Transdiagnostic Psychiatric Polygenic Scores Reveal Pleiotropic Effects Across Medical and Laboratory Phenome

Summary Background Current psychiatric diagnoses lack biological grounding. Using transdiagnostic psychiatric dimensions derived through data-driven genetic studies with large-scale clinical health records of multiple physiological and clinical outcomes, we can gain new insights into biological similarity and differences between such dimensions, informing nosological discourse. Methods Here, we examined data from 108,182 individuals of European-like ancestry and 13,229 African-like ancestry across two healthcare biobanks. Genetic liabilities of individuals were estimated as polygenic scores for five first-order psychopathology factors (compulsive, thought, neurodevelopmental, substance use, internalizing disorders) and one second-order factor (hierarchical/p-factor). Phenome-wide and laboratory-wide association scans encompassed 1,520 medical phenotypes and 123 laboratory metrics, meta-analyzed across sites. People with lived experience were involved in the design, preparation, interpretation and reporting of this work. Outcomes We observed robust associations with up to 143 conditions (14 disease categories) for first-order factors and 221 conditions (15 categories) for the hierarchical factor (OR=0.75-1.94). Circulatory, digestive, and respiratory diseases were linked to neurodevelopmental, internalizing, and substance use liabilities. Metabolic conditions were negatively associated with thought and compulsive liabilities but positively associated with the remaining three factors. Laboratory results, particularly lipid and glucose metabolism markers, supported these differential findings. Immune markers also showed differential associations, with C-reactive protein and Complement C4 specifically linked to neurodevelopmental and thought factors, respectively. Similar trends emerged in the smaller African-like ancestry sample. Interpretation Overall, these findings support ongoing efforts to define biologically informed subtypes in psychiatry, such as immuno-metabolic profiles, which can facilitate patient stratification in clinical trials and support transdiagnostic precision psychiatry approaches. Funding The work was supported by funding from the participating institutions. BF's and NRM's contributions were supported by the European Community's Horizon 2020 Programme (H2020/2014-2020) under grant agreement No. 847879 (PRIME). NRM was also supported by the Netherlands Organisation for Scientific Research (NWO) Innovation Programme (Vidi grant No. 09150172410043). Research reported in this publication was also supported by the National Institute of Mental Health of the National Institutes of Health under Award Number R01MH124851. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.