Phenotype and association results for facial factor 9.

<p>(A) Face showing the linear distances (in dark yellow) associated with factor 9; (B) LocusZoom plot showing the association (left y-axis; log10-transformed p-values) with factor 9. Genotyped SNPs are depicted by stars and imputed SNPs are depicted by circles. Shading of the points represents the linkage disequilibrium (r², based on the 1000 Genomes Project Europeans; gray indicates unknown LD) between each SNP and the top SNP, indicated by purple shading. The blue overlay shows the recombination rate (right y-axis). Positions of genes are shown below the plot. Note, gray points near the lead SNP are insertion-deletion variants in high LD (r2 = 0.91 and 0.77) with the lead SNP in our cohort.</p

Phenotype and association results for facial factor 14.

<p>(A) Face showing the linear distances (in red) associated with factor 14; (B) LocusZoom plot showing the association (left y-axis; log10-transformed p-values) with factor 14. Genotyped SNPs are depicted by stars and imputed SNPs are depicted by circles. Shading of the points represents the linkage disequilibrium (r², based on the 1000 Genomes Project Europeans; gray indicates unknown LD) between each SNP and the top SNP, indicated by purple shading. The blue overlay shows the recombination rate (right y-axis). Positions of genes are shown below the plot. Note, the gray point near the lead SNP is an insertion-deletion variant in high LD (r2 = 0.97) with the lead SNP in our cohort.</p

Genome-wide association study of facial morphology reveals novel associations with <i>FREM1</i> and <i>PARK2</i>

<div><p>Several studies have now shown evidence of association between common genetic variants and quantitative facial traits in humans. The reported associations generally involve simple univariate measures and likely represent only a small fraction of the genetic loci influencing facial morphology. In this study, we applied factor analysis to a set of 276 facial linear distances derived from 3D facial surface images of 2187 unrelated individuals of European ancestry. We retained 23 facial factors, which we then tested for genetic associations using a genome-wide panel of 10,677,593 single nucleotide polymorphisms (SNPs). In total, we identified genome-wide significant (p < 5 × 10⁻⁸) associations in three regions, including two that are novel: one involving measures of midface height at 6q26 within an intron of <i>PARK2</i> (lead SNP rs9456748; p = 4.99 × 10⁻⁸) and another involving measures of central upper lip height at 9p22 within <i>FREM1</i> (lead SNP rs72713618; p = 2.02 × 10⁻⁸). In both cases, the genetic association was stronger with the composite facial factor phenotype than with any of the individual linear distances that comprise those factors. While the biological role of <i>PARK2</i> in the craniofacial complex is currently unclear, there is evidence from both mouse models and Mendelian syndromes that <i>FREM1</i> may influence facial variation. These results highlight the potential value of data-driven multivariate phenotyping for genetic studies of human facial morphology.</p></div

Description of the 23 extracted factors describing facial morphology.

<p>Description of the 23 extracted factors describing facial morphology.</p

Association of Early Childhood Caries with Bitter Taste Receptors: A Meta-Analysis of Genome-Wide Association Studies and Transcriptome-Wide Association Study

Although genetics affects early childhood caries (ECC) risk, few studies have focused on finding its specific genetic determinants. Here, we performed genome-wide association studies (GWAS) in five cohorts of children (aged up to 5 years, total N = 2974, cohorts: Center for Oral Health Research in Appalachia cohorts one and two [COHRA1, COHRA2], Iowa Fluoride Study, Iowa Head Start, Avon Longitudinal Study of Parents and Children [ALSPAC]) aiming to identify genes with potential roles in ECC biology. We meta-analyzed the GWASs testing ~3.9 million genetic variants and found suggestive evidence for association at genetic regions previously associated with caries in primary and permanent dentition, including the β-defensin anti-microbial proteins. We then integrated the meta-analysis results with gene expression data in a transcriptome-wide association study (TWAS). This approach identified four genes whose genetically predicted expression was associated with ECC (p-values −6; CDH17, TAS2R43, SMIM10L1, TAS2R14). Some of the strongest associations were with genes encoding members of the bitter taste receptor family (TAS2R); other members of this family have previously been associated with caries. Of note, we identified the receptor encoded by TAS2R14, which stimulates innate immunity and anti-microbial defense in response to molecules released by the cariogenic bacteria, Streptococcus mutans and Staphylococcus aureus. These findings provide insight into ECC genetic architecture, underscore the importance of host-microbial interaction in caries risk, and identify novel risk genes

Modular 3D dense surface analysis and GWAS reveal localized genetic effects on human facial morphology involving multiple novel loci

Weinberg S.M., Lee M.K., Leslie E.J., Orlova E., Carlson J.C., Roosenboom J., Mattern B.C., Liebowitz C.R., White J.D., Zaidi A., Hernandez D., Gonzalez T., Pearson L.N., Sero D., Li J., Feingold E., Marazita M.L., Shaffer J.R., Wysocka J., Shriver M.D., Claes P., ''Modular 3D dense surface analysis and GWAS reveal localized genetic effects on human facial morphology involving multiple novel loci'', The FASEB journal, vol. 31, no. 1 Supplement 394.5, April 2017 (Experimental biology - EB 2017, April 22-26, 2017, Chicago, IL, USA).status: publishe

Genome-wide mapping of global-to-local genetic effects on human facial shape

Genome-wide association scans of complex multipartite traits like the human face typically use preselected phenotypic measures. Here we report a data-driven approach to phenotyping facial shape at multiple levels of organization, allowing for an open-ended description of facial variation while preserving statistical power. In a sample of 2,329 persons of European ancestry, we identified 38 loci, 15 of which replicated in an independent European sample (n = 1,719). Four loci were completely new. For the others, additional support (n = 9) or pleiotropic effects (n = 2) were found in the literature, but the results reported here were further refined. All 15 replicated loci highlighted distinctive patterns of global-to-local genetic effects on facial shape and showed enrichment for active chromatin elements in human cranial neural crest cells, suggesting an early developmental origin of the facial variation captured. These results have implications for studies of facial genetics and other complex morphological traits.Peter Claes , Jasmien Roosenboom , Julie D. White , Tomek Swigut , Dzemila Sero , Jiarui Li , Myoung Keun Lee , Arslan Zaidi , Brooke C. Mattern , Corey Liebowitz , Laurel Pearson , Tomás González , Elizabeth J. Leslie , Jenna C. Carlson , Ekaterina Orlova , Suetens P., Vandermeulen D., Eleanor Feingold , Mary L. Marazita , John R. Shaffer , Joanna Wysocka , Mark D. Shriver , Seth M. Weinberg , ''Genome-wide mapping of global-to-local genetic effects on human facial shape'', Nature genetics, 2018 (accepted).status: publishe

Multiethnic GWAS Reveals Polygenic Architecture of Earlobe Attachment

The genetic basis of earlobe attachment has been a matter of debate since the early 20th century, such that geneticists argue both for and against polygenic inheritance. Recent genetic studies have identified a few loci associated with the trait, but large-scale analyses are still lacking. Here, we performed a genome-wide association study of lobe attachment in a multiethnic sample of 74,660 individuals from four cohorts (three with the trait scored by an expert rater and one with the trait self-reported). Meta-analysis of the three expert-rater-scored cohorts revealed six associated loci harboring numerous candidate genes, including EDAR, SP5, MRPS22, ADGRG6 (GPR126), KIAA1217, and PAX9. The large self-reported 23andMe cohort recapitulated each of these six loci. Moreover, meta-analysis across all four cohorts revealed a total of 49 significant (p < 5 × 10−8) loci. Annotation and enrichment analyses of these 49 loci showed strong evidence of genes involved in ear development and syndromes with auricular phenotypes. RNA sequencing data from both human fetal ear and mouse second branchial arch tissue confirmed that genes located among associated loci showed evidence of expression. These results provide strong evidence for the polygenic nature of earlobe attachment and offer insights into the biological basis of normal and abnormal ear development.Fil: Shaffer, John R.. University of Pittsburgh; Estados UnidosFil: Li, Jinxi. University of Chinese Academy of Sciences; ChinaFil: Lee, Myoung Keun. University of Pittsburgh; Estados UnidosFil: Roosenboom, Jasmien. University of Pittsburgh; Estados UnidosFil: Orlova, Ekaterina. University of Pittsburgh; Estados UnidosFil: Adhikari, Kaustabh. Colegio Universitario de Londres; Reino UnidoFil: Gallo, Carla. Universidad Peruana Cayetano Heredia; PerúFil: Poletti, Giovanni. Universidad Peruana Cayetano Heredia; PerúFil: Schuler Faccini, Lavinia. Universidade Federal do Rio Grande do Sul; BrasilFil: Bortolini, Maria Catira. Universidade Federal do Rio Grande do Sul; BrasilFil: Canizales Quinteros, Samuel. Universidad Nacional Autónoma de México; MéxicoFil: Rothhammer, Francisco. Universidad de Tarapacá; ChileFil: Bedoya, Gabriel. Universidad de Antioquia; ColombiaFil: González José, Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico de Ciencias Sociales y Humanas; ArgentinaFil: Pfeffer, Paige E.. Saint Louis University; Estados UnidosFil: Wollenschlaeger, Christopher A.. University of Pittsburgh; Estados UnidosFil: Hecht, Jacqueline T.. University of Texas; Estados UnidosFil: Wehby, George. University of Iowa; Estados UnidosFil: Moreno, Lina M.. University of Iowa; Estados UnidosFil: Ding, Anan. University of Chinese Academy of Sciences; ChinaFil: Jin, Li. University of Chinese Academy of Sciences; China. Fudan University; ChinaFil: Yang, Yajun. Fudan University; ChinaFil: Carlson, Jenna C.. University of Pittsburgh; Estados UnidosFil: Leslie, Elizabeth J.. University of Pittsburgh; Estados UnidosFil: Feingold, Eleanor. University of Pittsburgh; Estados UnidosFil: Marazita, Mary L.. University of Pittsburgh; Estados UnidosFil: Hinds, David A.. 899 West Evelyn Avenue; Estados UnidosFil: Cox, Timothy C.. Seattle Children’s Research Institute; Estados Unidos. University of Washington; Estados Unidos. Monash University; AustraliaFil: Wang, Sijia. University of Chinese Academy of Sciences; China. Fudan University; ChinaFil: Ruiz Linares, Andrés. Colegio Universitario de Londres; Reino Unido. Fudan University; China. Aix-Marseille University; FranciaFil: Weinberg, Seth M.. University of Pittsburgh; Estados Unido

Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology

<div><p>Numerous lines of evidence point to a genetic basis for facial morphology in humans, yet little is known about how specific genetic variants relate to the phenotypic expression of many common facial features. We conducted genome-wide association meta-analyses of 20 quantitative facial measurements derived from the 3D surface images of 3118 healthy individuals of European ancestry belonging to two US cohorts. Analyses were performed on just under one million genotyped SNPs (Illumina OmniExpress+Exome v1.2 array) imputed to the 1000 Genomes reference panel (Phase 3). We observed genome-wide significant associations (p < 5 x 10⁻⁸) for cranial base width at 14q21.1 and 20q12, intercanthal width at 1p13.3 and Xq13.2, nasal width at 20p11.22, nasal ala length at 14q11.2, and upper facial depth at 11q22.1. Several genes in the associated regions are known to play roles in craniofacial development or in syndromes affecting the face: <i>MAFB</i>, <i>PAX9</i>, <i>MIPOL1</i>, <i>ALX3</i>, <i>HDAC8</i>, and <i>PAX1</i>. We also tested genotype-phenotype associations reported in two previous genome-wide studies and found evidence of replication for nasal ala length and SNPs in <i>CACNA2D3</i> and <i>PRDM16</i>. These results provide further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features. Improved understanding of the genes associated with facial morphology in healthy individuals can provide insights into the pathways and mechanisms controlling normal and abnormal facial morphogenesis.</p></div