Novel genetic loci affecting facial shape variation in humans

  1. Ziyi Xiong
  2. Gabriela Dankova
  3. Laurence J Howe
  4. Myoung Keun Lee
  5. Pirro G Hysi
  6. Markus A de Jong
  7. Gu Zhu
  8. Kaustubh Adhikari
  9. Dan Li
  10. Yi Li
  11. Bo Pan
  12. Eleanor Feingold
  13. Mary L Marazita
  14. John R Shaffer
  15. Kerrie McAloney
  16. Shu-Hua Xu
  17. Li Jin
  18. Sijia Wang
  19. Femke MS de Vrij
  20. Bas Lendemeijer
  21. Stephen Richmond
  22. Alexei Zhurov
  23. Sarah Lewis
  24. Gemma C Sharp
  25. Lavinia Paternoster
  26. Holly Thompson
  27. Rolando Gonzalez-Jose
  28. Maria Catira Bortolini
  29. Samuel Canizales-Quinteros
  30. Carla Gallo
  31. Giovanni Poletti
  32. Gabriel Bedoya
  33. Francisco Rothhammer
  34. André G Uitterlinden
  35. M Arfan Ikram
  36. Eppo Wolvius
  37. Steven A Kushner
  38. Tamar EC Nijsten
  39. Robert-Jan TS Palstra
  40. Stefan Boehringer
  41. Sarah E Medland
  42. Kun Tang
  43. Andrés Ruiz-Linares
  44. Nicholas G Martin
  45. Timothy D Spector
  46. Evie Stergiakouli
  47. Seth M Weinberg
  48. Fan Liu  Is a corresponding author
  49. Manfred Kayser  Is a corresponding author
  50. on behalf of the International Visible Trait Genetics (VisiGen) Consortium
  1. Erasmus MC University Medical Center, Netherlands
  2. University of Bristol, United Kingdom
  3. University of Pittsburgh, United States
  4. King's College London, United Kingdom
  5. QIMR Berghofer Medical Research Institute, Australia
  6. University College London, United Kingdom
  7. CAS-MPG Partner Institute for Computational Biology, China
  8. Bejing Institute of Genomics, China
  9. Plastic Surgery Hospital, China
  10. Cardiff University, United Kingdom
  11. Instituto Patagonico de Ciencias Sociales y Humanas, Argentina
  12. Universidade Federal do Rio Grande do Sul, Brazil
  13. UNAM-Instituto Nacional de Medicina Genomica, Mexico
  14. Universidad Peruana Cayetano Heredia, Peru
  15. Universidad de Antioquia, Colombia
  16. Universidad de Tarapaca, Chile
  17. Leiden University Medical Center, Netherlands
  18. Beijing Institute of Genomics, China

Abstract

The human face represents a combined set of highly heritable phenotypes, but knowledge on its genetic architecture remains limited, despite the relevance for various fields. 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 reaching study-wide suggestive association (p<5x10-8), among which 17 were previously unreported. A follow-up multi-ethnic study in additional 7,917 individuals confirmed 10 loci including 6 unreported ones (padjusted<2.1x10-3). A global map of derived polygenic face scores assembled facial features in major continental groups consistent with anthropological knowledge. Analyses of epigenomic datasets from cranial neural crest cells revealed abundant cis-regulatory activities at the face-associated genetic loci. Luciferase reporter assays in neural crest progenitor cells highlighted enhancer activities of several face-associated DNA variants. These results substantially advance our understanding of the genetic basis underlying human facial variation and provide candidates for future in-vivo functional studies.

Data availability

GWAS meta-analysis summary statistics data of the significantly associated SNPs are provided with the paper in the supplementary file 1. In addition, GWAS meta-analysis summary statistics of all SNPs and all facial phenotypes, including for each SNP the effect allele, non-effect allele and for each phenotype the effect size alligned to the effect allele with standard error and p-value, are made publically available via figshare under https://doi.org/10.6084/m9.figshare.10298396 (updated file). Moreover, after the paper is accepted for publication, we will upload to the EBI GWAS Catalogue the complete summary statistics of all SNPs (same information as on figshare now) into the GWAS Catalogue. We included this information and the website links in the Material and Method section.

Article and author information

Author details

  1. Ziyi Xiong

    Department of Genetic Identification, Erasmus MC University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  2. Gabriela Dankova

    Department of Genetic Identification, Erasmus MC University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  3. Laurence J Howe

    Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Myoung Keun Lee

    Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Pirro G Hysi

    Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Markus A de Jong

    Department of Genetic Identification, Erasmus MC University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  7. Gu Zhu

    QIMR Berghofer Medical Research Institute, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Kaustubh Adhikari

    Department of Genetics, Evolution, and Environment, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5825-4191
  9. Dan Li

    CAS-MPG Partner Institute for Computational Biology, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Yi Li

    CAS Key Laboratory of Genomic and Precision Medicine, Bejing Institute of Genomics, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Bo Pan

    Department of Auricular Reconstruction, Plastic Surgery Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Eleanor Feingold

    Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Mary L Marazita

    Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2648-2832
  14. John R Shaffer

    Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1897-1131
  15. Kerrie McAloney

    QIMR Berghofer Medical Research Institute, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  16. Shu-Hua Xu

    CAS-MPG Partner Institute for Computational Biology, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  17. Li Jin

    CAS-MPG Partner Institute for Computational Biology, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  18. Sijia Wang

    CAS-MPG Partner Institute for Computational Biology, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  19. Femke MS de Vrij

    Department of Psychiatry, Erasmus MC University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0825-3806
  20. Bas Lendemeijer

    Department of Psychiatry, Erasmus MC University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  21. Stephen Richmond

    University Dental School, Cardiff University, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  22. Alexei Zhurov

    University Dental School, Cardiff University, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  23. Sarah Lewis

    Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  24. Gemma C Sharp

    Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2906-4035
  25. Lavinia Paternoster

    Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  26. Holly Thompson

    Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  27. Rolando Gonzalez-Jose

    CENPAT-CONICET, Instituto Patagonico de Ciencias Sociales y Humanas, Puerto Madryn, Argentina
    Competing interests
    The authors declare that no competing interests exist.
  28. Maria Catira Bortolini

    Departamento de Genetica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  29. Samuel Canizales-Quinteros

    Unidad de Genomica de Poblaciones Aplicada a la Salud, UNAM-Instituto Nacional de Medicina Genomica, Mexico City, Mexico
    Competing interests
    The authors declare that no competing interests exist.
  30. Carla Gallo

    Laboratorios de Investigacion y Desarrollo, Facultad de Ciencias y Filosofıa, Universidad Peruana Cayetano Heredia, Lima, Peru
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8348-0473
  31. Giovanni Poletti

    Laboratorios de Investigacion y Desarrollo, Facultad de Ciencias y Filosofıa, Universidad Peruana Cayetano Heredia, Lima, Peru
    Competing interests
    The authors declare that no competing interests exist.
  32. Gabriel Bedoya

    Genetica Molecular, Universidad de Antioquia, Medellin, Colombia
    Competing interests
    The authors declare that no competing interests exist.
  33. Francisco Rothhammer

    Instituto de Alta Investigacion, Universidad de Tarapaca, Arica, Chile
    Competing interests
    The authors declare that no competing interests exist.
  34. André G Uitterlinden

    Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  35. M Arfan Ikram

    Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  36. Eppo Wolvius

    Department of Oral and Maxillofacial Surgery, Special Dental Care, and Orthodontics, Erasmus MC University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  37. Steven A Kushner

    Department of Psychiatry, Erasmus MC University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9777-3338
  38. Tamar EC Nijsten

    Department of Dermatology, Erasmus MC University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  39. Robert-Jan TS Palstra

    Department of Biochemistry, Erasmus MC University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  40. Stefan Boehringer

    Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9108-9212
  41. Sarah E Medland

    QIMR Berghofer Medical Research Institute, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  42. Kun Tang

    CAS-MPG Partner Institute for Computational Biology, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  43. Andrés Ruiz-Linares

    Department of Genetics, Evolution, and Environment, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  44. Nicholas G Martin

    QIMR Berghofer Medical Research Institute, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  45. Timothy D Spector

    Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  46. Evie Stergiakouli

    Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  47. Seth M Weinberg

    Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  48. Fan Liu

    CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Bejing, China
    For correspondence
    liufan@big.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
  49. Manfred Kayser

    Department of Genetic Identification, Erasmus MC University Medical Center, Rotterdam, Netherlands
    For correspondence
    m.kayser@erasmusmc.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4958-847X

Funding

European Union Horizon 2020 Research and Innovation Programme (740580 (VISAGE))

  • Manfred Kayser

Levelhulm Trust (F/07 134/DF)

  • Andrés Ruiz-Linares

National Natural Science Foundation of China (91631307)

  • Sijia Wang

National Natural Science Foundation of China (91731303)

  • Shu-Hua Xu

National Natural Science Foundation of China (30890034)

  • Li Jin

Australian NHMRC

  • Nicholas G Martin

Australian NHMRC Fellowship (APP1103623)

  • Sarah E Medland

National Natural Science Foundation of China (31771388)

  • Shu-Hua Xu

National Natural Science Foundation of China (315014)

  • Shu-Hua Xu

National Natural Science Foundation of China (31711530331)

  • Shu-Hua Xu

National Natural Science Foundation of China (31271338)

  • Li Jin

National Science Foundation of China (91651507)

  • Fan Liu

National Institute of Dental and Craniofacial Research (R01-DE027023)

  • Seth M Weinberg

National Institute of Dental and Craniofacial Research (R01-DE016148)

  • Seth M Weinberg

National Institute of Dental and Craniofacial Research (X01-HG007821)

  • Seth M Weinberg

Netherlands Organization of Scientific Research (911-03-012)

  • M Arfan Ikram

National Key R&D Program of China (2017YFC083501)

  • Fan Liu

Strategic Priority Reserach Program Chinese Academy of Sciences (XDC010400100)

  • Fan Liu

China Scholarship Council (PhD Fellowship)

  • Ziyi Xiong

Netherlands Organization of Scientific Research (1750102005011)

  • M Arfan Ikram

Wellcome Trust

  • Timothy D Spector

Medical Research Council (102215/2/13/2)

  • Evie Stergiakouli

National Institute of Dental and Craniofacial Research (U01-DE20078)

  • Seth M Weinberg

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Andrew P Morris, University of Liverpool, United Kingdom

Ethics

Human subjects: All cohort participants gave informed consent and consent to publish. The different cohort studies involved have been approved by their local ethics committees and in part higher institutions such as ministries, as described in the Material and Method section. Protocol numbers can be found for each cohort in the Materials and Methods section.

Version history

  1. Received: July 3, 2019
  2. Accepted: November 22, 2019
  3. Accepted Manuscript published: November 25, 2019 (version 1)
  4. Accepted Manuscript updated: November 26, 2019 (version 2)
  5. Version of Record published: December 11, 2019 (version 3)

Copyright

© 2019, Xiong et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ziyi Xiong
  2. Gabriela Dankova
  3. Laurence J Howe
  4. Myoung Keun Lee
  5. Pirro G Hysi
  6. Markus A de Jong
  7. Gu Zhu
  8. Kaustubh Adhikari
  9. Dan Li
  10. Yi Li
  11. Bo Pan
  12. Eleanor Feingold
  13. Mary L Marazita
  14. John R Shaffer
  15. Kerrie McAloney
  16. Shu-Hua Xu
  17. Li Jin
  18. Sijia Wang
  19. Femke MS de Vrij
  20. Bas Lendemeijer
  21. Stephen Richmond
  22. Alexei Zhurov
  23. Sarah Lewis
  24. Gemma C Sharp
  25. Lavinia Paternoster
  26. Holly Thompson
  27. Rolando Gonzalez-Jose
  28. Maria Catira Bortolini
  29. Samuel Canizales-Quinteros
  30. Carla Gallo
  31. Giovanni Poletti
  32. Gabriel Bedoya
  33. Francisco Rothhammer
  34. André G Uitterlinden
  35. M Arfan Ikram
  36. Eppo Wolvius
  37. Steven A Kushner
  38. Tamar EC Nijsten
  39. Robert-Jan TS Palstra
  40. Stefan Boehringer
  41. Sarah E Medland
  42. Kun Tang
  43. Andrés Ruiz-Linares
  44. Nicholas G Martin
  45. Timothy D Spector
  46. Evie Stergiakouli
  47. Seth M Weinberg
  48. Fan Liu
  49. Manfred Kayser
  50. on behalf of the International Visible Trait Genetics (VisiGen) Consortium
(2019)
Novel genetic loci affecting facial shape variation in humans
eLife 8:e49898.
https://doi.org/10.7554/eLife.49898

Share this article

https://doi.org/10.7554/eLife.49898

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