A multi-ancestry GWAS meta-analysis of facial features and its application in predicting archaic human features

Siyuan Du; Jieyi Chen; Jiarui Li; Wei Qian; Sijie Wu; Qianqian Peng; Yu Liu; Ting Pan; Yi Li; Sibte Syed Hadi; Jingze Tan; Ziyu Yuan; Jiucun Wang; Kun Tang; Zhuo Wang; Yanqin Wen; Xinran Dong; Wenhao Zhou; Andr&#233;s Ruiz-Linares; Yongyong Shi; Li Jin; Fan Liu; Manfei Zhang; Sijia Wang

doi:10.1016/j.jgg.2024.07.005

Volume 52 Issue 4

Apr. 2025

Turn off MathJax

Article Contents

Article Navigation > Journal of Genetics and Genomics > 2025 > 52(4): 513-524

PDF( 0 KB)

A multi-ancestry GWAS meta-analysis of facial features and its application in predicting archaic human features

doi: 10.1016/j.jgg.2024.07.005

a. CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
b. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China;
c. Center for Molecular Medicine, Pediatrics Research Institute, Children's Hospital of Fudan University, Shanghai 201102, China;
d. Department of Forensic Sciences, College of Criminal Justice, Naif Arab University for Security Sciences, Riyadh 11452, Kingdom of Saudi Arabia;
e. Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200438, China;
f. Fudan-Taizhou Institute of Health Sciences, Taizhou, Jiangsu 225326, China;
g. Key Laboratory of Genetic Engineering, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai 200120, China;
h. Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Shanghai 200438, China;
i. Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, China;
j. Aix-Marseille Université, CNRS, EFS, ADES, Marseille 13005, France;
k. Department of Genetics, Evolution and Environment, and UCL Genetics Institute, University College London, London WC1E 6BT, UK;
l. Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, 3015 CN Rotterdam, the Netherlands;
m. Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan 650223, China

Funds:

This project was funded by the following grants and contracts: Strategic Priority Research Program of the Chinese Academy of Sciences (XDB38020400 to S.W.), the National Natural Science Foundation of China (32325013 to S.W., 32271186 to J.T., 31900408 to M.Z.), the CAS Project for Young Scientists in Basic Research (YSBR-077 to S.W.), Shanghai Science and Technology Commission Excellent Academic Leaders Program (22XD1424700 to S.W.), CAMS Innovation Fund for Medical Sciences (2019-I2M-5-066 to L.J. and J.W.), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01 to L.J. and S.W.), the National Science and Technology Basic Research Project (2015FY111700 to L.J.), and the 111 Project (B13016 to L.J.).

Received Date: 2024-07-04
Accepted Date: 2024-07-06
Rev Recd Date: 2024-07-06

Available Online: 2025-07-11

Publish Date: 2024-07-11

Abstract

Abstract

Facial morphology, a complex trait influenced by genetics, holds great significance in evolutionary research. However, due to limited fossil evidence, the facial characteristics of Neanderthals and Denisovans have remained largely unknown. In this study, we conduct a large-scale multi-ethnic meta-analysis of the genome-wide association study (GWAS), including 9674 East Asians and 10,115 Europeans, quantitatively assessing 78 facial traits using 3D facial images. We identify 71 genomic loci associated with facial features, including 21 novel loci. We develop a facial polygenic score (FPS) that enables the prediction of facial features based on genetic information. Interestingly, the distribution of FPSs among populations from diverse continental groups exhibits relevant correlations with observed facial features. Furthermore, we apply the FPS to predict the facial traits of seven Neanderthals and one Denisovan using ancient DNA and align predictions with the fossil records. Our results suggest that Neanderthals and Denisovans likely share similar facial features, such as a wider but shorter nose and a wider endocanthion distance. The decreased mouth width is characterized specifically in Denisovans. The integration of genomic data and facial trait analysis provides valuable insights into the evolutionary history and adaptive changes in human facial morphology.
- Genome-wide association study,
- Multi-ethnic meta-analysis,
- Facial morphology,
- Facial polygenic score,
- Ancient DNA,
- Archaic human

FullText(HTML)

References(63)

References

Adhikari, K., Fuentes-Guajardo, M., Quinto-Sanchez, M., Mendoza-Revilla, J., Camilo Chacon-Duque, J., Acuna-Alonzo, V., Jaramillo, C., Arias, W., Lozano, R.B., Perez, G.M., et al., 2016. A genome-wide association scan implicates dchs2, runx2, gli3, pax1 and edar in human facial variation. Nat. Commun. 7, 11616.

Adhikari, K., Reales, G., Smith, A.J., Konka, E., Palmen, J., Quinto-Sanchez, M., Acuna-Alonzo, V., Jaramillo, C., Arias, W., Fuentes, M., et al., 2015. A genome-wide association study identifies multiple loci for variation in human ear morphology. Nat. Commun. 6, 7500.

Altshuler, D.M., Durbin, R.M., Abecasis, G.R., Bentley, D.R., Chakravarti, A., Clark, A.G., Donnelly, P., Eichler, E.E., Flicek, P., Gabriel, S.B., et al., 2015. A global reference for human genetic variation. Nature. 526, 68-74.

Brown, B.C., Ye, C.J., Price, A.L.,Zaitlen, N., 2016. Transethnic genetic-correlation estimates from summary statistics. Am. J. Hum. Genet. 99, 76-88.

Bulik-Sullivan, B.K., Loh, P.R., Finucane, H.K., Ripke, S., Yang, J., Patterson, N., Daly, M.J., Price, A.L.,Neale, B.M., 2015. Ld score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291-295.

Bult, C.J., Blake, J.A., Smith, C.L., Kadin, J.A., Richardson, J.E.,Group, t.M.G.D., 2018. Mouse genome database (mgd) 2019. Nucleic Acids Res. 47, D801-D806.

Chen, F., Welker, F., Shen, C.C., Bailey, S.E., Bergmann, I., Davis, S., Xia, H., Wang, H., Fischer, R., Freidline, S.E., et al., 2019. A late Middle Pleistocene Denisovan mandible from the Tibetan Plateau. Nature. 569, 409-412.

Cox, S.L., Ruff, C.B., Maier, R.M.,Mathieson, I., 2019. Genetic contributions to variation in human stature in prehistoric Europe. Proc. Natl. Acad. Sci. USA. 116, 21484-21492.

Curtis, S.W., Chang, D., Lee, M.K., Shaffer, J.R., Indencleef, K., Epstein, M.P., Cutler, D.J., Murray, J.C., Feingold, E., Beaty, T.H., et al., 2021a. The pax1 locus at 20p11 is a potential genetic modifier for bilateral cleft lip. HGG Adv. 2.

Curtis, S.W., Chang, D., Sun, M.R., Epstein, M.P., Murray, J.C., Feingold, E., Beaty, T.H., Weinberg, S.M., Marazita, M.L., Lipinski, R.J., et al., 2021b. Fat4 identified as a potential modifier of orofacial cleft laterality. Genet. Epidemiol. 45, 721-735.

Delaneau, O., Marchini, J., McVean, G.A., Donnelly, P., Lunter, G., Marchini, J.L., Myers, S., Gupta-Hinch, A., Iqbal, Z., Mathieson, I., et al., 2014. Integrating sequence and array data to create an improved 1000 genomes project haplotype reference panel. Nat. Commun. 5, 3934.

Freidline, S.E., Gunz, P., Harvati, K.,Hublin, J.J., 2012. Middle Pleistocene human facial morphology in an evolutionary and developmental context. J. Hum. Evol. 63, 723-740.

Gargano, M.A., Matentzoglu, N., Coleman, B., Addo-Lartey, E.B., Anagnostopoulos, A.V., Anderton, J., Avillach, P., Bagley, A.M., Bakstein, E., Balhoff, J.P., et al., 2024. The human phenotype ontology in 2024: phenotypes around the world. Nucleic Acids Res. 52, D1333-D1346.

Gokhman, D., Mishol, N., de Manuel, M., de Juan, D., Shuqrun, J., Meshorer, E., Marques-Bonet, T., Rak, Y.,Carmel, L., 2019. Reconstructing Denisovan anatomy using DNA methylation maps. Cell. 179, 180-192 e110.

Guo, J., Tan, J., Yang, Y., Zhou, H., Hu, S., Hashan, A., Bahaxar, N., Xu, S., Weaver, T.D., Jin, L., et al., 2014. Variation and signatures of selection on the human face. J. Hum. Evol. 75, 143-152.

Guo, J., Wu, Y., Zhu, Z.H., Zheng, Z.L., Trzaskowski, M., Zeng, J., Robinson, M.R., Visscher, P.M.,Yang, J., 2018. Global genetic differentiation of complex traits shaped by natural selection in humans. Nat. Commun. 9.

Hajdinjak, M., Fu, Q.M., Hubner, A., Petr, M., Mafessoni, F., Grote, S., Skoglund, P., Narasimham, V., Rougier, H., Crevecoeur, I., et al., 2018. Reconstructing the genetic history of late Neanderthals. Nature. 555, 652-656.

Hanzelmann, S., Castelo, R.,Guinney, J., 2013. Gsva: gene set variation analysis for microarray and rna-seq data. BMC Bioinf. 14.

Harvati, K., Hublin, J.J.,Gunz, P., 2010. Evolution of middle-late pleistocene human cranio-facial form: a 3-d approach. J. Hum. Evol. 59, 445-464.

Holliday, T.W., 1997. Postcranial evidence of cold adaptation in European Neandertals. Am. J. Phys. Anthropol. 104, 245-258.

Howie, B.N., Donnelly, P.,Marchini, J., 2009. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529.

Huerta-Sanchez, E., Jin, X., Asan, Bianba, Z., Peter, B.M., Vinckenbosch, N., Liang, Y., Yi, X., He, M.Z., Somel, M., et al., 2014. Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. Nature. 512, 194-197.

Ju, D.,Mathieson, I., 2021. The evolution of skin pigmentation-associated variation in West Eurasia. Proc. Natl. Acad. Sci. USA. 118.

Kennedy, D.,Norman, C., 2005. What don't we know? Science. 309, 75.

Kichaev, G., Bhatia, G., Loh, P.R., Gazal, S., Burch, K., Freund, M.K., Schoech, A., Pasaniuc, B.,Price, A.L., 2019. Leveraging polygenic functional enrichment to improve gwas power. Am. J. Hum. Genet. 104, 65-75.

Kim, S.K., 2018. Identification of 613 new loci associated with heel bone mineral density and a polygenic risk score for bone mineral density, osteoporosis and fracture. PLoS One 13, e0200785.

Lee, M.K., Shaffer, J.R., Leslie, E.J., Orlova, E., Carlson, J.C., Feingold, E., Marazita, M.L.,Weinberg, S.M., 2017. Genome-wide association study of facial morphology reveals novel associations with frem1 and park2. PLoS One 12, e0176566.

Li, Q., Chen, J., Faux, P., Delgado, M.E., Bonfante, B., Fuentes-Guajardo, M., Mendoza-Revilla, J., Chacon-Duque, J.C., Hurtado, M., Villegas, V., et al., 2023. Automatic landmarking identifies new loci associated with face morphology and implicates Neanderthal introgression in human nasal shape. Commun. Biol. 6, 481.

Ma, Y., Tan, Y., Hu, Y., Pu, W., Xu, J., Jin, L.,Wang, J., 2023. Quantitative assessment of ultraviolet-induced erythema and tanning responses in the Han Chinese population. Phenomics.

Mahajan, A., Taliun, D., Thurner, M., Robertson, N.R., Torres, J.M., Rayner, N.W., Payne, A.J., Steinthorsdottir, V., Scott, R.A., Grarup, N., et al., 2018. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat. Genet. 50, 1505-1513.

Maller, J.B., McVean, G., Byrnes, J., Vukcevic, D., Palin, K., Su, Z., Howson, J.M., Auton, A., Myers, S., Morris, A., et al., 2012. Bayesian refinement of association signals for 14 loci in 3 common diseases. Nat. Genet. 44, 1294-1301.

Mallick, S.,Reich, D. 2023. The allen ancient DNA resource (aadr): a curated compendium of ancient human genomes, Harvard Dataverse.

Marquez, S., Pagano, A.S., Delson, E., Lawson, W.,Laitman, J.T., 2014. The nasal complex of Neanderthals: an entry portal to their place in human ancestry. Anat. Rec. 297, 2121-2137.

Meyer, M., Kircher, M., Gansauge, M.T., Li, H., Racimo, F., Mallick, S., Schraiber, J.G., Jay, F., Prufer, K., de Filippo, C., et al., 2012. A high-coverage genome sequence from an archaic Denisovan individual. Science. 338, 222-226.

Morris, J.A., Kemp, J.P., Youlten, S.E., Laurent, L., Logan, J.G., Chai, R.C., Vulpescu, N.A., Forgetta, V., Kleinman, A., Mohanty, S.T., et al., 2019. An atlas of genetic influences on osteoporosis in humans and mice. Nat. Genet. 51, 258-266.

Mounier, A.,Mirazon Lahr, M., 2016. Virtual ancestor reconstruction: revealing the ancestor of modern humans and Neandertals. J. Hum. Evol. 91, 57-72.

Mukhopadhyay, N., Feingold, E., Moreno-Uribe, L., Wehby, G., Valencia-Ramirez, L.C., Muneton, C.P.R., Padilla, C., Deleyiannis, F., Christensen, K., Poletta, F.A., et al., 2021. Genome-wide association study of non-syndromic orofacial clefts in a multiethnic sample of families and controls identifies novel regions. Front. Cell Dev. Biol. 9, 621482.

Peyregne, S., Slon, V.,Kelso, J., 2024. More than a decade of genetic research on the Denisovans. Nat. Rev. Genet. 25, 83-103.

Pickrell, J.K., Berisa, T., Liu, J.Z., Segurel, L., Tung, J.Y.,Hinds, D.A., 2016. Detection and interpretation of shared genetic influences on 42 human traits. Nat. Genet. 48, 709-717.

Ponce de Leon, M.S.,Zollikofer, C.P., 2001. Neanderthal cranial ontogeny and its implications for late hominid diversity. Nature. 412, 534-538.

Prescott, S.L., Srinivasan, R., Marchetto, M.C., Grishina, I., Narvaiza, I., Selleri, L., Gage, F.H., Swigut, T.,Wysocka, J., 2015. Enhancer divergence and regulatory evolution in the human and chimp neural crest. Cell. 163, 68-83.

Prufer, K., de Filippo, C., Grote, S., Mafessoni, F., Korlevic, P., Hajdinjak, M., Vernot, B., Skov, L., Hsieh, P.S., Peyregne, S., et al., 2017. A high-coverage Neandertal genome from Vindija Cave in Croatia. Science. 358, 655-658.

Prufer, K., Racimo, F., Patterson, N., Jay, F., Sankararaman, S., Sawyer, S., Heinze, A., Renaud, G., Sudmant, P.H., de Filippo, C., et al., 2014. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature. 505, 43-49.

Qian, W., Zhang, M.F., Wan, K.W., Xie, Y.X., Du, S.Y., Li, J.R., Mu, X.Z., Qiu, J.E., Xue, X.Y., Zhuang, X.H., et al., 2022. Genetic evidence for facial variation being a composite phenotype of cranial variation and facial soft tissue thickness. J. Genet. Genomics. 49, 934-942.

Qiao, H., Tan, J.Z., Wen, S.Q., Zhang, M.H., Xu, S.H.,Jin, L., 2023. De novo dissecting the three-dimensional facial morphology of 2379 Han Chinese individuals. Phenomics.

Rae, T.C., Koppe, T.,Stringer, C.B., 2011. The Neanderthal face is not cold adapted. J. Hum. Evol. 60, 234-239.

Ruan, Y.F., Lin, Y.F., Feng, Y.C.A., Chen, C.Y., Lam, M., Guo, Z.L., He, L., Sawa, A., Martin, A.R., Qin, S.Y., et al., 2022. Improving polygenic prediction in ancestrally diverse populations. Nat. Genet. 54, 573-580.

Sheehan, M.J.,Nachman, M.W., 2014. Morphological and population genomic evidence that human faces have evolved to signal individual identity. Nat. Commun. 5, 4800.

Spencer, M.A.,Demes, B., 1993. Biomechanical analysis of masticatory system configuration in Neandertals and Inuits. Am. J. Phys. Anthropol. 91, 1-20.

Stelzer, S., Neubauer, S., Hublin, J.J., Spoor, F.,Gunz, P., 2019. Morphological trends in arcade shape and size in Middle Pleistocene Homo. Am. J. Phys. Anthropol. 168, 70-91.

Wakefield, J., 2007. A Bayesian measure of the probability of false discovery in genetic epidemiology studies. Am. J. Hum. Genet. 81, 208-227.

Wakefield, J., 2009. Bayes factors for genome-wide association studies: comparison with p-values. Genet. Epidemiol. 33, 79-86.

White, J.D., Ortega-Castrillon, A., Matthews, H., Zaidi, A.A., Ekrami, O., Snyders, J., Fan, Y., Penington, T., Van Dongen, S., Shriver, M.D., et al., 2019. Meshmonk: open-source large-scale intensive 3d phenotyping. Sci. Rep. 9, 6085.

Willer, C.J., Li, Y.,Abecasis, G.R., 2010. Metal: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 26, 2190-2191.

Williams, F.L.,Cofran, Z., 2016. Postnatal craniofacial ontogeny in Neandertals and modern humans. Am. J. Phys. Anthropol. 159, 394-409.

Xia, H., Zhang, D., Wang, J., Fagernas, Z., Li, T., Li, Y., Yao, J., Lin, D., Troche, G., Smith, G.M., et al., 2024. Middle and Late Pleistocene Denisovan subsistence at Baishiya Karst Cave. Nature.

Xiong, Z., Dankova, G., Howe, L.J., Lee, M.K., Hysi, P.G., de Jong, M.A., Zhu, G., Adhikari, K., Li, D., Li, Y., et al., 2019. Novel genetic loci affecting facial shape variation in humans. Elife. 8.

Xiong, Z.Y., Gao, X.J., Chen, Y., Feng, Z.Y., Pan, S.Y., Lu, H.J., Uitterlinden, A.G., Nijsten, T., Ikram, A., Rivadeneira, F., et al., 2022. Combining genome-wide association studies highlight novel loci involved in human facial variation. Nat. Commun. 13.

Zaidi, A.A., Mattern, B.C., Claes, P., McEvoy, B., Hughes, C.,Shriver, M.D., 2017. Investigating the case of human nose shape and climate adaptation. PLoS Genet. 13, e1006616.

Zhang, M., Wu, S., Du, S., Qian, W., Chen, J., Qiao, L., Yang, Y., Tan, J., Yuan, Z., Peng, Q., et al., 2022. Genetic variants underlying differences in facial morphology in East Asian and European populations. Nat. Genet. 54, 403-411.

Zhou, Y.Y., Zhou, B., Pache, L., Chang, M., Khodabakhshi, A.H., Tanaseichuk, O., Benner, C.,Chanda, S.K., 2019. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun. 10.

Chang, C.C., Chow, C.C., Tellier, L.C.A.M., Vattikuti, S., Purcell, S.M.,Lee, J.J., 2015. Second-generation plink: rising to the challenge of larger and richer datasets. Gigascience. 4.

Mallick, S., Micco, A., Mah, M., Ringbauer, H., Lazaridis, I., Olalde, I., Patterson, N.,Reich, D., 2024. The allen ancient DNA resource (aadr) a curated compendium of ancient human genomes. Sci. Data 11,182.

Relative Articles

Supplements(0)

Cited By

Proportional views