Novel Genetic Loci Affecting Facial Shape Variation in Humans

Zhenzhen Xiong ,Nicholas G Martin,Pirro G Hysi,Gabriel Bedoya,Sijia Wang,Shuhua Xu,Carla Gallo,Fan Liu,Lavinia Paternoster,Bo Pan,Hui Yang,Kerrie Mcaloney,Francisco Rothhammer,Seth M Weinberg,Bas Lendemeijer,Evie Stergiakouli,M Arfan Ikram,Eppo B Wolvius,Steven A Kushner,Kun Tang,Kaustubh Adhikari,Erwei Zuo,Holly Thompson,Manfred Kayser,Giovanni Poletti,He Li,Gu Zhu,Eleanor Feingold,Dan Li,Li Jin,Robert-Jan Palstra,Mary L Marazita,Tamar Nijsten,Gabriela Dankova,Stephen Richmond,Haibo Zhou,John R Shaffer,Sarah J Lewis ,Yang Li ,Timothy D Spector,Rolando González‐José ,André G Uitterlinden ,Stefan Böehringer ,Laurence J Howe ,Andrés Ruiz‐Linares ,Sarah E Medland,M.a De Jong ,Gemma C Sharp ,María Cátira Bortolini ,Samuel Cañizales-Quinteros ,Alexei I Zhurov ,Femke M De Vrij,Myoung Keun Lee

doi:10.2139/ssrn.3307375

Abstract

The human face represents a combined set of highly heritable phenotypes, but knowledge on its genetic architecture remains limited. A series of genome-wide association studies on 78 facial shape phenotypes quantified from 3-dimensional facial images of 10,115 Europeans identified 24 genetic loci, among which 17 were previously unpublished. A multi-ethnic replication study in 7,917 individuals confirmed 13 loci including 8 unpublished ones. Allele frequencies at the face-associated loci were signiﬁcantly more differentiated among populations than genome background, supporting a role of nature selection in shaping genetic differentiation underlying facial variation. Analyses of epigenomic datasets from cranial neural crest cells revealed abundant cis-regulatory activities at the face-associated loci. Luciferase reporter assays in neural crest progenitor cells highlighted enhancer activities at INTU, PAX3, RPGRIP1L. Knocking-out two face-associated genes TBX15 and PAX1 in mice resulted in craniofacial dysmorphology. These results substantially advance our understanding of the genetic and functional basis of human facial variation.

Highlights

The human face represents a multi-dimensional set of correlated, mostly symmetric, complex phenotypes with high heritability
In order to maximize sample size via a collaborative study, we focused on linear distance measures of facial features that can be accurately derived from facial image datasets
We investigated the potential links between facial phenotypes and 60 SNPs in 38 loci previously implicated in non-syndromic cleft lip and palate (NSCL/P) phenotype, which is linked with normal variation of facial morphology as suggested previously (Beaty et al, 2010; Beaty et al, 2011; Birnbaum et al, 2009; Grant et al, 2009; Leslie et al, 2017; Ludwig et al, 2017; Ludwig et al, 2012; Mangold et al, 2010; Sun et al, 2015; Yu et al, 2017)

Summary

Introduction

The human face represents a multi-dimensional set of correlated, mostly symmetric, complex phenotypes with high heritability. The overlapping loci from independent facial GWASs, currently representing the most established genetic findings, include DNA variants in or close to 10 genes that is CACNA2D3 (Paternoster et al, 2012; Pickrell et al, 2016), DCHS2 (Adhikari et al, 2016; Claes et al, 2018), EPHB3 (Claes et al, 2018; Pickrell et al, 2016), HOXD cluster (Claes et al, 2018; Pickrell et al, 2016), PAX1 (Adhikari et al, 2016; Shaffer et al, 2016), PAX3 (Adhikari et al, 2016; Claes et al, 2018; Liu et al, 2012; Paternoster et al, 2012; Pickrell et al, 2016), PKDCC (Claes et al, 2018; Pickrell et al, 2016), SOX9 (Cha et al, 2018; Claes et al, 2018; Pickrell et al, 2016), SUPT3H (Adhikari et al, 2016; Claes et al, 2018; Pickrell et al, 2016), and TBX15 (Claes et al, 2018; Pickrell et al, 2016), which were identified mostly in Europeans

Methods

Results

Conclusion