Linking the Expression of Facial Shape and BMI via the Hippo Signaling Pathway
Authors: Ali Sareena , Ehrlich Daniel E. , Moreno Uribe Lina M. , Amendt Brad A. , Lee Myoung Keun , Shaffer John R. , Marazita Mary L. , Weinberg Seth M. , Miller Steven F. 
Published: June 2021

Obesity rates have more than tripled in children and adolescents in recent years. While many studies have examined the relationship between obesity and chronic illnesses, the impact of obesity on craniofacial form is less understood. Research in this area has suggested that obesity and facial form are risk factors for illnesses such as sleep apnea, but a mechanism that links these risk factors has been elusive. In order to explore a potential mechanism for linking risk for obesity and craniofacial abnormalities, this study examines variation within the Hippo signaling pathway. The Hippo signaling pathway plays an important role in organ size and tissue growth, as well as regulating craniofacial morphogenesis and adipocyte formation. For this study, we investigate the potential relationship between facial shape and BMI as a function of genetic variation within the Hippo signaling pathway.A sample of n=482 individuals with an age range of 3 to 16 years was targeted for the study. 3D facial images were captured using a 3dMD stereophotogrammetric camera and 34 coordinate landmarks were placed along the eyes, nose, mouth, and lower jaw for each face. Landmark data was registered via Generalized Procrustes Analysis (GPA) and then allometrically scaled to control for shape variation as a function of age. These allometric residuals were submitted to Principal Components Analysis (PCA), Canonical Variate Analysis (CVA) and linear regression within the software package MorphoJ in order to identify patterns of facial variation associated with BMI. These phenotypes were then tested for association with 23 single nucleotide polymorphisms (SNPs) in seven genes involved in Hippo signaling.The phenotypic results from the PCA, CVA, and the linear regressions between facial shape and high BMI/percentile BMI are characterized by having the eyes and chin shifted inferiorly, along with the nose being smaller in comparison to the normal weight category. This association between facial shape and obesity is significant at p<0.001. Principal component 1 (PC1) and PC2 also illustrated the above phenotypic features and both PCs were significantly different based on weight status (p<0.001). Genetic association testing indicated that shape variation along PC2 was significantly associated after Bonferroni correction with two SNPs in TEAD3 (p=0.002). Additionally, suggestive evidence for an association between phenotypic variation along PC1 and three SNPs located in RUNX2 was also identified (p=0.007).These results indicate that BMI and facial form are linked, and that genetic variation in TEAD3 (and possibly RUNX2) in the Hippo signaling pathway may be important for this relationship. Based on these results, further examination of the Hippo signaling pathway in both obesity and craniofacial form is warranted.Support or Funding InformationNIDCR: U01‐DE020078, R01‐DE016148, and R01‐DE027023This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.