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Polygenic risk scores (PRS) summarize genetic liability to a disease at the individual level, and the aim is to use them as biomarkers of disease and poor outcomes in real-world clinical practice. To date, few studies have assessed the prognostic value of PRS relative to standards of care. Schizophrenia (SCZ), the archetypal psychotic illness, is an ideal test case for this because the predictive power of the SCZ PRS exceeds that of most other common diseases. Here, we analyzed clinical and genetic data from two multi-ethnic cohorts totaling 8,541 adults with SCZ and related psychotic disorders, to assess whether the SCZ PRS improves the prediction of poor outcomes relative to clinical features captured in a standard psychiatric interview. For all outcomes investigated, the SCZ PRS did not improve the performance of predictive models, an observation that was generally robust to divergent case ascertainment strategies and the ancestral background of the study participants. The inclusion of polygenic risk scores does not improve the performance of standard-of-care predictive models of disease outcomes in patients with psychosis., Author(s): Isotta Landi [sup.1] [sup.2] [sup.3] [sup.4] , Deepak A. Kaji [sup.1] [sup.2] [sup.3] , Liam Cotter [sup.1] [sup.2] [sup.3] [sup.4] , Tielman Van Vleck [sup.3] [sup.4] [sup.5] [sup.6] , [...]

Background: Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional genome-wide association studies (GWAS) produce principal evidence for the association of genetic variants with disease. Transcriptomic imputation (TI) allows for the translation of those variants into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a broader setting through the use of phenome-wide association studies (pheWASs) in large and diverse clinical biobank populations with electronic health record phenotypes. Methods: Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai Bio Me ™ Biobank and performed pheWASs on over 2000 outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of body mass index (BMI) and sex on AN-GReX clinical associations. Results: Our S-PrediXcan analysis identified 53 genes associated with AN, including what is, to our knowledge, the first-genetic association of AN with the major histocompatibility complex. AN-GReX was associated with autoimmune, metabolic, and gastrointestinal diagnoses in our biobank cohort, as well as measures of cholesterol, medications, substance use, and pain. Additionally, our analyses showed moderation of AN-GReX associations with measures of cholesterol and substance use by BMI, and moderation of AN-GReX associations with celiac disease by sex. Conclusions: Our BMI-stratified results provide potential avenues of functional mechanism for AN-genes to investigate further. [ABSTRACT FROM AUTHOR]

The accumulation of ascites in patients with ovarian cancer increases their risk of transcoelomic metastasis. Although common routes of peritoneal dissemination are known to follow distinct paths of circulating ascites, the mechanisms that initiate these currents and subsequent fluid shear stresses are not well understood. Here, we developed a patient-based, boundary-driven computational fluid dynamics model to predict an upper range of fluid shear stress generated by the accumulation of ascites. We show that ovarian cancer cells exposed to ascitic shear stresses display heightened G protein-coupled receptor mechanosignaling and the induction of an epithelial to mesenchymal-like transition through p38α mitogen-activated protein kinase and mucin 15 modulation. These findings along with a shear-induced immunomodulatory secretome position elevated shear stress as a protumoural signal. Together, this study suggests inhibition of the Gαq protein and restriction of ascites accumulation as maintenance strategies for overcoming mechanotransduction-mediated metastasis within the peritoneal cavity., Competing Interests: Statement of Competing Interests. The authors have no competing or other interests that might be perceived to influence the results and/or discussion reported in this paper. Additional Declarations: There is NO Competing Interest.