A genome-wide association scan implicates DCHS2, RUNX2, GLI3, PAX1 and EDAR in human facial variation

We report a genome-wide association scan for facial features in ∼6,000 Latin Americans. We evaluated 14 traits on an ordinal scale and found significant association (P values<5 × 10−8) at single-nucleotide polymorphisms (SNPs) in four genomic regions for three nose-related traits: columella inclination (4q31), nose bridge breadth (6p21) and nose wing breadth (7p13 and 20p11). In a subsample of ∼3,000 individuals we obtained quantitative traits related to 9 of the ordinal phenotypes and, also, a measure of nasion position. Quantitative analyses confirmed the ordinal-based associations, identified SNPs in 2q12 associated to chin protrusion, and replicated the reported association of nasion position with SNPs in PAX3. Strongest association in 2q12, 4q31, 6p21 and 7p13 was observed for SNPs in the EDAR, DCHS2, RUNX2 and GLI3 genes, respectively. Associated SNPs in 20p11 extend to PAX1. Consistent with the effect of EDAR on chin protrusion, we documented alterations of mandible length in mice with modified Edar funtion.

[1]  G. Bedoya,et al.  Facial asymmetry and genetic ancestry in Latin American admixed populations. , 2015, American journal of physical anthropology.

[2]  T. Fujita,et al.  Runx2 induces osteoblast and chondrocyte differentiation and enhances their migration by coupling with PI3K-Akt signaling , 2004, The Journal of cell biology.

[3]  Dennis C. Dirkmaat,et al.  A Companion to Forensic Anthropology: Dirkmaat/A Companion to Forensic Anthropology , 2012 .

[4]  T. Smith.  The Evolution of the Human Head , 2012 .

[5]  J. Fleiss,et al.  Intraclass correlations: uses in assessing rater reliability. , 1979, Psychological bulletin.

[6]  Angel Pan,et al.  A review of hedgehog signaling in cranial bone development , 2013, Front. Physiol..

[7]  J. Marchini,et al.  Fast and accurate genotype imputation in genome-wide association studies through pre-phasing , 2012, Nature Genetics.

[8]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[9]  Mary L Marazita,et al.  Heritability of Face Shape in Twins: A Preliminary Study using 3D Stereophotogrammetry and Geometric Morphometrics. , 2013, Dentistry 3000.

[10]  M. Nachman,et al.  Morphological and population genomic evidence that human faces have evolved to signal individual identity , 2014, Nature Communications.

[11]  Pardis C Sabeti,et al.  EDARV370A associated facial characteristics in Uyghur population revealing further pleiotropic effects , 2015, Human Genetics.

[12]  Brendan H. Lee,et al.  Mutations and promoter SNPs in RUNX2, a transcriptional regulator of bone formation. , 2005, Molecular genetics and metabolism.

[13]  Wiro J Niessen,et al.  Genetic determination of human facial morphology: links between cleft-lips and normal variation , 2011, European Journal of Human Genetics.

[14]  D. Balding,et al.  Admixture in Latin America: Geographic Structure, Phenotypic Diversity and Self-Perception of Ancestry Based on 7,342 Individuals , 2014, PLoS genetics.

[15]  Carson C Chow,et al.  Second-generation PLINK: rising to the challenge of larger and richer datasets , 2014, GigaScience.

[16]  T. Kitamura,et al.  Wnt modulators, SFRP-1, and SFRP-2 are expressed in osteoblasts and differentially regulate hematopoietic stem cells. , 2009, Biochemical and biophysical research communications.

[17]  T. Schilling,et al.  Fat-Dachsous Signaling Coordinates Cartilage Differentiation and Polarity during Craniofacial Development , 2014, PLoS genetics.

[18]  Hang Zhou,et al.  Detecting Genetic Association of Common Human Facial Morphological Variation Using High Density 3D Image Registration , 2013, PLoS Comput. Biol..

[19]  S. Bellusci,et al.  Gli3Xt-J/Xt-J mice exhibit lambdoid suture craniosynostosis which results from altered osteoprogenitor proliferation and differentiation. , 2010, Human molecular genetics.

[20]  C. Kokubu,et al.  Pax1 acts as a negative regulator of chondrocyte maturation. , 2013, Experimental cell research.

[21]  Ken-ichi Inoue,et al.  Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. , 2004, Genes & development.

[22]  D De Angelis,et al.  Metric and morphological assessment of facial features: a study on three European populations. , 2011, Forensic science international.

[23]  Doug Speed,et al.  Improved heritability estimation from genome-wide SNPs. , 2012, American journal of human genetics.

[24]  K. Grzeschik,et al.  GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families , 1991, Nature.

[25]  A. Constantinesco,et al.  Subtle Morphological Changes in the Mandible of Tabby Mice Revealed by Micro-CT Imaging and Elliptical Fourier Quantification , 2011, Front. Physio..

[26]  C. Klingenberg.  MorphoJ: an integrated software package for geometric morphometrics , 2011, Molecular ecology resources.

[27]  Michael Boehnke,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[28]  Nicholas J Timpson,et al.  Genome-wide association study of three-dimensional facial morphology identifies a variant in PAX3 associated with nasion position. , 2012, American journal of human genetics.

[29]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[30]  Craniofacial morphometric analysis of individuals with X-linked hypohidrotic ectodermal dysplasia , 2014, Molecular genetics & genomic medicine.

[31]  Pardis C Sabeti,et al.  The adaptive variant EDARV370A is associated with straight hair in East Asians , 2013, Human Genetics.

[32]  David H. Alexander,et al.  Fast model-based estimation of ancestry in unrelated individuals. , 2009, Genome research.

[33]  David B. Witonsky,et al.  Reconstructing Native American Population History , 2012, Nature.

[34]  Ross M. Fraser,et al.  A General Approach for Haplotype Phasing across the Full Spectrum of Relatedness , 2014, PLoS genetics.

[35]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[36]  A. Smahi,et al.  Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases , 2011, Human mutation.

[37]  G. Wagner.  The developmental genetics of homology , 2007, Nature Reviews Genetics.

[38]  David Balding,et al.  A genome-wide association study identifies multiple loci for variation in human ear morphology , 2015, Nature Communications.

[39]  Li Jin,et al.  Modeling Recent Human Evolution in Mice by Expression of a Selected EDAR Variant , 2013, Cell.

[40]  P. Trainor,et al.  Disrupting hedgehog and WNT signaling interactions promotes cleft lip pathogenesis. , 2014, The Journal of clinical investigation.

[41]  Pasquale Poppa,et al.  A new atlas for the evaluation of facial features: advantages, limits, and applicability , 2011, International Journal of Legal Medicine.

[42]  Timothy D Weaver,et al.  Human cranial anatomy and the differential preservation of population history and climate signatures. , 2006, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.

[43]  Chi-Chung Hui,et al.  Interplays of Gli2 and Gli3 and their requirement in mediating Shh-dependent sclerotome induction , 2003, Development.

[44]  C. Stringer,et al.  Testing modern human out-of-Africa dispersal models and implications for modern human origins. , 2015, Journal of human evolution.

[45]  Mauro Santos,et al.  Heritability of human cranial dimensions: comparing the evolvability of different cranial regions , 2009, Journal of anatomy.

[46]  D. Balding,et al.  A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features , 2016, Nature Communications.

[47]  V. Laudet,et al.  The ectodysplasin pathway: from diseases to adaptations. , 2014, Trends in genetics : TIG.

[48]  T. Hanihara,et al.  Effects of an Asian-specific nonsynonymous EDAR variant on multiple dental traits , 2012, Journal of Human Genetics.

[49]  E. Carson,et al.  Maximum likelihood estimation of human craniometric heritabilities. , 2006, American journal of physical anthropology.

[50]  J. Zonana,et al.  Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia , 1999, Nature Genetics.

[51]  Jianfeng Xu,et al.  A Genome-Wide Survey over the ChIP-On-Chip Identified Androgen Receptor-Binding Genomic Regions Identifies a Novel Prostate Cancer Susceptibility Locus at 12q13.13 , 2011, Cancer Epidemiology, Biomarkers and Prevention.

[52]  M. Justice,et al.  Gene defect in ectodermal dysplasia implicates a death domain adapter in development , 2001, Nature.

[53]  J. Marchini,et al.  Genotype imputation for genome-wide association studies , 2010, Nature Reviews Genetics.

[54]  N. V. Cramon-Taubadel,et al.  Evolutionary insights into global patterns of human cranial diversity: population history, climatic and dietary effects. , 2014, Journal of anthropological sciences = Rivista di antropologia : JASS.

[55]  A. Joyner,et al.  A mouse model of Greig cephalo–polysyndactyly syndrome: the extra–toesJ mutation contains an intragenic deletion of the Gli3 gene , 1993, Nature Genetics.

[56]  Philip L. F. Johnson,et al.  The complete genome sequence of a Neanderthal from the Altai Mountains , 2013 .

[57]  Dennis C. Dirkmaat,et al.  A companion to forensic anthropology , 2015 .

[58]  Philip L. F. Johnson,et al.  A Draft Sequence of the Neandertal Genome , 2010, Science.

[59]  M. Dixon,et al.  Enhanced ectodysplasin‐A receptor (EDAR) signaling alters multiple fiber characteristics to produce the East Asian hair form , 2008, Human mutation.

[60]  D. Reich,et al.  Population Structure and Eigenanalysis , 2006, PLoS genetics.

[61]  Mark Stoneking,et al.  Positive selection in East Asians for an EDAR allele that enhances NF-kappaB activation. , 2008, PloS one.

[62]  J. J. Flynn,et al.  The correlated evolution of Runx2 tandem repeats, transcriptional activity, and facial length in Carnivora , 2007, Evolution & development.

[63]  Paul Suetens,et al.  Modeling 3D Facial Shape from DNA , 2014, PLoS genetics.

[64]  Marleen de Bruijne,et al.  A Genome-Wide Association Study Identifies Five Loci Influencing Facial Morphology in Europeans , 2012, PLoS genetics.

[65]  P. Visscher,et al.  GCTA: a tool for genome-wide complex trait analysis. , 2011, American journal of human genetics.

[66]  Stephen D Ousley,et al.  Statistical Classification Methods for Estimating Ancestry Using Morphoscopic Traits , , 2014, Journal of forensic sciences.

[67]  S. Twigg,et al.  New insights into craniofacial malformations. , 2015, Human molecular genetics.

[68]  P. O’Reilly,et al.  MultiPhen: Joint Model of Multiple Phenotypes Can Increase Discovery in GWAS , 2012, PloS one.

[69]  Borja Esteve-Altava,et al.  Anatomical networks reveal the musculoskeletal modularity of the human head , 2015, Scientific Reports.