Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology.

John R Shaffer,Ekaterina Orlova,George L Wehby,Richard A Spritz,Chung How Kau,Myoung Keun Lee,Mary L Marazita,Zachary D Raffensperger,Cathy C Laurie,Seth M Weinberg,Lina M Moreno,Eleanor Feingold,Elizabeth J Leslie,Carrie L Heike,Jeffrey C Murray,Michael L Cunningham,Washington Mio,Tracey M Ferrara ,Ophir D Klein ,Cecelia Laurie ,Jacqueline Hecht ,Joanne B Cole ,Stephanie A Santorico ,Benedikt Hallgrímsson ,Nichole Nidey

doi:10.1371/journal.pgen.1006149

Abstract

Numerous lines of evidence point to a genetic basis for facial morphology in humans, yet little is known about how specific genetic variants relate to the phenotypic expression of many common facial features. We conducted genome-wide association meta-analyses of 20 quantitative facial measurements derived from the 3D surface images of 3118 healthy individuals of European ancestry belonging to two US cohorts. Analyses were performed on just under one million genotyped SNPs (Illumina OmniExpress+Exome v1.2 array) imputed to the 1000 Genomes reference panel (Phase 3). We observed genome-wide significant associations (p < 5 x 10−8) for cranial base width at 14q21.1 and 20q12, intercanthal width at 1p13.3 and Xq13.2, nasal width at 20p11.22, nasal ala length at 14q11.2, and upper facial depth at 11q22.1. Several genes in the associated regions are known to play roles in craniofacial development or in syndromes affecting the face: MAFB, PAX9, MIPOL1, ALX3, HDAC8, and PAX1. We also tested genotype-phenotype associations reported in two previous genome-wide studies and found evidence of replication for nasal ala length and SNPs in CACNA2D3 and PRDM16. These results provide further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features. Improved understanding of the genes associated with facial morphology in healthy individuals can provide insights into the pathways and mechanisms controlling normal and abnormal facial morphogenesis.

Highlights

We tested genotype-phenotype associations reported in two previous genome-wide studies and found evidence of replication for nasal ala length and SNPs in CACNA2D3 and PRDM16. These results provide further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features
Little is known about how variation in specific regions of the genome relates to the kinds of distinguishing facial characteristics that give us our unique identities, e.g., the size and shape of our nose or how far apart our eyes are spaced. We investigate this question by examining the association between genetic variants across the whole genome and a set of measurements designed to capture key aspects of facial form
Numerous lines of converging evidence indicate that variation in facial morphology has a strong genetic basis

Summary

Introduction

Numerous lines of converging evidence indicate that variation in facial morphology has a strong genetic basis. These include the results of human heritability studies using twin and parent-offspring designs [1,2,3,4,5], Mendelian craniofacial syndromes [6], transgenic animal models with distinctive craniofacial phenotypes [7,8,9], and studies mapping QTLs for craniofacial shape in several mammalian models [10,11,12,13,14]. Understanding the genetic factors that contribute to normal facial trait variation may provide valuable insights into the causes of craniofacial dysmorphology, including common craniofacial birth defects such as orofacial clefts [15,16]

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Conclusion