Novel genetic loci affecting facial shape variation in humans
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.
Reviewing Editor
- 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
- Received: July 3, 2019
- Accepted: November 22, 2019
- Accepted Manuscript published: November 25, 2019 (version 1)
- Accepted Manuscript updated: November 26, 2019 (version 2)
- 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.
Metrics
-
- 5,508
- views
-
- 750
- downloads
-
- 57
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Genetics and Genomics
- Neuroscience
Adenine phosphoribosyltransferase (APRT) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT) are two structurally related enzymes involved in purine recycling in humans. Inherited mutations that suppress HGPRT activity are associated with Lesch–Nyhan disease (LND), a rare X-linked metabolic and neurological disorder in children, characterized by hyperuricemia, dystonia, and compulsive self-injury. To date, no treatment is available for these neurological defects and no animal model recapitulates all symptoms of LND patients. Here, we studied LND-related mechanisms in the fruit fly. By combining enzymatic assays and phylogenetic analysis, we confirm that no HGPRT activity is expressed in Drosophila melanogaster, making the APRT homolog (Aprt) the only purine-recycling enzyme in this organism. Whereas APRT deficiency does not trigger neurological defects in humans, we observed that Drosophila Aprt mutants show both metabolic and neurobehavioral disturbances, including increased uric acid levels, locomotor impairments, sleep alterations, seizure-like behavior, reduced lifespan, and reduction of adenosine signaling and content. Locomotor defects could be rescued by Aprt re-expression in neurons and reproduced by knocking down Aprt selectively in the protocerebral anterior medial (PAM) dopaminergic neurons, the mushroom bodies, or glia subsets. Ingestion of allopurinol rescued uric acid levels in Aprt-deficient mutants but not neurological defects, as is the case in LND patients, while feeding adenosine or N6-methyladenosine (m6A) during development fully rescued the epileptic behavior. Intriguingly, pan-neuronal expression of an LND-associated mutant form of human HGPRT (I42T), but not the wild-type enzyme, resulted in early locomotor defects and seizure in flies, similar to Aprt deficiency. Overall, our results suggest that Drosophila could be used in different ways to better understand LND and seek a cure for this dramatic disease.
-
- Genetics and Genomics
PARP-1 is central to transcriptional regulation under both normal and stress conditions, with the governing mechanisms yet to be fully understood. Our biochemical and ChIP-seq-based analyses showed that PARP-1 binds specifically to active histone marks, particularly H4K20me1. We found that H4K20me1 plays a critical role in facilitating PARP-1 binding and the regulation of PARP-1-dependent loci during both development and heat shock stress. Here, we report that the sole H4K20 mono-methylase, pr-set7, and parp-1 Drosophila mutants undergo developmental arrest. RNA-seq analysis showed an absolute correlation between PR-SET7- and PARP-1-dependent loci expression, confirming co-regulation during developmental phases. PARP-1 and PR-SET7 are both essential for activating hsp70 and other heat shock genes during heat stress, with a notable increase of H4K20me1 at their gene body. Mutating pr-set7 disrupts monomethylation of H4K20 along heat shock loci and abolish PARP-1 binding there. These data strongly suggest that H4 monomethylation is a key triggering point in PARP-1 dependent processes in chromatin.