Face-brain correlates as potential sex-specific biomarkers for schizophrenia and bipolar disorder.

Given the shared ectodermal origin and integrated development of the face and the brain, facial biomarkers emerge as potential candidates to assess vulnerability for disorders in which neurodevelopment is compromised, such as Schizophrenia (SZ) and bipolar disorder (BD). The sample comprised 188 individuals (67 SZ patients, 46 BD patients and 75 healthy controls (HC)). Using a landmark-based approach on 3D facial reconstructions, we quantified global and local facial shape differences between SZ/BD patients and HC using geometric morphometrics. We assessed correlations between facial and brain cortical measures. The analyses were performed separately by sex. Diagnosis explained 4.1% - 5.9% of global facial shape variance in males and females with SZ, and 4.5% - 4.1% in BD. Regarding local facial shape, we detected 43.2% of significantly different distances in males and 47.4% in females with SZ compared to HC, whereas in BD the percentages decreased to 35.8% and 26.8%, respectively. We detected that brain area and volume significantly explained 2.2% and 2% of facial shape variance in the male SZ - HC sample. Our results support facial shape as a neurodevelopmental marker for SZ and BD and reveal sex-specific pathophysiological mechanisms modulating the interplay between the brain and the face. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study received funding from: i) Agencia Espaňola de Investigacion (PID2020-113609RB-C21 /AEI/10.13039/501100011033) ii) Instituto de Salud Carlos III (ISCIII) through the project PI20/01002 and the contracts FI21/00093 to NH and CP20/00072 to MF-V (co-funded by European Regional Development Fund (ERDF)/European Social Fund Investing in your future) iii) the Comissionat per a Universitats i Recerca del DIUE of the Generalitat de Catalunya (Agencia de Gestio Ajuts Universitaris i de Recerca (AGAUR: 2021SGR01475 2021SGR01396 and 2021SGR00706) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the local ethics committee of FIDMAG Germanes Hospitalaries Research Foundation (PR-2023-21) and Universitat de Barcelona (IRB00003099-CER122317). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors