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.
Download links
Further reading
-
- Genetics and Genomics
Resistance to anthelmintics, particularly the macrocyclic lactone ivermectin (IVM), presents a substantial global challenge for parasite control. We found that the functional loss of an evolutionarily conserved E3 ubiquitin ligase, UBR-1, leads to IVM resistance in Caenorhabditis elegans. Multiple IVM-inhibiting activities, including viability, body size, pharyngeal pumping, and locomotion, were significantly ameliorated in various ubr-1 mutants. Interestingly, exogenous application of glutamate induces IVM resistance in wild-type animals. The sensitivity of all IVM-affected phenotypes of ubr-1 is restored by eliminating proteins associated with glutamate metabolism or signaling: GOT-1, a transaminase that converts aspartate to glutamate, and EAT-4, a vesicular glutamate transporter. We demonstrated that IVM-targeted GluCls (glutamate-gated chloride channels) are downregulated and that the IVM-mediated inhibition of serotonin-activated pharynx Ca2+ activity is diminished in ubr-1. Additionally, enhancing glutamate uptake in ubr-1 mutants through ceftriaxone completely restored their IVM sensitivity. Therefore, UBR-1 deficiency-mediated aberrant glutamate signaling leads to ivermectin resistance in C. elegans.
-
- Genetics and Genomics
Osteoporosis, characterized by reduced bone density and strength, increases fracture risk, pain, and limits mobility. Established therapies of parathyroid hormone (PTH) analogs effectively promote bone formation and reduce fractures in severe osteoporosis, but their use is limited by potential adverse effects. In the pursuit of safer osteoporosis treatments, we investigated R25CPTH, a PTH variant wherein the native arginine at position 25 is substituted by cysteine. These studies were prompted by our finding of high bone mineral density in a hypoparathyroidism patient with the R25C homozygous mutation, and we explored its effects on PTH type-1 receptor (PTH1R) signaling in cells and bone metabolism in mice. Our findings indicate that R25CPTH(1–84) forms dimers both intracellularly and extracellularly, and the synthetic dimeric peptide, R25CPTH(1–34), exhibits altered activity in PTH1R-mediated cyclic AMP (cAMP) response. Upon a single injection in mice, dimeric R25CPTH(1–34) induced acute calcemic and phosphaturic responses comparable to PTH(1–34). Furthermore, repeated daily injections increased calvarial bone thickness in intact mice and improved trabecular and cortical bone parameters in ovariectomized (OVX) mice, akin to PTH(1–34). The overall results reveal a capacity of a dimeric PTH peptide ligand to activate the PTH1R in vitro and in vivo as PTH, suggesting a potential path of therapeutic PTH analog development.
