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

Jorge Gómez-Valdés,David J Balding ,María Cátira Bortolini ,Claudia Jaramillo,Malena Hurtado,Hugo Villamil‐Ramírez ,Giovanni Poletti,Rolando González‐José ,Mirsha Quinto‐Sanchez ,Kaustubh Adhikari,Gastón Macín Pérez,Valeria Villegas,Francisco M Salzano,Javier Rosique,Caio César Silva De Cerqueira ,Francisco Rothhammer,Vanessa Granja,Carla Gallo,Javier Mendoza‐Revilla ,William Arias,Gabriel Bedoya,Samuel Cañizales-Quinteros ,Michael Cheeseman,Tábita Hünemeier ,Macarena Fuentes-Guajardo,Rodrigo Barquera ,Juan Camilo Chacón-Duque,Lavínia Schüler‐Faccini ,Victor Acuña‐Alonzo ,Andrés Ruiz-Linares,Denis J Headon ,Virgínia Ramallo

doi:10.1038/ncomms11616

Abstract

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.

Highlights

We report a genome-wide association scan for facial features in B6,000 Latin Americans
Our analyses allowed us to replicate the reported PAX3/nasion position association and to identify five other gene regions impacting on face morphology (EDAR, Dachsous Cadherin-Related 2 gene (DCHS2), RUNX2, GLI3 and PAX1)
We found a significant association of mandible length with genotype, with the length decreasing at greater Edar function, consistent with the association of the 370A variant with decreased chin protrusion detected in the CANDELA sample (Fig. 4, Supplementary Table 16)

Summary

Introduction

We report a genome-wide association scan for facial features in B6,000 Latin Americans. We recently reported the successful identification of genes influencing outer ear (pinna) morphology using a three-point ordinal phenotyping approach[12] We extend this methodology to other aspects of facial variation. Our analyses allowed us to replicate the reported PAX3/nasion position association and to identify five other gene regions impacting on face (mostly nose) morphology (EDAR, DCHS2, RUNX2, GLI3 and PAX1). These genes are known to play important roles in craniofacial development

Methods

Results

Conclusion