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Genome-wide mapping of global-to-local genetic effects on human facial shape
Open accessAbstract
Genome-wide association scans of complex multipartite traits like the human face typically use preselected phenotypic measures. Here we report a data-driven approach to phenotyping facial shape at multiple levels of organization, allowing for an open-ended description of facial variation while preserving statistical power. In a sample of 2,329 persons of European ancestry, we identified 38 loci, 15 of which replicated in an independent European sample (n = 1,719). Four loci were completely new. For the others, additional support (n = 9) or pleiotropic effects (n = 2) were found in the literature, but the results reported here were further refined. All 15 replicated loci highlighted distinctive patterns of global-to-local genetic effects on facial shape and showed enrichment for active chromatin elements in human cranial neural crest cells, suggesting an early developmental origin of the facial variation captured. These results have implications for studies of facial genetics and other complex morphological traits. The authors report a data-driven approach to phenotyping 3D facial shape. They apply their methodology to 2,329 individuals of European ancestry and identify 38 loci that associate with specific facial morphologies, some of which overlap with neural-crest-specific regulatory regions.
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“A significant portion of the 16 ear-related loci discussed here have been shown to have strong ties to human facial structure [8,15,21,22,30].”
From Combined genome-wide association study of 136 quantitative ear morphology traits in multiple populations reveal 8 novel loci (2023) · cites this paper as [22]
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Self-citationDe Novo Reconstruction of 3D Human Facial Images from DNA Sequence
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“A significant portion of the 16 ear-related loci discussed here have been shown to have strong ties to human facial structure [8,15,21,22,30].”
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Self-citationThe Facial Characteristics of Individuals with Posterior Crossbite: A Cross-Sectional Study
Kienkas, K., Jākobsone, G., & Šalms, Ģ. (2023) · Healthcare · doi:10.3390/healthcare11131881 · Cited by 2
“The landmarking errors can be overcome by aligning in dense correspondence to increase the ability to record even slight differences [2,3,28].”
BackgroundForensic DNA phenotyping using next-generation sequencing
Haidar, M., Mousawi, F., & Al-Matrouk, A. K. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-99144-5.00014-7 · Cited by 3
Qiao, H., Tan, J., Yan, J., Sun, C., Yin, X., Li, Z., Wu, J., Guan, H., Wen, S., Zhang, M., et al. (2024) · iScience · doi:10.1016/j.isci.2024.109325 · Cited by 2
“The second approach, DDA, was performed using the pipeline described by Claes et al. 7 The global-to-local facial phenotyping partitioned each facial surface into 127 segments, each of which consisted of several point clouds and was represented by multiple dimensions of variation (principal components, PCs).”
BackgroundMethodInfluentialSelf-citationBaek, S., Hong, H., Yoon, S.-J., et al. (2025) · Journal of Craniofacial Surgery · doi:10.1097/scs.0000000000011467 · Cited by 2
Genome‐wide associations of leaf spectral variation in MAGIC lines of Nicotiana attenuata
Li, C., Czyż, E. A., Schmid, B., et al. (2026) · Ecology · doi:10.1002/ecy.70366 · Cited by 2
“As discussed in studies on human facial shapes, from which the HSC-PA method was adapted (Claes et al., 2018), this methodological shift allows for a transition from a global to a local understanding of spectral variation, and a holistic view of its genetic basis.”
How the diversity of the faces arises
Wu, Z., & Jung, H.-S. (2019) · Journal of Oral Biosciences · doi:10.1016/j.job.2019.08.001 · Cited by 2
Abouelhoda, M. I., & Naït-Ali, A. (2019) · Series in bioengineering · doi:10.1007/978-981-13-0956-4_1 · Cited by 2
Knocking-out the human face genes TBX15 and PAX1 in mice alters facial and other physical morphologyPreprint
Yu, Q., Xiong, Z., Li, Y., Zhou, H., Kayser, M., Liu, L., & Liu, F. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.05.26.445773 · Cited by 2
“WT mice were largely consistent with the genetic association effects observed in previous human GWASs (Fig 4) [1-6,20,21].”
BackgroundResultInfluentialNucleolin loss-of-function leads to aberrant FGF signaling and craniofacial anomaliesPreprint
Dash, S., & Trainor, P. A. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.09.14.460382 · Cited by 2
Automated 3D Landmarking of the Skull: A Novel Approach for Craniofacial AnalysisPreprint
Wilke, F., Matthews, H. S., Herrick, N., Dopkins, N., Claes, P. D., & Walsh, S. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.09.579642 · Cited by 2
Self-citationA genome-wide association scan reveals novel loci for facial traits of Koreans
Cho, H., Ban, H., Jin, H., Cha, S., & Eom, Y. (2023) · Genomics · doi:10.1016/j.ygeno.2023.110710 · Cited by 1
Exploring the association between SNPs and facial morphology in a Spanish population
Navarro-López, B., Wilke, F., Suárez-Ulloa, V., Baeta, M., Martos, R., Moreno-López, O., Olalde, Í., Martínez‐Jarreta, B., Jiménez, S., Walsh, S., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-98748-9 · Cited by 2
“Notably, seven of the identified SNPs corroborate associations with facial regions previously established in different studies 4,8,9,11,12,14,15,30 , emphasizing their significance across various populations.”
Brachmann, M. K., & Jacobs, C. T. (2025) · Evolutionary Biology · doi:10.1007/s11692-025-09655-w · Cited by 1
Shchetinina, A., Liu, X., Slopen, N. B., Chambers, C., Wolvius, E. B., Kayser, M., Roshchupkin, G. V., & Tiemeier, H. W. (2026) · Journal of Developmental Origins of Health and Disease · doi:10.1017/s2040174425100391 · Cited by 1
“12,45,46 However, growing evidence from developmental biology and epigenetics underscores a role of prenatal environmental factors.”
The Occasional Perils of Reflection (Across the Midline; in Geometric Morphometrics)
Katz, D. C. (2020) · Evolutionary Biology · doi:10.1007/s11692-020-09501-1 · Cited by 1
Methods in Genetic Analysis for Evaluation Mandibular Shape and Size Variations in Human Mandible
Yamaguchi, T., Kim, Y., Adel, M., Hikita, Y., Takahashi, M., Haga, S., Park, S., & Maki, K. (2021) · Journal of Craniofacial Surgery · doi:10.1097/scs.0000000000007686 · Cited by 1
Denault, W. R. P., Romanowska, J., Haaland, Ø. A., Lyle, R., Taylor, J. A., Xu, Z., Lie, R. T., Gjessing, H. K., & Jugessur, A. (2021) · NAR Genomics and Bioinformatics · doi:10.1093/nargab/lqab035 · Cited by 1
“These connections also point to the potential involvement of a large number of genes acting in concert to orchestrate the many delicate processes that contribute to the morphogenesis of the human face (70).”
BackgroundRosa, J. L. R. L., Restrepo, M., Murillo, E. A. T., et al. (2021) · Revista Estomatológica Herediana · doi:10.20453/reh.v31i2.3967 · Cited by 1
“genotipo (11); varios autores muestran y explican el fenotipo de la asimetría, con los respectivos genes (29,30,31).”
BackgroundaDNA, ethnography, and facial approximations of the Teouma Lapita burials (c. 3000BP)
Hayes, S., Buckley, H. R., Valentin, F., Bedford, S., & Spriggs, M. (2023) · Journal of Archaeological Science · doi:10.1016/j.jas.2023.105916 · Cited by 1
Yu, J. Q., Jin, X., Du, W., Bai, Y., Zhou, X., Gao, M., Li, S., Qin, J., Chen, X., Liu, Y., et al. (2023) · Electrophoresis · doi:10.1002/elps.202300169 · Cited by 1
Craniofacial Reconstruction of a 4000-year-old Human Skull
Tu, L., Li, S., Caixia, L., et al. (2025) · Journal of Forensic Science and Medicine · doi:10.4103/jfsm.jfsm_191_23 · Cited by 1
Iwaya, C., & Iwata, J. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1587052 · Cited by 1
Deep learning based face shape classification system with binary feature selection model
Adapa, S., & Enireddy, V. (2025) · Expert Systems with Applications · doi:10.1016/j.eswa.2025.129115 · Cited by 1
Facial Biometrics: From Security to Biomedical Applications
Naït-Ali, A. (2018) · Series in bioengineering · doi:10.1007/978-981-13-1144-4_7 · Cited by 1
van den Heuvel, M. P., & Danielle Posthuma, B. (2021) · Nature Genetics · doi:10.1038/s41588-021-00858-3 · Cited by 1
Biological aspects of bone growth and metabolism in orthodontics
Chen, S., Hartsfield, J. K., & Roberts, W. E. (2015) · Wiley eBooks · doi:10.1002/9781118916148.ch5 · Cited by 1
Yasri, S., & Wiwanitkit, V. (2020) · British Journal of Oral and Maxillofacial Surgery · doi:10.1016/j.bjoms.2020.01.015 · Cited by 1
Shared heritability of face and brain shape distinct from cognitive traitsPreprint
Naqvi, S., Sleyp, Y., Hoskens, H., Indencleef, K., Spence, J. P., Bruffaerts, R., Radwan, A., Eller, R. J., Richmond, S., Shriver, M. D., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.08.29.269258 · Cited by 1
Self-citationNovel Genetic Loci Affecting Facial Shape Variation in HumansPreprint
Xiong, Z., Zhou, H., Dankova, G., Howe, L. J., Lee, M. K., Hysi, P. G., de Jong, M. A., Zhu, G., Adhikari, K., Li, D., et al. (2018) · SSRN Electronic Journal · doi:10.2139/ssrn.3307375 · Cited by 1
Self-citationJordan, B. (2021) · médecine/sciences · doi:10.1051/medsci/2021008 · Cited by 1
Li, Y., Zhao, W., Li, D., Tao, X., Xiong, Z., Liu, J., Zhang, W., Ji, A., Tang, K., Liu, F., et al. (2021) · Human Genetics · doi:10.1007/s00439-021-02352-6 · Cited by 1
RetractedPrinz, M., & Lessig, R. (2022) · Wiley eBooks · doi:10.1002/9781119648628.ch64 · Cited by 2
Saitou, N. (2018) · Computational biology · doi:10.1007/978-3-319-92642-1_18
Serrano, A. C. (2020) · Revista Española de Medicina Legal · doi:10.1016/j.reml.2020.01.003 · Cited by 1
Bertól, J. W., Johnston, S., Ahmed, R., Xie, V. K., Hubka, K. M., Cruz, L. A., Nitschke, L., Stetsiv, M., Goering, J. P., Nistor, P., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.08.22.457283
Self-citationNot Only Olfaction: The Nose, Protagonist of the Diversity and Individuality of the Human Face
Cilli, E., & Gruppioni, G. (2021) · Human perspectives in health sciences and technology · doi:10.1007/978-3-030-75205-7_3
Metadata
- Authors
- Claes, P., Roosenboom, J., White, J. D., Swigut, T., Sero, D., Li, J., Lee, M. K., Zaidi, A., Mattern, B. C., Liebowitz, C., Pearson, L., González, T., Leslie, E. J., Carlson, J. C., Orlova, E., Suetens, P., Vandermeulen, D., Feingold, E., Marazita, M. L., Shaffer, J. R., Wysocka, J., Shriver, M. D., & Weinberg, S. M.
- Affiliations
- Universitair Ziekenhuis Leuven (BE)
- University of Pittsburgh (US)
- Pennsylvania State University (US)
- Stanford Medicine (US)
- Corresponding author
- Claes, Peter
- Wysocka, Joanna
- Shriver, Mark D.
- Weinberg, Seth M.
- ORCID
- Claes, Peter
- Roosenboom, Jasmien
- White, Julie D.
- Swigut, Tomek
- Sero, Dzemila
- Lee, Myoung Keun
- Zaidi, Arslan
- Mattern, Brooke C.
- Pearson, Laurel
- Leslie, Elizabeth J.
- Carlson, Jenna C.
- Orlova, Ekaterina
- Suetens, Paul
- Vandermeulen, Dirk
- Feingold, Eleanor
- Marazita, Mary L.
- Shaffer, John R.
- Wysocka, Joanna
- Shriver, Mark D.
- Weinberg, Seth M.
- Venue
- Nature Genetics
- Published
- 2018-02-19
- Volume
- 50
- Issue
- 3
- Pages
- 414-423
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5937280
- OpenAlex
- W2789017128
- Semantic Scholar
- c3fa862579fa588c95e4d3f5a5445fc1c2531c54
- Cited by
- 235
- References
- 62
- Citations by year
- 2026: 21 · 2025: 24 · 2024: 17 · 2023: 31 · 2022: 24 · 2021: 44 · 2020: 29 · 2019: 30 · 2018: 14
- FWCI
- 17.94
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Funders
- KU Leuven
- National Institute of Dental and Craniofacial Research (R01DE027023, R01DE016148, U01DE020078, K99DE025060, R00DE025060, U01DE024430, U01DE020057)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Morphological variations and asymmetry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- facial shape, facial morphology, genetic loci, cranial neural crest cells, pleiotropy, morphological characters, European ancestry
- MeSH terms
- Adult, Chromosome Mapping, Face, Genotype, Humans, Maxillofacial Development, Phenotype, United States, Cohort Studies, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Quantitative Trait Loci, White People, Genome-Wide Association Study, Young Adult, Genetic Association Studies
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