Novel genetic loci affecting facial shape variation in humans
- Erasmus MC University Medical Center Rotterdam, Netherlands
- University of Chinese Academy of Sciences (CAS), China
- University of Bristol, United Kingdom
- University of Pittsburgh, United States
- King’s College London, United Kingdom
- Leiden University Medical Center, Netherlands
- QIMR Berghofer Medical Research Institute, Australia
- University College London, United Kingdom
- Chinese Academy of Sciences (CAS), China
- Plastic Surgery Hospital, China
- ShanghaiTech University, China
- Chinese Academy of Sciences, China
- Fudan University, China
- Cardiff University, United Kingdom
- Instituto Patagonico de Ciencias Sociales y Humanas, CENPAT-CONICET, Argentina
- Universidade Federal do Rio Grande do Sul, Brazil
- Unidad de Genomica de Poblaciones Aplicada a la Salud, Mexico
- Universidad Peruana Cayetano Heredia, Peru
- Universidad de Antioquia, Colombia
- Universidad de Tarapaca, Chile
- Aix-Marseille Université, CNRS, EFS, ADES, France
Figures
Figure 1 with 5 supplements
Manhattan plot from meta-analysis discovery GWAS (N = 10,115 Europeans) for 78 Euclidean distances between 13 facial landmarks.
Results from meta-analysis of four GWASs in Europeans (N = 10,115), which were separately conducted in RS, TwinsUK, ALSPAC, and PITT for 78 facial shape phenotypes that are displayed in a signal …
Figure 1—figure supplement 1
An example of GPA, facial landmarks obtained from 3dMD images in 3193 participants from the discovery cohorts RS.
(A) All raw landmarks before GPA process; (B) after GPA process.
Figure 1—figure supplement 2
Phenotype characteristics of 78 facial traits.
(A) Sex difference (RS, N = 3,193); (B) Aging effect (RS, N = 3,193); (C) Variance explained by sex and age (RS, N = 3,193); (D) Unsupervised hierarchical clustering of phenotype correlation matrix …
Figure 1—figure supplement 3
Phenotypic and genetic correlation matrix between all facial phenotypes in cohort RS.
Positive correlations are shown as brown squares; Negative correlations are shown as blue squares. Phenotypic correlation is shown above the diagonal and SNP-based genetic correlation is shown below …
Figure 1—figure supplement 4
Quantile-Quantile plots and genomic inflation factors for 22 significant associated facial traits.
Figure 1—figure supplement 5
Power analysis.
The power of association tests under a variety of sample sizes (N = 3,000, 6,000, 10,000 and 15,000) with varied proportions of explained phenotypic variance (R2), absolute effect size (|ES|) and …
Figure 2 with 24 supplements
Six novel genetic loci associated with facial shape phenotypes and successfully replicated.
The figure is composed by six parts, (A) 1p36.22 CASZ1 region, (B) 4q28.1 INTU region, (C) 6p21.2 KIF6 region, (D) 12q24.21 TBX3 region, (E) 14q32.2 C14orf64 region, and (F) 16q12.2 RPGRIP1L region. …
Figure 2—figure supplement 1
Overviews of association, selection, LD and regulation patterns in 24 associated regions.
(Figure 2—figure supplements 1–6 show six novel replicated loci, Figure 2—figure supplements 7–17 show 11 novel non-replicated loci, Figure 2—figure supplements 18–24 show seven previously reported …
Figure 2—figure supplement 2
Association, selection, LD and regulation patterns for rs12504954 located around INTU.
Figure 2—figure supplement 3
Association, selection, LD and regulation patterns for rs7738892 located around KIF6.
Figure 2—figure supplement 4
Association, selection, LD and regulation patterns for rs1863716 located around TBX3.
Figure 2—figure supplement 5
Association, selection, LD and regulation patterns for rs1989285 located around C14orf64.
Figure 2—figure supplement 6
Association, selection, LD and regulation patterns for rs7404301 located around RPGRIP1L.
Figure 2—figure supplement 7
Association, selection, LD and regulation patterns for rs200243292 located around ARHGEF19.
Figure 2—figure supplement 8
Association, selection, LD and regulation patterns for rs77142479 located around RPE65.
Figure 2—figure supplement 9
Association, selection, LD and regulation patterns for rs10202675 located around LRRTM4.
Figure 2—figure supplement 10
Association, selection, LD and regulation patterns for rs2884836 located around KIAA1715.
Figure 2—figure supplement 11
Association, selection, LD and regulation patterns for rs113663609 located around CMSS1.
Figure 2—figure supplement 12
Association, selection, LD and regulation patterns for rs2225718 located around RNF144B.
Figure 2—figure supplement 13
Association, selection, LD and regulation patterns for rs1700048 located around CSMD1.
Figure 2—figure supplement 14
Association, selection, LD and regulation patterns for rs9642796 located around DCAF4L2.
Figure 2—figure supplement 15
Association, selection, LD and regulation patterns for rs201719697 located around SUPV3L1.
Figure 2—figure supplement 16
Association, selection, LD and regulation patterns for rs7325564 located around LINC00371.
Figure 2—figure supplement 17
Association, selection, LD and regulation patterns for rs16949899 located around SALL1.
Figure 2—figure supplement 18
Association, selection, LD and regulation patterns for rs1229119 located around TBX15.
Figure 2—figure supplement 19
Association, selection, LD and regulation patterns for rs34032897 located around PAX3.
Figure 2—figure supplement 20
Association, selection, LD and regulation patterns for rs6535972 located around SFRP2.
Figure 2—figure supplement 21
Association, selection, LD and regulation patterns for rs2230578 located around ROR2.
Figure 2—figure supplement 22
Association, selection, LD and regulation patterns for rs8077906 located around CASC17.
Figure 2—figure supplement 23
Association, selection, LD and regulation patterns for rs35473710 located around SOX9.
Figure 2—figure supplement 24
Association, selection, LD and regulation patterns for rs4813454 located around PAX1.
Figure 3 with 1 supplement
Polygenic scores of 78 facial phenotypes.
(A) Facial phenotype variance is explained by a multivariable model consisting of 31 face-associated SNPs with independent effects. (B) Unsupervised clustering reveals the details on the explained …
Figure 3—figure supplement 1
Effects of NSCL/P-associated SNPs to 78 facial phenotypes.
Facial phenotype variance is explained by polygenic scores of 47 NSCL/P-associated SNPs after LD prune (r2 > 0.5).
Figure 4 with 1 supplement
Expression of 24 genes located at the identified 24 face-associated genetic loci in 50 cell types.
Expression levels of the genes nearest to the 24 top-associated SNPs (see Table 1) in 50 cell types were displayed in boxplots based on published data from the study of Prescott et al. (2015), the …
Figure 4—figure supplement 1
Gene ontology enrichment analysis for 24 face-associated genes.
Enrichment of the genes annotating the 24 identified face-associated genes. Enriched terms (FDR < 0.01 and n > 2, x-axis) are indicated by corrected P-value (FDR, different color), candidate genes …
Figure 5 with 1 supplement
Three examples of genetic loci associated with facial shape phenotypes.
Three examples of facial shape associated loci we discovered are depicted in details, including two novel loci (INTU; RPGRIP1L) and one (PAX3) that overlaps with previous face GWAS findings. The …
Figure 5—figure supplement 1
Overview of regulation activity of 24 face-associated loci in CNCCs.
For the top-associated SNPs at the 24 face associated loci, their base-pairs in vicinity within 20 kb (red bar) and LD (r2 > 0.25) SNPs (blue bar) were examined for cis-regulatory entries in six …
Tables
Table 1
SNPs significantly associated (p<5×10−8) with facial shape phenotypes from European discovery GWAS meta-analysis (RS, TwinksUK, ALSPAC, and PITT), and their multi-ethnic replication (UYG, CANDELA and QIMR).
| Discovery meta-analysis | Replication | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| (N = 10,115) | (N = 7,917) | ||||||||
| Region | SNP | Nearest Gene | EA | OA | Trait | Beta | P | Q | Com. P |
| Novel face-associated loci | |||||||||
| 1p36.22 | rs143353512 | CASZ1 | A | G | Prn-AlL | −0.29 | 6.44 × 10−9 | 0.73 | 0.0001 |
| 1p36.13 | rs200243292 | ARHGEF19 | I | T | EnR-ChL | −0.11 | 1.46 × 10−8 | 0.54 | 0.0640 |
| 1p31.2 | rs77142479 | RPE65 | C | A | EnL-Sn | −0.08 | 7.65 × 10−9 | 0.90 | 0.0121 |
| 2p12 | rs10202675 | LRRTM4 | T | C | EnR-AlR | −0.26 | 4.43 × 10−8 | 0.40 | 0.0226 |
| 2q31.1 | rs2884836 | KIAA1715 | T | C | ExR-ChR | −0.09 | 3.04 × 10−8 | 0.52 | 0.1096 |
| 3q12.1 | rs113663609 | CMSS1 | A | G | EnR-ChR | −0.12 | 3.46 × 10−8 | 0.96 | 0.0782 |
| 4q28.1 | rs12504954 | INTU | A | G | Prn-AlL | −0.09 | 3.03 × 10−10 | 0.52 | 0.0015 |
| 6p22.3 | rs2225718 | RNF144B | C | T | EnR-AlR | −0.09 | 2.97 × 10−8 | 0.60 | 0.0071 |
| 6p21.2 | rs7738892 | KIF6 | T | C | EnR-N | 0.11 | 1.34 × 10−8 | 0.09 | 0.0018 |
| 8p23.2 | rs1700048 | CSMD1 | C | A | ExR-ChL | −0.22 | 3.94 × 10−8 | 0.73 | 0.1131 |
| 8q21.3 | rs9642796 | DCAF4L2 | A | G | AlL-Ls | −0.11 | 4.52 × 10−8 | 0.07 | 0.3090 |
| 10q22.1 | rs201719697 | SUPV3L1 | A | D | ExL-AlL | −0.28 | 3.42 × 10−8 | 0.66 | NA |
| 12q24.21 | rs1863716 | TBX3 | A | C | Prn-AlR | −0.09 | 1.47 × 10−10 | 0.53 | 2.45 × 10−5 |
| 13q14.3 | rs7325564 | LINC00371 | T | C | N-Prn | 0.09 | 1.34 × 10−8 | 0.16 | 0.3519 |
| 14q32.2 | rs1989285 | C14orf64 | G | C | N-Prn | −0.10 | 4.54 × 10−8 | 0.82 | 0.0019 |
| 16q12.1 | rs16949899 | SALL1 | T | G | ExR-ChL | −0.13 | 3.35 × 10−8 | 0.76 | 0.8912 |
| 16q12.2 | rs7404301 | RPGRIP1L | G | A | AlL-Ls | −0.09 | 3.49 × 10−9 | 0.43 | 2.87 × 10−7 |
| Previously reported face-associated loci | |||||||||
| 1p12 | rs1229119 | TBX15 | T | C | ExR-ChR | 0.08 | 2.25 × 10−8 | 0.26 | 0.1219 |
| 2q36.1 | rs34032897 | PAX3 | G | A | EnR-N | 0.14 | 1.96 × 10−17 | 0.04 | 0.0020 |
| 4q31.3 | rs6535972 | SFRP2 | C | G | EnL-AlL | 0.12 | 3.51 × 10−12 | 0.12 | 5.89 × 10−12 |
| 9q22.31 | rs2230578 | ROR2 | C | T | EnL-Sn | 0.09 | 9.02 × 10−9 | 0.66 | 1.09 × 10−6 |
| 17q24.3 | rs8077906 | CASC17 | A | G | Prn-EnL | −0.09 | 3.00 × 10−11 | 0.24 | 0.0505 |
| 17q24.3 | rs35473710 | SOX9 | G | A | AlR-ChL | 0.19 | 3.95 × 10−8 | 0.37 | 0.2634 |
| 20p11.22 | rs4813454 | PAX1 | T | C | AlL-AlR | −0.10 | 2.32 × 10−11 | 0.58 | 0.0002 |
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Except rs2230578 (3'-UTR of ROR2) and rs7738892 (a synonymous variant of KIF6), all SNPs are intronic or intergenic. Gene symbols in bold indicate successful replication after Bonferroni correction of 24 loci (p<2.1×10−3). Meta P in bold indicates study-wide significance in the discovery analysis after multiple trait correction (p<1.2×10−9). Replication P in bold means significant after Bonferroni correction for multiple tests (p<2.1×10−3). Q: p-value from the Cochran's Q test for testing heterogeneity between discovery cohorts. EA and OA, the effect allele and the another allele. Com. P: p-values from a combined test of dependent tests. NA, not available.
Additional files
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Supplementary file 1
Supplementary Tables.
Includes: Supplementary Table 1. Characteristics of the all cohorts. Supplementary Table 2 Characteristics of 78 facial phenotypes in RS. Supplementary Table 3 Effects of 6 covariates to 78 facial phenotypes in RS. Supplementary Table 4. Phenotype correlations between all facial phenotypes in RS. Supplementary Table 5. Genetic correlation between all facial phenotypes in RS. Supplementary Table 6. Twins heritability and SNP-based heritability of all facial phenotypes in TwinsUK and QIMR. Supplementary Table7. 494 SNPs associated (p<5e-8) with facial shape phenotypes in meta-analysis of GWAS. Supplementary Table 8. Replication of reported variants of facial variation. Supplementary Table 9. GWAS Catalog entries (release on 2018-01-01), for polymorphisms that were significantly associated with facial traits in meta-analyses. Supplementary Table 10. Significant pleiotropic effect of study-wide suggestive SNPs on GeneATLAS traits. Supplementary Table 11. Frequency distribution of 24 top-associated SNPs. Supplementary Table 12. Population differentiation and positive selection at the suggestive significant GWAS SNPs. Supplementary Table 13. Replication of reported variants of NSCL/P trait. Supplementary Table 14. Multiple linear regression for 31 top-associated SNPs fitting with SEX and AGE in RS. Supplementary Table 15. Enrichment of the genes annotating the associated 24 regions. Supplementary Table 16. Significant expression quantitative trait loci effects for 494 SNPs significantly associated with facial traits and the target genes. Supplementary Table 17. Overviews of 5 selected candidate regulatory SNPs. Supplementary Table 18. Luciferase reporter assay results overview presented as relative luciferase activity fold change compared to construct containing less active allele ± standard deviation. Supplementary Table 19. Key Resource Table for functional experiments.
- https://cdn.elifesciences.org/articles/49898/elife-49898-supp1-v3.xlsx
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Transparent reporting form
- https://cdn.elifesciences.org/articles/49898/elife-49898-transrepform-v3.pdf
