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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-citationPredicting Physical Appearance from DNA Data—Towards Genomic Solutions
Pośpiech, E., Teisseyre, P., Mielniczuk, J., & Branicki, W. (2022) · Genes · doi:10.3390/genes13010121 · Cited by 25
“The study by Claes et al. (2018) involved 2329 individuals at the discovery stage and an additional 1719 at the replication stage, and found associations for 15 loci with facial features, including four new genes, nine consistently confirmed, and two linked with pleiotropic facial phenotypic…”
BackgroundThe Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel
Fitzgerald, T. W., Brettell, I., Léger, A., Wolf, N., Kusminski, N., Monahan, J., Barton, C., Herder, C., Aadepu, N., Gierten, J., et al. (2022) · Genome biology · doi:10.1186/s13059-022-02623-z · Cited by 24
Katz, D. C., Aponte, J. D., Liu, W., Green, R. M., Mayeux, J., Pollard, K. M., Pomp, D., Munger, S. C., Murray, S. A., Roseman, C. C., et al. (2020) · PLoS ONE · doi:10.1371/journal.pone.0233377 · Cited by 22
“Face QTL signals in mouse datasets may be swamped in a whole skull analysis because QTL effect sizes are likely to be small for complex quantitative traits like facial shape [15] and because the most commonly used shape registration algorithm tends to redistribute variation among the coordinates of a landmark configur…”
BackgroundNavic, P., Inthasan, C., Chaimongkhol, T., et al. (2023) · Legal Medicine · doi:10.1016/j.legalmed.2023.102239 · Cited by 22
Genome-wide association study reveals sex-specific genetic architecture of facial attractiveness
Hu, B., Shen, N., Li, J. J., Kang, H., Hong, J., Fletcher, J. M., Greenberg, J. S., Seltzer, M. M., & Lu, Q. (2019) · PLoS Genetics · doi:10.1371/journal.pgen.1007973 · Cited by 21
Self-citationA genome-wide association study of facial morphology identifies novel genetic loci in Han Chinese
Huang, Y., Li, D., Qiao, L., Liu, Y., Peng, Q., Wu, S., Zhang, M., Yang, Y., Tan, J., Xu, S., et al. (2020) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2020.10.004 · Cited by 22
“The region has been reported to be associated with chin morphology, but was linked to another candidate gene, ASPM (Claes et al., 2018).”
BackgroundMethodResultInfluentialSelf-citationFeng, Z., Duren, Z., Xiong, Z., Wang, S., Liu, F., Wong, W. H., & Wang, Y. (2021) · Communications Biology · doi:10.1038/s42003-021-01970-0 · Cited by 20
Forensic DNA phenotyping: Inferring phenotypic traits from crime scene DNA
Dabas, P., Jain, S. G., Khajuria, H., & Nayak, B. P. (2022) · Journal of Forensic and Legal Medicine · doi:10.1016/j.jflm.2022.102351 · Cited by 25
Zhang, X., Liu, Q., Zhang, H., Zhao, S., Huang, J., Sovannary, T., Bunnath, L., Aun, H. S., Samnom, H., Su, B., et al. (2021) · National Science Review · doi:10.1093/nsr/nwab072 · Cited by 19
Connecting the dots towards precision orthodontics
Kapila, S., Vora, S. R., Venugopalan, S. R., Elnagar, M. H., & Akyalçın, S. (2023) · Orthodontics and Craniofacial Research · doi:10.1111/ocr.12725 · Cited by 23
“54 57”
Prenatal alcohol exposure and facial morphology in a UK cohort
Howe, L. J., Sharp, G. C., Hemani, G., Zuccolo, L., Richmond, S., & Lewis, S. J. (2019) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2018.11.031 · Cited by 17
Advancement in Human Face Prediction Using DNA
Alshehhi, A., Almarzooqi, A., Alhammadi, K., Werghi, N., Tay, G. K., & AlSafar, H. S. (2023) · Genes · doi:10.3390/genes14010136 · Cited by 18
“Moreover, it is recommended that researchers investigate faces globally and locally by correlating grouped features or measurements with individual or multiple genetic factors [167].”
BackgroundGenetic basis of right and left ventricular heart shape
Burns, R., Young, W. J., Aung, N., Lopes, L. R., Elliot, P. M., Syrris, P., Villa, R. B., Sohrabi, C., Petersen, S. E., Ramírez, J., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-53594-7 · Cited by 18
“Although many aspects of this paper are clearly novel, I do not think the authors can claim to be the first to study the genet basis of heart shape.”
Is the “Habsburg jaw” related to inbreeding?
Vilas, R., Ceballos, F. C., Al‐Soufi, L., González‐García, R., Moreno, C., Moreno, M., Villanueva, L., Ruiz, L., Mateos, J., González, D., et al. (2019) · Annals of Human Biology · doi:10.1080/03014460.2019.1687752 · Cited by 16
“In addition, they suggest a greater sensitivity to inbreeding for the lower third of the face, which is consistent with the modular nature of the human face and differences in heritability between the upper and lower facial parts (Claes et al. 2018; Hoskens et al. 2018).”
BackgroundTFAP2 paralogs regulate midfacial development in part through a conserved ALX genetic pathway
Nguyen, T., Mitchell, J. M., Kiel, M. D., Kenny, C., Li, H., Jones, K. L., Cornell, R. A., Williams, T., Nichols, J. T., & Otterloo, E. V. (2023) · Development · doi:10.1242/dev.202095 · Cited by 17
Individuals with nonsyndromic orofacial clefts have increased asymmetry of fingerprint patterns
Neiswanger, K., Mukhopadhyay, N., Rajagopalan, S. S., et al. (2020) · PLoS ONE · doi:10.1371/journal.pone.0230534 · Cited by 15
“For example, a number of cleft-related syndromes include limb defects as well (OMIM search term = “cleft lip/palate and limb”, and a recent GWAS study of human facial shape reported that associated loci were enriched for genes involved in limb development [55].”
BackgroundSelf-citationSpatially Dense 3D Facial Heritability and Modules of Co-heritability in a Father-Offspring Design
Hoskens, H., Li, J., Indencleef, K., Gors, D., Larmuseau, M., Richmond, S., Zhurov, A. I., Hens, G., Peeters, H., & Claes, P. D. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00554 · Cited by 15
“Partial least squares regression (PLSR; function plsregress from Matlab 2017b) was performed to predict facial variation in children given the father’s facial variation.”
InfluentialSelf-citationForensic inference of biogeographical ancestry from genotype: The Genetic Ancestry Lab
McNevin, D. B. (2019) · Wiley Interdisciplinary Reviews Forensic Science · doi:10.1002/wfs2.1356 · Cited by 15
Bonazzola, R., Ravikumar, N., Attar, R., Ferrante, E., Syeda-Mahmood, T. F., & Frangi, A. F. (2021) · Lecture notes in computer science · doi:10.1007/978-3-030-87240-3_67 · Cited by 13
Forensic DNA phenotyping: A promising tool to aid forensic investigation. Current situation
Serrano, A. C. (2020) · Revista Española de Medicina Legal · doi:10.1016/j.remle.2020.01.002 · Cited by 15
Quantification of Facial Traits
Böhringer, S., & de Jong, M. A. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00397 · Cited by 14
“Such quantities are of interest in genome wide association studies (GWASs), syndrome classification, and other prediction settings.”
BackgroundMethodInfluentialSearching for improvements in predicting human eye colour from DNA
Kukla‐Bartoszek, M., Teisseyre, P., Pośpiech, E., Karłowska-Pik, J., Zieliński, P., Woźniak, A., Boroń, M., Dąbrowski, M., Zubańska, M., Jarosz, A., et al. (2021) · International Journal of Legal Medicine · doi:10.1007/s00414-021-02645-5 · Cited by 19
Muggli, E., Halliday, J., Elliott, E., Penington, A., Thompson, D. K., Spittle, A., Forster, D. A., Lewis, S., Hearps, S. J. C., & Anderson, P. (2022) · BMJ Open · doi:10.1136/bmjopen-2021-054706 · Cited by 9
Dash, S., & Trainor, P. A. (2022) · Development · doi:10.1242/dev.200349 · Cited by 14
Using data‐driven phenotyping to investigate the impact of sex on 3D human facial surface morphology
Matthews, H. S., Mahdi, S. S., Penington, A., Marazita, M. L., Shaffer, J. R., Walsh, S., Shriver, M. D., Claes, P. D., & Weinberg, S. M. (2023) · Journal of Anatomy · doi:10.1111/joa.13866 · Cited by 16
“In 2018, we introduced an innovative extension of spatially dense geometric morphometrics involving the segmentation of 3D facial surfaces into 63 regions or modules based on patterns of multivariate correlation among the ~ 8000 aligned quasi-landmarks (Claes et al., 2018 ).”
MethodSelf-citationAl-baker, B., Alkalaly, A., Ayoub, A. F., Ju, X., & Mossey, P. A. (2023) · European Journal of Orthodontics · doi:10.1093/ejo/cjac077 · Cited by 14
Multilevel principal components analysis of three-dimensional facial growth in adolescents
FARNELL, D. J. J., Richmond, S., Galloway, J., et al. (2019) · Computer Methods and Programs in Biomedicine · doi:10.1016/j.cmpb.2019.105272 · Cited by 13
“Normal facial development (“growth” or “ageing”) begins at conception and can be influenced by genetics with over 50 genes discovered [15-19].”
Self-citationNon-syndromic Cleft Lip and Palate Polymorphisms Affect Normal Lip Morphology
Wilson-Nagrani, C. E., Richmond, S., & Paternoster, L. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00413 · Cited by 13
“More recently, a data driven approach of phenotyping has been described, which successfully identified loci in cranial neural crest cells (Claes et al., 2018).”
BackgroundRedefining the research hospital
Nachev, P., Herron, D., McNally, N., Rees, G. E., & Williams, B. (2019) · npj Digital Medicine · doi:10.1038/s41746-019-0201-2 · Cited by 14
Sumiyama, K., & Tanave, A. (2020) · Development Growth & Differentiation · doi:10.1111/dgd.12671 · Cited by 15
“Regarding craniofacial variations in human, a SNP (rs10238953, A > G mutation, G is minor allele, minor allele frequency is about 0.14) in eDlx#18 cis-regulatory element is associated with non-pathogenic human morphological variation of chin (Claes et al., 2018).”
BackgroundInfluentialPilli, E., Palamenghi, A., & Cattaneo, C. (2025) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.15398 · Cited by 17
Sentinel cells programmed to respond to environmental DNA including human sequences
Nou, X. A., & Voigt, C. A. (2023) · Nature Chemical Biology · doi:10.1038/s41589-023-01431-1 · Cited by 15
“1b and Supplementary Tables 2 and 3) 45,46 .”
Faria‐Teixeira, M. C., Tordera, C., Salvado, F., Carneiro, A. V., & Iglesias‐Linares, A. (2024) · Pediatric Research · doi:10.1038/s41390-023-02907-5 · Cited by 14
de Velde, F. E. G. V., Ortega-Castrillón, A., Thierens, L. A. M., et al. (2020) · Oral Surgery Oral Medicine Oral Pathology and Oral Radiology · doi:10.1016/j.oooo.2020.05.017 · Cited by 12
Self-citationMusMorph, a database of standardized mouse morphology data for morphometric meta-analyses
Devine, J., Vidal‐García, M., Liu, W., Neves, A., Vercio, L. L., Green, R. M., Richbourg, H. A., Marchini, M., Unger, C. M., Nickle, A. C., et al. (2022) · Scientific Data · doi:10.1038/s41597-022-01338-x · Cited by 12
Sánchez‐Bermejo, P. C., Carmona, C. P., Schuman, M. C., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-67265-8 · Cited by 11
“To do so, we used a Hierarchical Spectral Clustering with Parallel analysis (HPS-CA), a data-driven dimension reduction approach originally developed for the segmentation of human facial features 91,92 .”
Yun, S., Han, M., Kim, H. J., et al. (2019) · Clinical and Experimental Nephrology · doi:10.1007/s10157-019-01731-8 · Cited by 11
Incisor Occlusion Affects Profile Shape Variation in Middle-Aged Adults
Kanavakis, G., Silvola, A., Halazonetis, D. J., Lähdesmäki, R. E., & Pirttiniemi, P. M. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10040800 · Cited by 11
“The morphology of the lower facial third, in particular, contributes significantly to the variation in facial appearance among humans [4].”
Background
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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