A genome-wide association study identifies five loci influencing facial morphology in Europeans

Fan Liu; Fedde van der Lijn; Claudia Schurmann; Gu Zhu; M. Mallar Chakravarty; Pirro G. Hysi; Andreas Wollstein; Oscar Lao; Marleen de Bruijne; M. Arfan Ikram; Aad van der Lugt; Fernando Rivadeneira; Andre G.  Uitterlinden; Albert Hofman; Wiro J. Niessen; Georg Homuth; Greig de Zubicaray; Katie L. McMahon; Paul M. Thompson; Amro Daboul; Ralf Puls; Katrin Hegenscheid; Liisa Bevan; Zdenka Pausova; Sarah E. Medland; Grant W. Montgomery; Margaret J. Wright; Carol Wicking; Stefan Boehringer; Timothy D. Spector; Tomas Paus; Nicholas G. Martin; Reiner Biffar; Manfred Kayser

doi:10.1371/journal.pgen.1002932

A genome-wide association study identifies five loci influencing facial morphology in Europeans

Fan Liu, Fedde van der Lijn, Claudia Schurmann, Gu Zhu, M. Mallar Chakravarty, Pirro G. Hysi, Andreas Wollstein, Oscar Lao, Marleen de Bruijne, M. Arfan Ikram, Aad van der Lugt, Fernando Rivadeneira, Andre G. Uitterlinden, Albert Hofman, Wiro J. Niessen, Georg Homuth, Greig de Zubicaray, Katie L. McMahon, Paul M. Thompson, Amro DaboulRalf Puls, Katrin Hegenscheid, Liisa Bevan, Zdenka Pausova, Sarah E. Medland, Grant W. Montgomery, Margaret J. Wright, Carol Wicking, Stefan Boehringer, Timothy D. Spector, Tomas Paus, Nicholas G. Martin, Reiner Biffar, Manfred Kayser

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Abstract

Inter-individual variation in facial shape is one of the most noticeable phenotypes in humans, and it is clearly under genetic regulation; however, almost nothing is known about the genetic basis of normal human facial morphology. We therefore conducted a genome-wide association study for facial shape phenotypes in multiple discovery and replication cohorts, considering almost ten thousand individuals of European descent from several countries. Phenotyping of facial shape features was based on landmark data obtained from three-dimensional head magnetic resonance images (MRIs) and two-dimensional portrait images. We identified five independent genetic loci associated with different facial phenotypes, suggesting the involvement of five candidate genes-PRDM16, PAX3, TP63, C5orf50, and COL17A1-in the determination of the human face. Three of them have been implicated previously in vertebrate craniofacial development and disease, and the remaining two genes potentially represent novel players in the molecular networks governing facial development. Our finding at PAX3 influencing the position of the nasion replicates a recent GWAS of facial features. In addition to the reported GWA findings, we established links between common DNA variants previously associated with NSCL/P at 2p21, 8q24, 13q31, and 17q22 and normal facial-shape variations based on a candidate gene approach. Overall our study implies that DNA variants in genes essential for craniofacial development contribute with relatively small effect size to the spectrum of normal variation in human facial morphology. This observation has important consequences for future studies aiming to identify more genes involved in the human facial morphology, as well as for potential applications of DNA prediction of facial shape such as in future forensic applications.

Original language	English
Article number	e1002932
Journal	P L o S Genetics
Volume	8
Issue number	9
Number of pages	13
ISSN	1553-7390
DOIs	https://doi.org/10.1371/journal.pgen.1002932
Publication status	Published - Sept 2012
Externally published	Yes

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A Genome-Wide Association Study Identifies Five Loci Influencing Facial Morphology in EuropeansFinal published version, 564 KBLicence: CC BY

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Liu, F., van der Lijn, F., Schurmann, C., Zhu, G., Chakravarty, M. M., Hysi, P. G., Wollstein, A., Lao, O., de Bruijne, M., Ikram, M. A., van der Lugt, A., Rivadeneira, F., Uitterlinden, A. G., Hofman, A., Niessen, W. J., Homuth, G., de Zubicaray, G., McMahon, K. L., Thompson, P. M., ... Kayser, M. (2012). A genome-wide association study identifies five loci influencing facial morphology in Europeans. P L o S Genetics, 8(9), [e1002932]. https://doi.org/10.1371/journal.pgen.1002932

Liu, F, van der Lijn, F, Schurmann, C, Zhu, G, Chakravarty, MM, Hysi, PG, Wollstein, A, Lao, O, de Bruijne, M, Ikram, MA, van der Lugt, A, Rivadeneira, F, Uitterlinden, AG, Hofman, A, Niessen, WJ, Homuth, G, de Zubicaray, G, McMahon, KL, Thompson, PM, Daboul, A, Puls, R, Hegenscheid, K, Bevan, L, Pausova, Z, Medland, SE, Montgomery, GW, Wright, MJ, Wicking, C, Boehringer, S, Spector, TD, Paus, T, Martin, NG, Biffar, R & Kayser, M 2012, 'A genome-wide association study identifies five loci influencing facial morphology in Europeans', P L o S Genetics, vol. 8, no. 9, e1002932. https://doi.org/10.1371/journal.pgen.1002932

@article{e9b2de052ba24465acb7b2a25134ee66,

title = "A genome-wide association study identifies five loci influencing facial morphology in Europeans",

abstract = "Inter-individual variation in facial shape is one of the most noticeable phenotypes in humans, and it is clearly under genetic regulation; however, almost nothing is known about the genetic basis of normal human facial morphology. We therefore conducted a genome-wide association study for facial shape phenotypes in multiple discovery and replication cohorts, considering almost ten thousand individuals of European descent from several countries. Phenotyping of facial shape features was based on landmark data obtained from three-dimensional head magnetic resonance images (MRIs) and two-dimensional portrait images. We identified five independent genetic loci associated with different facial phenotypes, suggesting the involvement of five candidate genes-PRDM16, PAX3, TP63, C5orf50, and COL17A1-in the determination of the human face. Three of them have been implicated previously in vertebrate craniofacial development and disease, and the remaining two genes potentially represent novel players in the molecular networks governing facial development. Our finding at PAX3 influencing the position of the nasion replicates a recent GWAS of facial features. In addition to the reported GWA findings, we established links between common DNA variants previously associated with NSCL/P at 2p21, 8q24, 13q31, and 17q22 and normal facial-shape variations based on a candidate gene approach. Overall our study implies that DNA variants in genes essential for craniofacial development contribute with relatively small effect size to the spectrum of normal variation in human facial morphology. This observation has important consequences for future studies aiming to identify more genes involved in the human facial morphology, as well as for potential applications of DNA prediction of facial shape such as in future forensic applications.",

author = "Fan Liu and {van der Lijn}, Fedde and Claudia Schurmann and Gu Zhu and Chakravarty, {M. Mallar} and Hysi, {Pirro G.} and Andreas Wollstein and Oscar Lao and {de Bruijne}, Marleen and Ikram, {M. Arfan} and {van der Lugt}, Aad and Fernando Rivadeneira and Uitterlinden, {Andre G.} and Albert Hofman and Niessen, {Wiro J.} and Georg Homuth and {de Zubicaray}, Greig and McMahon, {Katie L.} and Thompson, {Paul M.} and Amro Daboul and Ralf Puls and Katrin Hegenscheid and Liisa Bevan and Zdenka Pausova and Medland, {Sarah E.} and Montgomery, {Grant W.} and Wright, {Margaret J.} and Carol Wicking and Stefan Boehringer and Spector, {Timothy D.} and Tomas Paus and Martin, {Nicholas G.} and Reiner Biffar and Manfred Kayser",

year = "2012",

month = sep,

doi = "10.1371/journal.pgen.1002932",

language = "English",

volume = "8",

journal = "P L o S Genetics",

issn = "1553-7390",

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TY - JOUR

T1 - A genome-wide association study identifies five loci influencing facial morphology in Europeans

AU - Liu, Fan

AU - van der Lijn, Fedde

AU - Schurmann, Claudia

AU - Zhu, Gu

AU - Chakravarty, M. Mallar

AU - Hysi, Pirro G.

AU - Wollstein, Andreas

AU - Lao, Oscar

AU - de Bruijne, Marleen

AU - Ikram, M. Arfan

AU - van der Lugt, Aad

AU - Rivadeneira, Fernando

AU - Uitterlinden, Andre G.

AU - Hofman, Albert

AU - Niessen, Wiro J.

AU - Homuth, Georg

AU - de Zubicaray, Greig

AU - McMahon, Katie L.

AU - Thompson, Paul M.

AU - Daboul, Amro

AU - Puls, Ralf

AU - Hegenscheid, Katrin

AU - Bevan, Liisa

AU - Pausova, Zdenka

AU - Medland, Sarah E.

AU - Montgomery, Grant W.

AU - Wright, Margaret J.

AU - Wicking, Carol

AU - Boehringer, Stefan

AU - Spector, Timothy D.

AU - Paus, Tomas

AU - Martin, Nicholas G.

AU - Biffar, Reiner

AU - Kayser, Manfred

PY - 2012/9

Y1 - 2012/9

N2 - Inter-individual variation in facial shape is one of the most noticeable phenotypes in humans, and it is clearly under genetic regulation; however, almost nothing is known about the genetic basis of normal human facial morphology. We therefore conducted a genome-wide association study for facial shape phenotypes in multiple discovery and replication cohorts, considering almost ten thousand individuals of European descent from several countries. Phenotyping of facial shape features was based on landmark data obtained from three-dimensional head magnetic resonance images (MRIs) and two-dimensional portrait images. We identified five independent genetic loci associated with different facial phenotypes, suggesting the involvement of five candidate genes-PRDM16, PAX3, TP63, C5orf50, and COL17A1-in the determination of the human face. Three of them have been implicated previously in vertebrate craniofacial development and disease, and the remaining two genes potentially represent novel players in the molecular networks governing facial development. Our finding at PAX3 influencing the position of the nasion replicates a recent GWAS of facial features. In addition to the reported GWA findings, we established links between common DNA variants previously associated with NSCL/P at 2p21, 8q24, 13q31, and 17q22 and normal facial-shape variations based on a candidate gene approach. Overall our study implies that DNA variants in genes essential for craniofacial development contribute with relatively small effect size to the spectrum of normal variation in human facial morphology. This observation has important consequences for future studies aiming to identify more genes involved in the human facial morphology, as well as for potential applications of DNA prediction of facial shape such as in future forensic applications.

AB - Inter-individual variation in facial shape is one of the most noticeable phenotypes in humans, and it is clearly under genetic regulation; however, almost nothing is known about the genetic basis of normal human facial morphology. We therefore conducted a genome-wide association study for facial shape phenotypes in multiple discovery and replication cohorts, considering almost ten thousand individuals of European descent from several countries. Phenotyping of facial shape features was based on landmark data obtained from three-dimensional head magnetic resonance images (MRIs) and two-dimensional portrait images. We identified five independent genetic loci associated with different facial phenotypes, suggesting the involvement of five candidate genes-PRDM16, PAX3, TP63, C5orf50, and COL17A1-in the determination of the human face. Three of them have been implicated previously in vertebrate craniofacial development and disease, and the remaining two genes potentially represent novel players in the molecular networks governing facial development. Our finding at PAX3 influencing the position of the nasion replicates a recent GWAS of facial features. In addition to the reported GWA findings, we established links between common DNA variants previously associated with NSCL/P at 2p21, 8q24, 13q31, and 17q22 and normal facial-shape variations based on a candidate gene approach. Overall our study implies that DNA variants in genes essential for craniofacial development contribute with relatively small effect size to the spectrum of normal variation in human facial morphology. This observation has important consequences for future studies aiming to identify more genes involved in the human facial morphology, as well as for potential applications of DNA prediction of facial shape such as in future forensic applications.

U2 - 10.1371/journal.pgen.1002932

DO - 10.1371/journal.pgen.1002932

M3 - Journal article

C2 - 23028347

SN - 1553-7390

VL - 8

JO - P L o S Genetics

JF - P L o S Genetics

IS - 9

M1 - e1002932

ER -

A genome-wide association study identifies five loci influencing facial morphology in Europeans

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