Novel genetic loci affecting facial shape variation in humans
- Erasmus MC University Medical Center, Netherlands
- University of Bristol, United Kingdom
- University of Pittsburgh, United States
- King's College London, United Kingdom
- QIMR Berghofer Medical Research Institute, Australia
- University College London, United Kingdom
- CAS-MPG Partner Institute for Computational Biology, China
- Bejing Institute of Genomics, China
- Plastic Surgery Hospital, China
- Cardiff University, United Kingdom
- Instituto Patagonico de Ciencias Sociales y Humanas, Argentina
- Universidade Federal do Rio Grande do Sul, Brazil
- UNAM-Instituto Nacional de Medicina Genomica, Mexico
- Universidad Peruana Cayetano Heredia, Peru
- Universidad de Antioquia, Colombia
- Universidad de Tarapaca, Chile
- Leiden University Medical Center, Netherlands
- 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
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.
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.
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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Novel genetic loci affecting facial shape variation in humans
eLife 8:e49898.
https://doi.org/10.7554/eLife.49898
Further reading
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- Chromosomes and Gene Expression
- Genetics and Genomics
The enhancer-promoter looping model, in which enhancers activate their target genes via physical contact, has long dominated the field of gene regulation. However, the ubiquity of this model has been questioned due to evidence of alternative mechanisms and the lack of its systematic validation, primarily owing to the absence of suitable experimental techniques. In this study, we present a new MNase-based proximity ligation method called MChIP-C, allowing for the measurement of protein-mediated chromatin interactions at single-nucleosome resolution on a genome-wide scale. By applying MChIP-C to study H3K4me3 promoter-centered interactions in K562 cells, we found that it had greatly improved resolution and sensitivity compared to restriction endonuclease-based C-methods. This allowed us to identify EP300 histone acetyltransferase and the SWI/SNF remodeling complex as potential candidates for establishing and/or maintaining enhancer-promoter interactions. Finally, leveraging data from published CRISPRi screens, we found that most functionally verified enhancers do physically interact with their cognate promoters, supporting the enhancer-promoter looping model.
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- Genetics and Genomics
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Continued methodological advances have enabled numerous statistical approaches for the analysis of summary statistics from genome-wide association studies. Genetic correlation analysis within specific regions enables a new strategy for identifying pleiotropy. Genomic regions with significant ‘local’ genetic correlations can be investigated further using state-of-the-art methodologies for statistical fine-mapping and variant colocalisation. We explored the utility of a genome-wide local genetic correlation analysis approach for identifying genetic overlaps between the candidate neuropsychiatric disorders, Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Parkinson’s disease, and schizophrenia. The correlation analysis identified several associations between traits, the majority of which were loci in the human leukocyte antigen region. Colocalisation analysis suggested that disease-implicated variants in these loci often differ between traits and, in one locus, indicated a shared causal variant between ALS and AD. Our study identified candidate loci that might play a role in multiple neuropsychiatric diseases and suggested the role of distinct mechanisms across diseases despite shared loci. The fine-mapping and colocalisation analysis protocol designed for this study has been implemented in a flexible analysis pipeline that produces HTML reports and is available at: https://github.com/ThomasPSpargo/COLOC-reporter.
