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. 2021 Feb 5;7(6):eabc6160.
doi: 10.1126/sciadv.abc6160. Print 2021 Feb.

A GWAS in Latin Americans identifies novel face shape loci, implicating VPS13B and a Denisovan introgressed region in facial variation

Betty Bonfante  1 , Pierre Faux  1 , Nicolas Navarro  2   3 , Javier Mendoza-Revilla  4   5 , Morgane Dubied  2 , Charlotte Montillot  6 , Emma Wentworth  7 , Lauriane Poloni  2   3 , Ceferino Varón-González  8 , Philip Jones  9 , Ziyi Xiong  10 , Macarena Fuentes-Guajardo  11 , Sagnik Palmal  1 , Juan Camilo Chacón-Duque  12 , Malena Hurtado  4 , Valeria Villegas  4 , Vanessa Granja  4 , Claudia Jaramillo  13 , William Arias  13 , Rodrigo Barquera  14   15 , Paola Everardo-Martínez  14 , Mirsha Sánchez-Quinto  16 , Jorge Gómez-Valdés  14 , Hugo Villamil-Ramírez  17 , Caio C Silva de Cerqueira  18 , Tábita Hünemeier  19 , Virginia Ramallo  20   21 , Fan Liu  10   22   23 , Seth M Weinberg  24   25   26 , John R Shaffer  24   25 , Evie Stergiakouli  27   28 , Laurence J Howe  27 , Pirro G Hysi  29 , Timothy D Spector  29 , Rolando Gonzalez-José  21 , Lavinia Schüler-Faccini  20 , Maria-Cátira Bortolini  20 , Victor Acuña-Alonzo  14 , Samuel Canizales-Quinteros  17 , Carla Gallo  4 , Giovanni Poletti  4 , Gabriel Bedoya  13 , Francisco Rothhammer  30 , Christel Thauvin-Robinet  6   31 , Laurence Faivre  6   31 , Caroline Costedoat  1 , David Balding  9   32 , Timothy Cox  33 , Manfred Kayser  10 , Laurence Duplomb  6 , Binnaz Yalcin  6 , Justin Cotney  7 , Kaustubh Adhikari  34   9 , Andrés Ruiz-Linares  35   9   36
Affiliations

A GWAS in Latin Americans identifies novel face shape loci, implicating VPS13B and a Denisovan introgressed region in facial variation

Betty Bonfante et al. Sci Adv. .

Abstract

To characterize the genetic basis of facial features in Latin Americans, we performed a genome-wide association study (GWAS) of more than 6000 individuals using 59 landmark-based measurements from two-dimensional profile photographs and ~9,000,000 genotyped or imputed single-nucleotide polymorphisms. We detected significant association of 32 traits with at least 1 (and up to 6) of 32 different genomic regions, more than doubling the number of robustly associated face morphology loci reported until now (from 11 to 23). These GWAS hits are strongly enriched in regulatory sequences active specifically during craniofacial development. The associated region in 1p12 includes a tract of archaic adaptive introgression, with a Denisovan haplotype common in Native Americans affecting particularly lip thickness. Among the nine previously unidentified face morphology loci we identified is the VPS13B gene region, and we show that variants in this region also affect midfacial morphology in mice.

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Figures

Fig. 1
Fig. 1. Face profile features showing genome-wide significant association.
Top: Drawings indicate the features for which the 32 traits listed below were measured in the CANDELA individuals (as defined in table S1). Bottom: Aggregate of the GWAS signals detected (across all traits). The chromosomal region (and nearest candidate gene) showing strongest association to a trait is indicated above each GWAS peak (bold type marks the previously unidentified face morphology regions identified here). Curved lines in the middle of the figure connect the previously unidentified face morphology region to their associated traits.
Fig. 2
Fig. 2. Thirty-two chromosomal regions associated with face profile traits.
The 32 traits showing genome-wide significant association are listed at the top (Fig. 1 and table S1). For ease of visualization, association P values are represented by colored boxes as follows: red, genome-wide significant (<5 × 10−8); orange, genome-wide suggestive (<10−5) (P values are provided in table S5). Chromosomal regions in bold were previously unidentified (Fig. 1 and Table 1). Prior evidence: GWASa, associated with a similar face trait; GWASb, associated with a different facial trait; GWASc, associated with a facial development disorder [e.g., nonsyndromic cleft lip/palate (NSCL/P)]; HDD, human developmental defect reported (e.g., Mendelian disorder); MDD, model developmental defect (related phenotype involving a homologous region reported in animal models).
Fig. 3
Fig. 3. Evidence of association, Denisovan introgression, and selection in the WARS2-TBX15 region.
(A) Association P values (right y-axis) with lip thickness ratio 2 and the location and frequency (left y-axis) of introgressed haplotypes inferred in the CANDELA data. Filled dots indicate the SNPs retained for introgression analysis. Dots are plotted accordingly to the significance of their association and have been colored to reflect r2 with the index SNP for association with that trait (rs3790553). The location of the index SNPs associated previously with ear morphology (15), chin dimples (7), and forehead shape (10) is indicated. SNPs associated with facial features in the European meta-analysis (18) are outside the region shown here. The green bins show the introgressed region, and their height displays the allelic frequency and their shade refers to the confidence level at which the tract was called (pale, 20%; dark, 90%). The dashed lines denote the bounds of the Denisovan introgression region previously estimated with the same approach used here (green) (31) or using a Conditional Random Field approach (purple) (32). (B) Standardized PBS scores obtained for genotyped SNPs when contrasting Native Americans (NAM) to CHB + CEU (red triangles) or Greenland Inuits (GI) to CHB + CEU (blue triangles). The location of the TBX15 and WARS2 genes is indicated by black arrows along with various annotations inferred from human embryonic tissue (27) (the color key for combined craniofacial annotations can be found in table S6).
Fig. 4
Fig. 4. Features of four genomic regions newly associated with face features in the CANDELA sample and replicating in Europeans.
Regional association P values (index SNP is labeled) are shown at the top. Regulatory annotations from human embryonic tissue (27) (combined chromatin states at various Carnegie stages and craniofacial-specific enhancers and superenhancers; the color key for combined craniofacial annotations is in table S6) are provided below each association plot. A heatmap of pairwise LD (r2) in the region is shown at the bottom of each panel. Similar plots for the other previously unidentified regions, detected in the CANDELA sample but not replicating in the European meta-analysis, are shown in Supplementary Notes.
Fig. 5
Fig. 5. Vps13b and mouse craniofacial shape.
(A) Shape changes in the Vps13b KO mutant male mice relative to WT. Effect is predicted according to the expected marginal means at the populational average centroid size. Darker colors represent strong positive (blue) or negative (brown) deviation from the WT, given in Procrustes distance. Positive distance represents expansion from the WT, whereas negative distance represents contraction from the WT. Mesh warping is amplified by a factor of 2 to facilitate the visualization (see also movie S1). (B) Regional association plot for the VPS13 homologous region in chromosome 15 among outbred mice. Significantly associated SNPs are shown as green dots (FDR < 5%). Ensembl annotations for genes (brown) and enhancers active in embryonic facial prominence (orange) are shown at the top. (C) Phenotypic effect associated with allele dosage at the Vps13b index SNP among outbred mice. Skull zones with an expansion/contraction relative to the mean shape are shown in brown/blue (see also movie S2). To facilitate visualization, shape variation has been magnified by ×20.
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