not com-
mon genetic variation, and the remaining residual variance
explained by the environment.
We found that facial shape and size phenotypes are highly
heritable, and additionally are highly genetically correlated, and
that a large fraction of the genetic component of facial differences
can be explained by common variation genome-wide.Our ndings
help elucidate the complex genetic relationships and pathways
underlying facial shape, augment basic biological understanding
of facial development, enable better modeling of facial shape
based on genetic correlations, and may assist in delineation and
diagnosis of facial dysmorphism syndromes.
Materials and Methods
Study subjects
Samples and data were collected from 3631 Bantu African
children aged 321 over a 3-year period in the Mwanza region
of Tanzania. Subjects with a known birth defect or a relative
with known orofacial cleft or facial birth defect were excluded.
Additional data collected were age, sex, height, weight, head
circumference, school, and detailed parental and grandparen-
tal ethnicity, and tribe information. Subjects with non-Bantu
tribal ancestry in one or more grandparents were excluded
from the study. Written informed consent was obtained from
all study subjects or their parents as appropriate.
3D facial imaging and automated landmarking
3D images were obtained using the Creaform MegaCapturor 3D
photogrammetry imaging system. Each subject was imaged
twice at six standard positions. Meshes were reconstructed at
the highest possible resolution and assembled using Inspeck
software to form a complete 3D mesh of the face (Figure 1).
A set of 29 morphometric facial landmarks (Figure 1 and
Table S1) was applied to each individual facial mesh using a
novel automated landmarking method (Li et al. 2016). Briey,
this method morphs a 29-landmark template (created from a
training set of manually landmarked faces) to each individual
face through the guidance of anchor points dened by the local
curvature features of the face. Presenting the same image to
the automated landmarking system twice generates identical
landmark positions. Errors, when they occur, tend to be fairly
large, readily detectible, and easily removed.
Derivation of phenotypic variables
Landmarks were subjected to Procrustes superimposition for
geometric morphometric analysis (Bookstein 1997; Dryden
and Mardia 1998; Mitteroecker and Gunz 2009). Supercial
artifacts (smiling, squinting, mouth open, lateral nasal defor-
mity, etc.) were identied by manual quality inspection of
each facial mesh, and were corrected using a multiple linear
model in which all factors and their interactions were con-
sidered. For each correction, we determined the signicance
of the artifact using a Procrustes distance permutation test on
age- and size-adjusted data. We performed the corrections
jointly using a linear model in Rto avoid overcorrection
caused by overlap among the artifacts. Additionally, we de-
termined whether the corrections affected biological signals
such as the estimates of ontogenetic or static allometry and
the heritabilities of the traits. For all artifacts, we performed
canonical variate analysis both before and after to visualize
the effect of the correction (Figure S1 and Figure S2).
An additional artifact in 3D photogrammetry is skew,
dened as coordinated asymmetric displacement of land-
marks due either to variation in assembly of the facial views
to produce the assembled mesh or from parallax. Most land-
marks are affected by skew when it occurs, but individuals
are not equally affected. Therefore, we regressed the land-
mark data on the principal component (PC) scores for PCs
968 J. B. Cole et al.
corresponding to skew variation. Skew corrections have min-
imal effects on most subjects but graded effects on those to-
ward the ends of the skew PC. Figure S2 shows morphs that
correspond to the extreme skew values in the sample. Skew
corrections were applied to the linear distances as this im-
proved heritability, but not to the multivariate measures as this
did not affect heritability. We validated artifact and skew cor-
rections by determining their inuences on the estimates of
allometric shape variation and on heritabilities.
We obtained 25 linear distance phenotypes representing
heights, widths, and depths of different facial structures from
the fully corrected landmark coordinates after restoring size.
Size was calculated as centroid size, as is standard in geo-
metric morphometrics (Mitteroecker and Gunz 2009). Table
S2 lists means and standard deviations for all linear distances
and centroid size.
Multivariate measures were calculated from artifact but
not skew-corrected data. We removed variation related to age
and size in symmetrized landmark data using multiple mul-
tivariate regression and centering the residuals on the sample
mean (Klingenberg and Zimmermann 1992; Klingenberg
1998). Symmetrizing the data removes facial asymmetry var-
iation. While there is biological variation in asymmetry, this
did not signicantly affect the rst 10 PCs, aside from the
skew artifacts discussed above. The age-shape relationship
is nonlinear, particularly when an analysis includes both
young children and adults. Within our sample, however,
polynomial ts for age or centroid size did not signicantly
improve the t(Figure S3). As our sample mostly excludes
the major shape changes occurring early in facial growth and
the slowing of changes that occur in late ontogeny, linear
regression sufciently captures the shape variation associ-
ated with age and centroid size. Shape variation related to
size, or static allometry, was estimated using the regression
scores corresponding to size independent of age. We
obtained the scores for the rst10PCsbasedontheage
and size-standardized landmark coordinate data (Figure
S4). All references to PCs in the results refer to the PC
scores derived from the phenotypic data.
We used Klingenbergs permutation test for EscofersRV
coefcient to identify the set of spatially contiguous land-
marks that maximized the ratio of covariation among them-
selves to covariation with landmarks outside of that set
(Klingenberg 2009). This method does not consider overlap-
ping determinants of covariation structure (Hallgrímsson
et al. 2009), but it reveals sets of strongly covarying, spatially
adjacent landmarks. The resulting set, dened by the nasal
region and upper lip (Figure S5), was subjected to separate
Procrustes alignment, and a principal component analysis
(PCA). The rst PC (40% of variance) served as a measure
of variation within this module.
The nal phenotype values then adjusted for biological
covariates as follows: multivariate measures including all PCs
and allometry were adjusted for sex; linear distances were
adjusted for age, sex, and centroid size (after age-sex adjust-
ment); and centroid size was adjusted for age and sex. In this
way, all multivariate measures and linear distances were
corrected for age, sex, and size prior to downstream analysis.
Phenotypic correlations used throughout are based on phe-
notype residual correlations on a subset of unrelated individuals.
All morphometric analyses were done in MorphoJ (Klingenberg
2011) or in Rusing the Geomorph (Adams and Otárola-Castillo
2013; Adams et al. 2014) and Morpho (Schlager 2016) packages.
Genome-wide genotyping and quality control
Genome-wide genotyping, quality control, and imputation of
3480 study subjects used in these analyses were described
previously (Cole et al. 2016). The nal postquality-control
Figure 1 3D facial scan with annotated
landmarks. Landmarks annotated are
dened in Table S1.
Heritability of Human Facial Shape 969
dataset included 3480 individuals with complete phenotyp-
ing information and imputed genotypes at .15 million
markers with INFO scores .0.30. A sensitivity analysis com-
paring heritability estimates from the full imputed data set
and from a data set of only genotyped markers demonstrated
no bias in using imputed genotypes (Figure S6).
Heritability estimates
Both h
2
and h
2
g
were estimated using GCTA software (Yang
et al. 2010, 2011). We t a joint linear mixed model with two
variance components for each phenotype as described (Zaitlen
et al. 2013). Briey, one variance component represented close
relatives only, in which any pairwise genetic correlation in the
full genetic relatedness matrix as calculated by GCTA ,0.05
was set to 0. Specically, our variance component highlighting
close relationships contained 4425 pairwise relationships $0.05
from a total of 2937 individuals in each triangle half of the
matrix. While this variance component represents a small pro-
portion of all pairwise relationships in our sample (0.07%), it
includes 84% of our total sample. Therefore the missing heri-
tabilityexplained by this additional variance component of
close relatives is based on a large number of independent nu-
clear families, and thus is not biased by a small number of large
families (Figure S7). Heritability estimates obtained using dif-
ferent relatedness thresholds demonstrated that 0.05 was both
unbiased and conservative when compared to 0.00 and 0.025.
The other variance component represented the full genetic
relatedness matrix for all individuals. The joint model uses
4,307,014 more pairwise comparisons from 3480 individuals
to estimate h
2
g
than the traditional GCTA unrelateds only model
(n= 1869), using their recommended relatedness threshold
cutoff value of 0.025 (Table S3)(Yanget al. 2010). GCTA uses
restricted maximum likelihood to estimate the variance of each
component, the sum of which represents total genetic variance,
used for calculating h
2
. By default, GCTA estimates that escape
from the parameter space were set to 1.0 310
26
3phenotypic
variance. To adjust our signicance threshold for multiple testing
of correlated phenotypes, we performed PCA of the 38 phenotype
residuals in unrelated individualstodeterminethenumber
of effectively independent phenotypes. The rst 11 eigen-
vectors had eigenvalues .1, making them each representative
of at least one phenotype. We divided the traditional P,0.05
threshold by 11, making our signicance threshold P,0.0045.
To calculate heritabilities and genetic variances for each
landmark, we obtained the genetic and phenotypic variance-
covariance matrices for the symmetrized landmarks. This
leaves out one dimension for midline landmarks and treats
the landmark coordinates for both sides as a single variable.
Heritabilities are calculated as the ratio of genetic to pheno-
typic variance for each landmark coordinate. We then used
a heatmap method to visualize these variance components
across the face. Here, each component is represented as a
vector that has a length proportional to the variance compo-
nent, an origin at each landmark, and a direction parallel to a
vector that connects each landmark to the landmark centroid.
These vectors are then used to produce a face morph using the
thin-plate-spline method that is then superimposed on the
unmorphed mean face to generate a heatmap.
Genetic correlation
Genetic correlations between all phenotypes were also esti-
mated using GCTA software (Yang et al. 2011). We elimi-
nated PC8 and LS_STO, for which the joint heritability LRT
models were not signicant (Table 2), from the genetic cor-
relation matrix. Due to nonconvergence of such a large pa-
rameter space, 148/630 bivariate analyses failed the joint
analysis and instead, for the sake of having a complete ge-
netic correlation matrix, were t by the standard GCTA ap-
proach, using a single genetic relatedness matrix of only
unrelated individuals (n=1869). Of those 148 bivariate
models, 36 failed the single component model of unrelateds
due to constraining genetic or environmental components.
To construct a complete genetic correlation matrix, we esti-
mated these 36 values based on both univariate and bivariate
models of the traits affected. If the bivariate models genetic
component was constrained or the univariate models herita-
bility estimate was less than the SE of that estimate, we set
the genetic covariance to 1.0 310
26
3phenotypic covari-
ance. If the bivariate models environmental component was
constrained or the univariate models heritability was essentially
equal to one, we set the genetic covariance as equal to the total
phenotypic covariance between the two traits. Therefore, the
genetic correlation matrix represents only the shared genetic
correlation which can be explained by .15 million common
variants. Table S4 includes all h
2
g
genetic correlation estimates,
SE, and models in which those values were derived.
Data availability
Phenotype data were deposited in FaceBase (https://www.
facebase.org/; accession number: FB00000667.01). Genotype
data were deposited in the Database of Genotypes and Pheno-
types (dbGaP) (http://www.ncbi.nlm.nih.gov/gap; accession
number: phs000622.v1.p1). This study was carried out with
overall approval and oversight of the Colorado Multiple Insti-
tutional Review Board (protocol #09-0731), was additionally
approved by the institutional review boards of the University
of Calgary, Florida State University, the University of California
San Francisco, and the Catholic University of Health and Allied
Sciences (Mwanza, Tanzania), and was carried out with the ap-
proval of the National Institute for Medical Research (Tanzania).
Results
Study population and phenotypes
The study population consisted of 3480 normal African Bantu
children and adolescents ages 321 from the Mwanza region of
Tanzania. Over 70% of subjects were aged 712, and 44.4%
were male and 55.6% female (Figure 2). As described previ-
ously (Cole et al. 2016), PCA of population substructure dem-
onstrated minimal genetic clustering and an analysis of xation
index demonstrated no apparent subgroups by school or tribe.
970 J. B. Cole et al.
For each subject, we captured 3D facial scans, applied
29 standard facial morphometric landmarks (Figure 1 and
Table S1) (Bookstein 1997), derived 38 facial shape pheno-
types based on the landmarks, carried out genome-wide SNP
genotyping, and used these data to estimate h
2
and h
2
g
for
each phenotype. These facial phenotypes represent several
different classes, including 3D summary variables in the form
of PCs derived from PCA of the whole face and PCA of the
most highly correlated landmarks positioned around the
midface, interlandmark linear distances, and global mea-
sures of overall facial size and the relationship between
sizeandshape(Table1).Inaddition, for each subject we
obtained height and weight, from which we calculated
body mass index (BMI). Analysis of these data showed that
the mean BMI of the study population was 1 SD below the
2007WorldHealthOrganizationworldstandards(Figure
S8). Furthermore, the correlations between all age- and
sex-adjusted facial traits with age- and sex-adjusted BMI
in unrelated individuals are small (r
2
=20.18 to 0.14),
suggesting that BMI is not a confounding factor in our
study population.
Heritability of facial phenotypes
AsshowninFigure3andTable2,36ofour38phenotypeswere
signicantly heritable (P,0.0045), with h
2
28.366.9%. The
most heritable facial traits include PC7, representing nasal root
shape and mouth width (h
2
= 66.9%, SE = 7.2%); total facial
width (T_R_T_L) (h
2
= 66.2%, SE = 7.5%); the allometric vari-
able (h
2
= 64.3%, SE = 7.2%); centroid size (h
2
= 64.1%,
SE = 7.6%); and nasion to midendocanthion distance
(N_MEN) (h
2
= 63.9%, SE = 7.5%). Furthermore, by com-
bining genetic variance across all 10 orthogonal PCs, which
explain .87% of total shape variation captured by sparse
landmarking (Figure S4), we obtained a single global esti-
mate of total facial shape of h
2
= 50.1%. Previous studies
have suggested that vertical measures have greater heritabil-
ity than horizontal measures (Manfredi et al. 1997; Carson
2006; Amini and Borzabadi-Farahani 2009; AlKhudhairi and
AlKode 2010). However, we observed a trend toward horizon-
talfacialmeasureshavinggreaterheritability than vertical mea-
sures. Figure 4 depicts h
2
and h
2
g
estimates for the 25 linear
distances, clustered by physical orientation and phenotypic cor-
relation. The three facial depth measurements, lower facial
depth (GN_T), midfacial depth (SN_T), and upper facial depth
(N_T), share the tragion landmark and have very similar h
2
estimates (h
2
= 48.6%, SE = 7.6%; h
2
= 48.7%, SE = 7.6%;
and h
2
= 51.2%, SE = 7.6%; respectively), but exhibit very
different phenotypic correlations (GN_T:SN_T = 0.31,
GN_T:N_T = 20.04, and SN_T:N_T = 0.67). Similarly,
the three horizontal eye measurements, inner canthal dis-
tance (EN_R_EN_L), outer canthal distance (EX_R_EX_L),
and average palpebral ssure length (EN_EX), likewise share
some landmarks in common and have fairly similar h
2
esti-
mates, (h
2
= 41.1%, SE = 7.6%; h
2
= 52.2%, SE = 7.6%;
and h
2
= 56.6%, SE = 7.8%; respectively), but exhibit very
different phenotypic correlations (EN_R_EN_L:EX_R_EX_L =
0.49, EN_R_EN_L:EN_EX = 20.03, and EX_R_EX_L:EN_EX =
0.82). In contrast, three midfacial horizontal measures, mouth
Figure 2 Study age distribution by sex.
Heritability of Human Facial Shape 971
width (CH_R_CH_L), philtrum width (CPH_R_CPH_L), and
subnasal width (SBAL_R_SBAL_L), share no overlapping
landmarks, have similar h
2
estimates (h
2
=37.8%,SE=
7.7%; h
2
= 33.7%, SE = 7.7%; and h
2
= 37.2%, SE =
8.0%; respectively), and also exhibit fairly high phenotypic
correlations (CH_R_CH_L:CPH_R_CPH_L = 0.55, CH_R_CH_L:
SBAL_R_SBAL_L = 0.62, and CPH_R_CPH_L:SBAL_R_SBAL_L =
0.48). It appears that facial traits of similar orientation
that either share overlapping morphological points or
have high phenotypic correlations are inuenced by ad-
ditive genetic effects and environmental effects to similar
degrees.
Figure 5 shows the anatomic distribution of phenotypic
and genetic variance as well as heritability by landmark. The
pattern is consistent with Figure 3 and Figure 4 in that the
landmarks dening facial width and the orbital region tend
to have higher genetic variances and heritabilities.
Genetic basis of observed heritability
For 22 of the 38 facial phenotypes analyzed, .90% of the
narrow-sense heritability (h
2
) can be explained by the effects
of common genetic variation (h
2
g
/h
2
). However, for a number
of other traits, common variation (h
2
g
) accounts for ,50% of
h
2
; indicating signicant additional genetic contributions be-
yond common variants that can be imputed for Africans from
the Illumina HumanOmni 2.5-8 array, which captures 54% of
common African variation (minor allele frequency .1%;
http://www.illumina.com/content/dam/illumina-marketing/
documents/products/datasheets/datasheet-human-omni2.5-
exome-8.pdf). However, we caution that these conclusions
Table 1 The 38 facial phenotypes derived from landmarks on 3D facial scans
Phenotype abbreviation Physical description
PCA
PC1 upper facial height, midfacial width
PC2 overall facial height, lower facial height
PC3 upper and middle facial width
PC4 width of the nose, mandible height
PC5 nose shape, height of the mouth
PC6 nasal width, maxillary prognathism
PC7 nasal root shape, mouth width
PC8 cheek protrusion
PC9 midface protrusion, upper facial height
P10 chin height, nasion protrusion
PC1 from a PCA of the midfacial landmark
network (MidfaceModPC1)
midfacial landmark network around the nose and mouth
Size-related measurements
Centroid size facial size
Allometry variation in shape due to size
Linear distances
a
AL_R_AL_L nasal width
AC_PRN nasal ala length (average)
CH_R_CH_L mouth width
CPH_R_CPH_L philtrum width
EN_EX palpebral ssure length (average)
EN_R_EN_L inner canthal width
EX_R_EX_L outer canthal width
GN_T lower facial depth (average)
LI_SL cutaneous lower lip height
LS_STO upper vermilion height
N_GN morphological facial height
N_MEN nasion to midendocanthion
N_PRN nasal bridge length
N_SN nasal height
N_STO upper facial height
N_T upper facial depth (average)
SBAL_R_SBAL_L subnasal width
SN_GN lower facial height
SN_LS philtrum length
SN_PRN nasal protrusion
SN_STO upper lip height
SN_T midfacial depth (average)
STO_LI lower vermilion height
STO_SL lower lip height
T_R_T_L facial width
a
Linear distances are the distance between two landmarks (e.g., AL_R and AL_L).
972 J. B. Cole et al.
are based on estimates of h
2
g
/h
2
that have high SE (Table
2). These traits include centroid size, nasion to midendo-
canthion (N_MEN), palpebral ssure length (EN_EX), PC5
representing nose shape and height of the mouth, PC8
representing cheek protrusion, and morphological facial
height (N_GN).
To elucidate underlying genetic relationships between
different facial traits, we estimated pairwise genetic correla-
tions between all signicantly heritable traits (Table S4) and
constructed a genetic correlation matrix of all signicantly
heritable linear distances (Figure 6). Due to lack of power
to detect h
2
in joint bivariate models between all traits
(Visscher et al. 2014), these genetic correlations are based
on the genetic covariance calculated from .15 million com-
mon variants and not total genetic covariance, resulting in
higher SE. Although not all genetic correlation estimates are
signicantly different from 0 (P,0.05), Figure 6 depicts
striking patterns of shared heritability among distinct facial
traits. A number of horizontal measurements mostly dened
by nonoverlapping landmarks have high positive genetic cor-
relations with each other. These phenotypes include palpebral
ssure length (EN_EX), outer canthal width (EX_R_EX_L),
facial width (T_R_T_L), mouth width (CH_R_CH_L), subnasal
width (SBAL_R_SBAL_L), philtrum width (CPH_R_CPH_L),
andtwoPCsthatbothaccountformidfacialwidth(PC1
and MidfaceModPC1). We observed a similar pattern of
high positive genetic correlations, though to a lesser extent,
among midline vertical measurements. These include upper
lip height (SN_STO), morphological facial height (N_GN),
upperfacialheight(N_STO),PC2 representing both overall
and lower facial height, lower lip height (STO_SL), and
philtrum length (SN_LS). Importantly, the horizontal and
vertical measurements exhibit large negative genetic corre-
lationswitheachother,indicating that phenotypic variation
along both horizontal and vertical measurements are largely
caused by the same genetic variation acting to increase one
direction while decreasing the other. In a simple sense, this
means that the same alleles that cause an individual to have
a broad face also cause that individual to have a short face,
and vice versa.
Discussion
We report here the rst estimates of both heritability and
genetic correlation of facial shape phenotypes derived from
3D facial scans and true genome-wide genetic correlations
between 1000s of individuals. Facial scans provide far more
accurate measurements than previous approaches based on
direct manual measurements between prominent facial
features (Ozsoy et al. 2009). Furthermore, direct calcula-
tion of genome sharing from genome-wide data are more
accurate than kinship coefcients used in traditional her-
itability analyses, which represent the average genetic
sharing for any given relationship and not the actual ge-
netic correlation for any specic pair of relatives (Hayes
et al. 2009).
Our analysis, carried out in Bantu children from Tanza-
nia, provides the opportunity to assess heritability of facial
shape and size in a young, lean population. The choice of
population is both a strength and a limitation of this anal-
ysis. In any population, heritability is determined by a
combination of genetic variance and environmental inu-
ences. Variation in facial adiposity, for instance, is small in
this population while it may be large in others (Figure S8)
(Cole et al. 2016). The focus on children creates the need
to adjust for age and size but also avoids facial shape
changes that occur later in life due to injury, weight gain,
and disease.
Not surprisingly, we found that many quantitative facial-
shape phenotypes, derived with high accuracy from 3D facial
Figure 3 Heritability of 38 facial traits.
The bar plot represents h
2
g
(yellow),
missing h
2
(blue), and total h
2
(yellow +
blue) with error bars for all 38 facial
phenotypes analyzed. Bars that ap-
parently have no missing h
2
(blue) in-
dicate that h
2
g
equals h
2
; therefore,
narrow-sense heritability of that pheno-
type can be explained fully by common
genetic variation.
Heritability of Human Facial Shape 973
scans, are highly heritable. Furthermore, most of these quan-
titative facial phenotypes can be explained by common genetic
variants across the genome. In particular, based on h
2
, several
horizontal measurements including facial width (T_R_T_L; h
2
=
66.2%, SE = 7.5%), nasal width (AL_R_AL_L; h
2
=62.3%,
SE = 7.6%), outer canthalwidth(EX_R_EX_L;h
2
= 56.6%,
SE = 7.6%), and palpebral ssure length (EN_EX; h
2
=52.2%,
SE = 7.8%) appear to be among the most heritable facial
features; contrary to ndings of previous heritability
studies of the face. There are several obvious potential
explanations for this difference. First, heritability of some
facial attributes may be population specic, driven by dif-
ferent underlying genetic variants in different populations;
thus reecting differing underlying biological bases of
facial shape and size. Second, the present study popula-
tion, Tanzanian Bantu children, is a much leaner popula-
tion than has been studied previously. BMI in our cohort
of Tanzanian Bantu children is signicantly lower than
world standards (Figure S8)(deOniset al. 2004) and is
uncorrelated with our measures of facial shape after
adjusting for age, sex, and centroid size (see Materials
and Methods). Linear measures, particularly horizontal dis-
tances, collected in populations with higher BMI, may be
more affected by excess subcutaneous fat, reecting a
greater environmental component, and thus proportion-
ately smaller genetic component. Third, genetic inu-
ences on horizontal facial distances may be proportionately
greater at younger ages, as in our cohort of children and ado-
lescents ages 321, whereas these distances may become pro-
portionately more affected by environmental components
with increasing age. This model of age-related shape differ-
ences ts well with what is already known about how the face
matures and morphs into the adult form. As the face reaches
adult shape at 16 years of age (as determined in males of
Table 2 Heritability of 38 facial traits
Trait h
2
g
SE (h
2
g
)h
2
SE (h
2
) LRT P-value
a
h
2
g
/h
2
SE (h
2
g
/h
2
)
PC7 0.669 0.138 0.669 0.072 1.00 310
217b
1.000 0.560
T_R_T_L 0.521 0.138 0.662 0.075 1.00 310
217b
0.786 0.482
Allometry 0.643 0.132 0.643 0.072 1.00 310
217b
1.000 0.562
Centroid Size 0.277 0.134 0.641 0.076 3.66 310
215
0.432 0.335
N_MEN 0.260 0.134 0.639 0.075 3.89 310
216
0.406 0.322
AL_R_AL_L 0.623 0.131 0.623 0.076 1.00 310
217b
1.000 0.575
PC4 0.604 0.131 0.604 0.075 5.55 310
217
1.000 0.583
PC2 0.579 0.139 0.579 0.074 1.00 310
217b
1.000 0.607
EX_R_EX_L 0.421 0.141 0.566 0.076 8.11 310
214
0.744 0.509
N_PRN 0.456 0.142 0.544 0.075 3.94 310
215
0.839 0.562
EN_EX 0.208 0.140 0.522 0.078 4.35 310
210
0.399 0.360
N_T 0.419 0.136 0.512 0.076 4.52 310
214
0.819 0.564
PC5 0.211 0.138 0.491 0.077 6.33 310
210
0.430 0.385
N_STO 0.443 0.140 0.490 0.076 2.22 310
213
0.903 0.621
GN_T 0.487 0.140 0.487 0.076 2.97 310
212
1.000 0.663
SN_LS 0.486 0.130 0.486 0.077 5.26 310
211
1.000 0.651
SN_T 0.469 0.139 0.486 0.076 2.97 310
213
0.966 0.650
PC3 0.308 0.139 0.478 0.078 2.03 310
210
0.643 0.504
PC1 0.477 0.140 0.477 0.076 5.76 310
213
1.000 0.672
PC8 0.074 0.137 0.471 0.079 2.50 310
28
0.158 0.223
N_SN 0.244 0.137 0.456 0.075 1.95 310
210
0.535 0.455
PC9 0.431 0.125 0.452 0.076 1.16 310
213
0.953 0.643
MidfaceModPC1 0.433 0.138 0.433 0.078 2.23 310
29
1.000 0.706
N_GN 0.159 0.137 0.426 0.078 1.11 310
27
0.373 0.380
EN_R_EN_L 0.392 0.142 0.411 0.076 2.09 310
29
0.952 0.699
AC_PRN 0.311 0.140 0.410 0.079 1.47 310
27
0.758 0.604
SN_GN 0.239 0.139 0.386 0.079 8.70 310
27
0.619 0.546
CH_R_CH_L 0.378 0.137 0.378 0.077 7.99 310
26
1.000 0.747
SBAL_R_SBAL_L 0.373 0.134 0.373 0.080 2.76 310
26
1.000 0.754
LI_SL 0.177 0.134 0.342 0.077 5.61 310
26
0.518 0.510
SN_PRN 0.242 0.139 0.340 0.074 1.37 310
26
0.711 0.629
CPH_R_CPH_L 0.337 0.126 0.337 0.077 3.45 310
26
1.000 0.775
STO_LI 0.324 0.139 0.324 0.075 2.48 310
25
1.000 0.810
SN_STO 0.314 0.131 0.314 0.079 1.57 310
25
1.000 0.819
PC10 0.291 0.140 0.291 0.080 0.000570 1.000 0.860
STO_SL 0.283 0.134 0.283 0.078 0.000102 1.000 0.863
PC6 0.169 0.131 0.169 0.077 0.0152 1.000 1.10
LS_STO 0.076 0.116 0.076 0.077 0.259 1.000 1.61
h
2
,h
2
g
, and the proportion of narrow-sense heritability explained by common genetic variants (h
2
g
/h
2
), all with SE.
a
LRT P-value for the joint model vs. the null model (H
0
:h
2
=0).
b
LRT P-value was reported as 0, indicating it was less than the GCTA limit 1 310
217
.
974 J. B. Cole et al.
European descent), the midface undergoes a strong vertical
expansion and becomes relatively taller than the rest of the
face (Bastir et al. 2006).
The 10 PCs displayed similar heritabilities as the linear
distances. PCs represent axes of covariation within the data
and most combine variation from multiple if not most land-
marks. A limitation of PCA is that the assumption that each PC
is orthogonal to the previous may not map well onto the
underlying biological determinants of covariation structure.
In the absence of knowledge about those determinants, how-
ever, PCA is a widely accepted and rational approach to
multivariate data. In this context, each PC represents a distinct
facial shape transformation that emerges from the covariance
structure of the data and can be treated as a univariate trait.
Interestingly, global facial size appears to be among the
most heritable of facial traits. Allometry, a measure of the
variation in shape due to size, has h
2
of 64.3% (SE =
7.2%). Centroid size, a measure of overall face size, has
h
2
of 64.1% (SE = 7.6%). These ndings indicate that
there may be a strong genetic basis underlying global size
of the face and how size drives shape variation; whereas
facial shape per se, irrespective of size, may be somewhat
more inuenced by environmental factors. Although our
ndings also indicate that the majority of facial shape
variation can be explained by the effects of common ge-
netic variation, there were several facial phenotypes, in-
cluding centroid size, for which h
2
g
did not explain the
majority of h
2
. Potential explanations for such missing
heritability include variants not in linkage disequilibrium
with variants on our array, rare causal genetic variants,
uncharacterized structural variation, and epistatic ef-
fects. Our genome-wide association studies (GWAS) of
Figure 4 Heritability of linear distances by measurement
orientation. The bar plot represents h
2
g
(yellow), missing h
2
(blue), and total h
2
(yellow + blue) with error bars for
25 linear distances. Traits are rst clustered by orientation,
then by facial structure with between-trait phenotypic cor-
relations seen in the colored matrix in the bottom half of
the gure.
Heritability of Human Facial Shape 975
these same facial traits in Africans identied two loci
that were signicantly associated with either centroid
size or allometry (Cole et al. 2016); traits with high h
2
but variable h
2
g
. While these heritability estimates sup-
port an overall genetic contribution, the specicesti-
mate of h
2
g
does not provide information on the magnitude
of effect of contributing loci, and thus is not necessarily
an indicator of GWAS success. Irrespective of the spe-
cich
2
g
estimates for centroid size and allometry, our
GWAS of 6300 individuals had the power to detect ge-
netic determinants with relatively large effect sizes for
both traits.
We observed high positive genetic correlations among
variables that represent similar orientations on the face,
and rather high negative genetic correlations among var-
iables that represent different orientations. The highest
genetic correlations, of horizontal measures across the
facial midline, likely correspond to related genetic effects
on biological relationships underlying facial structure
during development, in which the two sides of the face
meet and fuse at the midline (Sperber et al. 2001). The
negative genetic correlations we observe between horizon-
tal and vertical facial measures are consistent with overall
phenotypic correlations between these measures. Further-
more, high positive and negative genetic correlations be-
tween a wide array of facial traits support the presence of
anite set of underlying genes involved in overall facial
development.
Finally, our analysis of genetic variance and covariance
structure shows that genetic variation in the face is both
highly integrated and modular. Integration refers to the
developmentally based tendencies for traits to covary
(Hallgrímsson et al. 2009; Klingenberg 2013), while
modularity refers to suites of traits connected by devel-
opment (Wagner et al. 2007). We nd a large number of
both positive and negative correlations among traits,
attesting to highly structured patterns of variation. For
craniofacial morphology more generally, somatic growth,
Figure 5 Distribution of variance components across the face. (AC) The anatomical distribution of phenotypic and genetic variances as well as
heritabilities is shown. These are represented as heatmaps based on a thin-plate-spine morph as described in Materials and Methods. (D) The heritability
estimates or the Procrustes-superimposed symmetrized landmarks are shown. (E) The vectors, magnied 10-fold, used to generate the heritability
heatmap are depicted.
976 J. B. Cole et al.
chondrocranial growth, and brain growth are known to
drive such patterns of integrated variation in both mouse
and human crania (Cooper et al. 2004; Hallgrímsson et al.
2006, 2009; Marcucio et al. 2011; Martínez-Abadías et al.
2012). Here, both facial size and facial shape allometry ex-
hibit a pattern of genetic correlations with facial measures
that capture aspects of facial height, midfacial width, and
lower facial prognathism. This pattern of genetic correla-
tions likely reects the overall inuence of somatic growth
on facial shape, forming a developmentally based module
within the face. Further work integrating developmental
studies with results such as these will shed light on the
mechanistic basis for the structure of variation in the face.
Acknowledgments
This work was funded by grants from the National Institutes of
Health under the National Institute of Dental and Craniofacial
Research (NIDCR) FaceBase Initiative (http://www.nidcr.nih.
gov/; NIDCR DE-020054 to R.A.S.), the Center for Inherited
Disease Research (http://www.cidr.jhmi.edu/; HG006829 to
R.A.S.), the National Institute of Justice (http://www.nij.
gov/Pages/welcome.aspx; 2013-DN-BX-K005 to R.A.S.),
and the National Science and Engineering Council Discov-
ery Grant (http://www.nserc-crsng.gc.ca/index_eng.asp;
DG#238992-12 to B.H.). The funders had no role in study
design, data collection and analysis, decision to publish,
or preparation of the manuscript.
Figure 6 Pairwise genetic correlation matrix of the linear distances. Genetic correlation was calculated from .15 million common genetic variants.
Traits that have high positive genetic correlations with each other are shown in blue, indicating that the same genetic loci alter the magnitude of those
traits in the same direction. Traits that have high negative genetic correlations with each other are shown in red, indicating that the same genetic loci are
contributing to each phenotype in opposite directions, increasing one while decreasing the other. Genetic correlation estimates that are signicantly
different (P,0.05) from 0 to +1 or 0 to 21 are marked with sand genetic correlation estimates that are signicantly different (P,0.05) than 0, +1,
and 21 are marked with s.
Heritability of Human Facial Shape 977
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Communicating editor: N. R. Wray
978 J. B. Cole et al.
... Previous quantitative genetic studies of human facial traits have included soft tissue and skeletal features, traditional cephalometrics and landmark-based methods, and a variety of methodological designs and analyses including twin studies, genome wide association studies (GWAS), quantitative trait loci (QTL) mapping, and pedigree-based estimation of parameters (e.g., Alvesalo & Tigerstedt, 1974;Baydaş et al., 2007;Brito et al., 2011;Carels et al., 2001;Claes & Shriver, 2016;Cole et al., 2016Cole et al., , 2017Crouch et al., 2018;Martínez-Abadías et al., 2009;Šešelj et al., 2015;Sherwood, Duren, Demerath, et al., 2008;Sherwood, Duren, Havill, et al., 2008;Weinberg et al., 2013). These studies have found moderate to high heritability estimates throughout the face, with several studies finding especially high heritability estimates in the orbital and nasal regions relative to other facial regions (Carson, 2006;Cole et al., 2017;Kim et al., 2013;Martínez-Abadías et al., 2009;Tsagkrasoulis et al., 2017). ...
... Previous quantitative genetic studies of human facial traits have included soft tissue and skeletal features, traditional cephalometrics and landmark-based methods, and a variety of methodological designs and analyses including twin studies, genome wide association studies (GWAS), quantitative trait loci (QTL) mapping, and pedigree-based estimation of parameters (e.g., Alvesalo & Tigerstedt, 1974;Baydaş et al., 2007;Brito et al., 2011;Carels et al., 2001;Claes & Shriver, 2016;Cole et al., 2016Cole et al., , 2017Crouch et al., 2018;Martínez-Abadías et al., 2009;Šešelj et al., 2015;Sherwood, Duren, Demerath, et al., 2008;Sherwood, Duren, Havill, et al., 2008;Weinberg et al., 2013). These studies have found moderate to high heritability estimates throughout the face, with several studies finding especially high heritability estimates in the orbital and nasal regions relative to other facial regions (Carson, 2006;Cole et al., 2017;Kim et al., 2013;Martínez-Abadías et al., 2009;Tsagkrasoulis et al., 2017). Studies of human dental dimensions also indicate high heritability estimates across tooth types (Dempsey & Townsend, 2001;Hughes et al., 2014;Paul et al., 2020;Stojanowski et al., 2017;Townsend et al., 2009). ...
... Studies of human dental dimensions also indicate high heritability estimates across tooth types (Dempsey & Townsend, 2001;Hughes et al., 2014;Paul et al., 2020;Stojanowski et al., 2017;Townsend et al., 2009). A smaller set of studies have estimated genetic correlations between human craniofacial traits, finding positive genetic correlations in some regions of the skull (Martínez-Abadías et al., 2009;Sherwood, Duren, Demerath, et al., 2008;Sherwood, Duren, Havill, et al., 2008) and, in one study, negative correlations between horizontal and vertical measurements (Cole et al., 2017). ...
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Patterns of genetic variation and covariation impact the evolution of the craniofacial complex and contribute to clinically significant malocclusions in modern human populations. Previous quantitative genetic studies have estimated the heritabilities and genetic correlations of skeletal and dental traits in humans and non-human primates, but none have estimated these quantitative genetic parameters across the dentognathic complex. A large and powerful pedigree from the Jirel population of Nepal was leveraged to estimate heritabilities and genetic correlations in 62 maxillary and mandibular arch dimensions, incisor and canine lengths, and post-canine tooth crown areas (N ≥ 739). Quantitative genetic parameter estimation was performed using maximum likelihood-based variance decomposition. Residual heritability estimates were significant for all traits, ranging from 0.269 to 0.898. Genetic correlations were positive for all trait pairs. Principal components analyses of the phenotypic and genetic correlation matrices indicate an overall size effect across all measurements on the first principal component. Additional principal components demonstrate positive relationships between post-canine tooth crown areas and arch lengths and negative relationships between post-canine tooth crown areas and arch widths, and between arch lengths and arch widths. Based on these findings, morphological variation in the human dentognathic complex may be constrained by genetic relationships between dental dimensions and arch lengths, with weaker genetic correlations between these traits and arch widths allowing for variation in arch shape. The patterns identified are expected to have impacted the evolution of the dentognathic complex and its genetic architecture as well as the prevalence of dental crowding in modern human populations. This article is protected by copyright. All rights reserved.
... Traditionally, this is done by measuring the facial similarity between relatives, such as twins (39,154,162) or parents and offspring (60,73). The widespread availability of whole-genome microarrays and recent advances in statistical methods allow for these traditional family-based designs to be extended to large data sets of unrelated individuals where the degree of genetic relatedness is determined from genome-wide single-nucleotide polymorphisms (SNPs) (28,171). However, these differences in study design, as well as differences in study populations and facial descriptors employed, have produced widely varying estimates of heritability in the literature, making direct comparisons across studies challenging. ...
... In particular, high heritability has consistently been reported for aspects of nasal shape such as the position of the nasion, which is closely linked to the PAX3 locus (1,11,19,25,61,118,164,170). In addition to aspects of facial shape, facial size and allometry have been found to be highly heritable (28,39). By contrast, stronger environmental contributions have been reported for the lower parts of the face, including the cheeks, mandible, and mouth, which are known to be affected by nutrition (141), aging (119), and oral function (123). ...
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Variations in the form of the human face, which plays a role in our individual identities and societal interactions and exhibits extreme forms in a broad range of craniofacial syndromes and birth defects, have fascinated both geneticists and developmental biologists. Here, we review our current understanding of the genetics underlying variation in craniofacial morphology and dysmorphology, synthesizing decades of progress on Mendelian syndromes in addition to more recent results from genome-wide association studies of human facial shape and disease risk. We also discuss the various approaches used to phenotype and quantify facial shape, which are of particular importance due to the complex, multipartite nature of the craniofacial form. We close by discussing how experimental studies have contributed and will further contribute to our understanding of human genetic variation and then proposing future directions and applications for the field. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 23 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... Previous studies of the sample of Bantu African children studied here have shown that facial shape measures have considerable narrow sense heritability (28%-67% for 32 of 33 facial measurements). 4 Cole et al. 4 found that much of this heritability is explained by common (minor allele frequency, MAF > 1%) SNPs; nevertheless, for a number of facial phenotype measures, a considerable fraction (26%-64%) of estimated heritability is not explained by common SNPs. We hypothesize that some of this missing heritability may reflect genomic structural variation (SV), especially CNVs that may cause dosage imbalance of genes involved in facial development. ...
... Particularly little is known about the role of copy number variants (CNVs). Previous studies of the sample of Bantu African children studied here have shown that facial shape measures have considerable narrow sense heritability (28%-67% for 32 of 33 facial measurements). 4 Cole et al. 4 found that much of this heritability is explained by common (minor allele frequency, MAF > 1%) SNPs; nevertheless, for a number of facial phenotype measures, a considerable fraction (26%-64%) of estimated heritability is not explained by common SNPs. We hypothesize that some of this missing heritability may reflect genomic structural variation (SV), especially CNVs that may cause dosage imbalance of genes involved in facial development. ...
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Similarity in facial characteristics between relatives suggests a strong genetic component underlies facial variation. While there have been numerous studies of the genetics of facial abnormalities and, more recently, single nucleotide polymorphism (SNP) genome-wide association studies (GWAS) of normal facial variation, little is known about the role of genetic structural variation in determining facial shape. In a sample of Bantu African children, we found that only 9% of common CNVs and 10 kb CNV analysis windows are well tagged by SNPs (r² ≥ 0.8), indicating that associations with our internally called CNVs were not captured by previous SNP-based GWAS. Here, we present a GWAS and gene set analysis of the relationship between normal facial variation and CNVs in a sample of Bantu African children. We report the top five regions, which had p-values ≤ 9.35 x10−6, and find nominal evidence of independent CNV association (p < 0.05) in three regions previously identified in SNP-based GWAS. The CNV region with strongest association (p = 1.16 x10−6, 55 losses and 7 gains) contains NFATC1, which has been linked to facial morphogenesis and Cherubism, a syndrome involving abnormal lower facial development. Genomic loss in the region is associated with smaller average lower facial depth. Importantly, new loci identified here were not identified in a SNP-based GWAS, suggesting that CNVs are likely involved in determining facial shape variation. Given the plethora of SNP-based GWAS, calling CNVs from existing data may be a relatively inexpensive way to aid in the study of complex traits.
... As well known, the face is essentially the most distinct feature used to identify individuals [14] and used as one of the main inputs in measuring anthropological variances among ethnic groups [15]. Compared to body features like body height, head and facial features are less affected by environmental factors and more significantly affected by genetic factors [16,17]. This, in turn, means head and facial features could be used as one of the main factors to identify one person or ethnic group and even used to analyze the relationship between different ethnic groups. ...
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The striking realism of the life-sized ceramic terracotta warriors has been attracting the interest of the public and archaeologists since they were discovered from the mausoleum complex of the first Chinese Emperor Qin Shihuang in the 1970s. It is still debated whether the life-size models were based on individual people or were just crafted from the standardized models. This research examined the facial features of the terracotta warriors in a quantitative and contactless way with the support of the High-precision 3D point cloud modelling technology and the anthropometric method. The similarities and dissimilarities were analyzed among the facial features of terracotta warriors and 29 modern Chinese ethnic groups using mathematical statistics methods such as MDS, ANOVA, ranking analysis and cluster analysis. The results reveal that the features of the terracotta warriors highly resemble those of contemporary Chinese people and indicate that terracotta warriors were crafted from real portraits and intended to constitute a real army to protect the Emperor Qin Shihuang in the afterlife.
... The heritability of craniofacial morphology is high in families [19]. Some craniofacial traits, such as facial shape and position of the eyes and nose, appear to be more heritable than others [20]. The general morphology of craniofacial development and tumor formation both is largely genetically determined and partly attributable to environmental factors [21]. ...
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Background: Early diagnosis of malignant tumors effectively reduces the mortality rate. The special craniofacial structure serves as a diagnosis basis of early screening for many hereditary diseases. However, cancer is also considered a genetic disorder. Could facial images direct tumor screening? Methods: We developed an image recognition program, the artificial intelligence watcher, which could extract implicit knowledge from faces and distinguish cancer patients from normal persons. The artificial intelligence program used a convolution neural network with 6 layers. Then, we conducted a retrospective clinical study of 643 cancer patients and 219 local normal people at 20–80 ages from China to analyze their photos and medical history. By analyzing their facial features, disease and family gene sequencing, the relationship between appearance and cancer can be inferred. Results: We demonstrated that the accuracy of artificial intelligence watcher achieved up to about 90%. Statistical results showed lung and gastric cancer patients have more narrow-set eyes. Furthermore, we suspected the physiological basis for artificial intelligence watcher is craniofacial genes are closely related to cancer susceptibility genes. Through the analysis of the tumor database and craniofacial development gene database, we found many single nucleotide polymorphism mutations related to appearance are also related to the tumor, in particular, WW domain containing E3 ubiquitin protein ligase 2, SH3 and PX domains 2B, DNA-directed RNA polymerase III core subunit and coatomer subunit zeta. Conclusion: According to our gene sequencing results, there are some polymorphisms of the same locus in patients with similar facial features different from their healthy relatives, such as WW domain containing E3 ubiquitin protein ligase 2 and ATP binding cassette subfamily A member 4 genes. Our model provides a new efficient auxiliary diagnosis method for tumor screening.
... Recent work has demonstrated that under certain conditions individuals can be reidentified from seemingly anonymous MRI scan images [11]. Patients' medical images have inadvertently appeared in Google image searches [12], and analysis of human faces can enable inferences about one's health status [e.g., [13][14][15][16][17][18][19][20] and even one's genomic information [21]. Understandably, many in and out of the precision health research community wonder whether the measures taken to ensure responsible stewardship of facial imaging and imaging-derived data are appropriate and adequate. ...
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Facial imaging and facial recognition technologies, now common in our daily lives, also are increasingly incorporated into health care processes, enabling touch-free appointment check-in, matching patients accurately, and assisting with the diagnosis of certain medical conditions. The use, sharing, and storage of facial data is expected to expand in coming years, yet little is documented about the perspectives of patients and participants regarding these uses. We developed a pair of surveys to gather public perspectives on uses of facial images and facial recognition technologies in healthcare and in health-related research in the United States. We used Qualtrics Panels to collect responses from general public respondents using two complementary and overlapping survey instruments; one focused on six types of biometrics (including facial images and DNA) and their uses in a wide range of societal contexts (including healthcare and research) and the other focused on facial imaging, facial recognition technology, and related data practices in health and research contexts specifically. We collected responses from a diverse group of 4,048 adults in the United States (2,038 and 2,010, from each survey respectively). A majority of respondents (55.5%) indicated they were equally worried about the privacy of medical records, DNA, and facial images collected for precision health research. A vignette was used to gauge willingness to participate in a hypothetical precision health study, with respondents split as willing to (39.6%), unwilling to (30.1%), and unsure about (30.3%) participating. Nearly one-quarter of respondents (24.8%) reported they would prefer to opt out of the DNA component of a study, and 22.0% reported they would prefer to opt out of both the DNA and facial imaging component of the study. Few indicated willingness to pay a fee to opt-out of the collection of their research data. Finally, respondents were offered options for ideal governance design of their data, as “open science”; “gated science”; and “closed science.” No option elicited a majority response. Our findings indicate that while a majority of research participants might be comfortable with facial images and facial recognition technologies in healthcare and health-related research, a significant fraction expressed concern for the privacy of their own face-based data, similar to the privacy concerns of DNA data and medical records. A nuanced approach to uses of face-based data in healthcare and health-related research is needed, taking into consideration storage protection plans and the contexts of use.
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Background: The aesthetic facial traits are closely related to life quality and strongly influenced by genetic factors, but the genetic predispositions in the Chinese population remain poorly understood. Methods: A genome-wide association studies (GWAS) and subsequent validations were performed in 26,806 Chinese on five facial traits: widow’s peak, unibrow, double eyelid, earlobe attachment, and freckles. Functional annotation was performed based on the expression quantitative trait loci (eQTL) variants, genome-wide polygenic scores (GPSs) were developed to represent the combined polygenic effects, and single nucleotide polymorphism (SNP) heritability was presented to evaluate the contributions of the variants. Results: In total, 21 genetic associations were identified, of which ten were novel: GMDS-AS1 (rs4959669, p = 1.29 × 10−49) and SPRED2 (rs13423753, p = 2.99 × 10−14) for widow’s peak, a previously unreported trait; FARSB (rs36015125, p = 1.96 × 10−21) for unibrow; KIF26B (rs7549180, p = 2.41 × 10−15), CASC2 (rs79852633, p = 4.78 × 10−11), RPGRIP1L (rs6499632, p = 9.15 × 10−11), and PAX1 (rs147581439, p = 3.07 × 10−8) for double eyelid; ZFHX3 (rs74030209, p = 9.77 × 10−14) and LINC01107 (rs10211400, p = 6.25 × 10−10) for earlobe attachment; and SPATA33 (rs35415928, p = 1.08 × 10−8) for freckles. Functionally, seven identified SNPs tag the missense variants and six may function as eQTLs. The combined polygenic effect of the associations was represented by GPSs and contributions of the variants were evaluated using SNP heritability. Conclusion: These identifications may facilitate a better understanding of the genetic basis of features in the Chinese population and hopefully inspire further genetic research on facial development.
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Facial and cranial variation represent a multidimensional set of highly correlated and heritable phenotypes. Little is known about the genetic basis explaining this correlation. We develop a software package ALoSFL for simultaneous localization of facial and cranial landmarks from head computed tomography (CT) images, apply it in the analysis of head CT images of 777 Han Chinese women, and obtain a set of phenotypes representing variation in face, skull and facial soft tissue thickness (FSTT). Association analysis of 301 single nucleotide polymorphisms (SNPs) from 191 distinct genomic loci previously associated with facial variation reveals an unexpected larger number of loci showing significant (P < 1e–3) association with cranial phenotypes than expected under the null (O/E = 3.39), suggesting facial and cranial phenotypes share a substantial proportion of genetic components. Adding FSTT to a SNP-only model shows a large impact in explaining facial variance. A gene ontology analysis reveals that bone morphogenesis and osteoblast differentiation likely underlie our cranial-significant findings. Overall, this study simultaneously investigates the genetic effects on both facial and cranial variation of the same sample, supporting that facial variation is a composite phenotype of cranial variation and FSTT.
Chapter
Besides being involved in respiratory and olfactory functions, the human nose presents the peculiar morphological and functional characteristics that have emerged during the evolution of the face and neural skull. In particular, following the nasalization process, i.e., the formation of the nasal bone bridge and the development of the nasal cartilage, it took the form of a triangular pyramid protruding on the median plane of the face, contributing to defining those physiognomic traits that make the face of each individual unique and unmistakable. This chapter examines the genetic, physiological and climatic factors that are at the origin of the evolution and morphological variability of the nose and face. It also considers the possible selective mechanisms of a cultural and social nature which may lead to the unforeseeable and peculiar combinations of physiognomic traits of the nose and face that are the basis of personal identity and individual recognition. Finally, it looks at the genes involved in the characterization of specific traits of the nose and face and how they are contributing to skull-facial reconstruction.
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Realistic mappings of genes to morphology are inherently multivariate on both sides of the equation. The importance of coordinated gene effects on morphological phenotypes is clear from the intertwining of gene actions in signaling pathways, gene regulatory networks, and developmental processes underlying the development of shape and size. Yet, current approaches tend to focus on identifying and localizing the effects of individual genes and rarely leverage the information content of high dimensional phenotypes. Here, we explicitly model the joint effects of biologically coherent collections of genes on a multivariate trait-craniofacial shape - in a sample of n = 1,145 mice from the Diversity Outbred (DO) experimental line. We use biological process gene ontology (GO) annotations to select skeletal and facial development gene sets and solve for the axis of shape variation that maximally covaries with gene set marker variation. We use our process-centered, multivariate genotype-phenotype (process MGP) approach to determine the overall contributions to craniofacial variation of genes involved in relevant processes and how variation in different processes corresponds to multivariate axes of shape variation. Further, we compare the directions of effect in phenotype space of mutations to the primary axis of shape variation associated with broader pathways within which they are thought to function. Finally, we leverage the relationship between mutational and pathway-level effects to predict phenotypic effects beyond craniofacial shape in specific mutants. We also introduce an online application which provides users the means to customize their own process-centered craniofacial shape analyses in the DO. The process-centered approach is generally applicable to any continuously varying phenotype and thus has wide-reaching implications for complex-trait genetics.
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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 SCHIP1 and PDE8A 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 SCHIP1 and PDE8A, we demonstrated clear expression in the developing mouse face by both whole-mount in situ 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.
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This study introduces a new multivariate approach for analyzing the effects of quantitative trait loci (QTL) on shape and demonstrates this method for the mouse mandible. We quantified size and shape with the methods of geometric morphometrics, based on Procrustes superimposition of fi ie morphological landmarks recorded on each mandible. Interval mapping for F(2) mice originating from an intercross of the LG/J and SM/J inbred strains revealed 12 QTL for size, 25 QTL for shape, and 5 QTL for left-right asymmetry. Multivariate ordination of QTL effects by principal component analysis identified two recurrent features of shape variation, which involved the positions of the coronoid and angular processes relative to each other and to the rest of the mandible. These patterns are reminiscent of the knockout phenotypes of a number of genes involved in mandible development although only a few of these are possible candidates for QTL in our study. The variation of shape effects among the QTL showed no evidence of clustering into distinct groups, as would be expected from theories of morphological integration. Fur ther, for most QTL, additive and dominance effects on shape were markedly different, implying overdominance for specific features of shape. We conclude that geometric morphometrics offers a promising new approach to address problems at the interface of evolutionary and developmental genetics.
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A new updated edition of "Craniofacial Embryogenetics & Development", published by: www.pmphusa.com is now available. G.H. Sperber gsperber@ualberta.ca
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Automated phenotyping is essential for the creation of large, highly standardized datasets from anatomical imaging data. Such datasets can support large-scale studies of complex traits or clinical studies related to precision medicine or clinical trials. We have developed a method that generates three-dimensional landmark data that meet the requirements of standard geometric morphometric analyses. The method is robust and can be implemented without high-performance computing resources. We validated the method using both direct comparison to manual landmarking on the same individuals and also analyses of the variation patterns and outlier patterns in a large dataset of automated and manual landmark data. Direct comparison of manual and automated landmarks reveals that automated landmark data are less variable, but more highly integrated and reproducible. Automated data produce covariation structure that closely resembles that of manual landmarks. We further find that while our method does produce some landmarking errors, they tend to be readily detectable and can be fixed by adjusting parameters used in the registration and control-point steps. Data generated using the method described here have been successfully used to study the genomic architecture of facial shape in two different genome-wide association studies of facial shape.
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It is well known that the human skull achieves adult size through a superior–inferior gradient of maturation. Because the basicranium matures in size before the face, it has been suggested that the form of the basicranium might have ontogenetic knock-on effects on that of the face. However, although sequential spatially organized maturation of size is well described in the cranium, the maturation of skull shape is not. Knowledge of the maturation of shape is important, nevertheless, because it is claimed that the early determination of the spatial configuration of basicranial components, where the facial skeleton attaches, is relevant in the spatio-temporal ontogenetic cascade from basicranium to face. This paper examines the ontogeny of various components of the human skull in 28 individuals from the longitudinal Denver Growth Study. Sixty-six landmarks and semilandmarks were digitized on 228 X-rays and analysed using geometric morphometric methods. Bootstrapped confidence intervals for centroid size support previous studies suggesting a supero-inferior gradient of growth maturation (size over time), while developmental maturation (shape over time) is more complex. A sequence of shape maturation is described, in which the earliest structure to mature in shape was the midline cranial base (7–8 years), followed by the lateral cranial floor (11–12), midline neurocranium (9–10) and facial and mandibular structures (15–16). The absolute ages of shape maturation of the latter three depended on the criterion of maturity used, which was not the case for the basicranial components. Additionally, ontogenetic dissociations were found between the maturation of size and shape of the midline cranial base and lateral floor, possibly underlining its role as structural 'interface' between brain and facial ontogeny. These findings imply potential for bidirectional developmental influences between the lateral cranial floor and the face until about 11–12 years. The findings are discussed with regard to their relevance for palaeoanthropology and especially the evolutionary and developmental bases of skull morphological variation.