Towards Scalable Biomarker Discovery in Posttraumatic Stress Disorder: Triangulating Genomic and Phenotypic Evidence from a Health System Biobank

ImportanceBiomarkers can potentially improve the diagnosis, monitoring, and treatment of posttraumatic stress disorder (PTSD). However, PTSD biomarkers that are scalable and easily integrated into real-world clinical settings have not been identified. ObjectiveTo triangulate phenotypic and genomic evidence from a health system biobank with a goal of identifying scalable and clinically relevant biomarkers for PTSD. Design, setting, and participantsThe analysis was conducted between June to November 2024 using genomic samples and laboratory test results recorded in the Mass General Brigham (MGB) Health System. The analysis included 23,743 European ancestry participants from the nested MGB Biobank study. ExposuresThe first exposure was polygenic risk score (PRS) for PTSD, calculated using the largest available European ancestry genome-wide association study (GWAS), employing a Bayesian polygenic scoring method. The second exposure was a clinical diagnosis of PTSD, determined by the presence of two or more qualifying PTSD phecodes in the longitudinal electronic health records (EHR). Main outcomes and measuresThe primary outcomes were the inverse normal quantile transformed, median lab values of 241 laboratory traits with non-zero h2SNPestimates. ResultsSixteen unique laboratory traits across the cardiometabolic, hematologic, hepatic, and immune systems were implicated in both genomic and phenotypic lab-wide association scans (LabWAS). Two-sample Mendelian randomization analyses provided evidence of potential unidirectional causal effects of PTSD liability on five laboratory traits. Conclusion and relevanceThese findings demonstrate the potential of a triangulation approach to uncover scalable and clinically relevant biomarkers for PTSD. Key pointsO_ST_ABSQuestionC_ST_ABSIs genetic liability or diagnosis of PTSD associated with clinical laboratory measures? FindingsAmong European ancestry participants in the MGB Biobank, we identified 16 unique laboratory traits in cardiometabolic, hematologic, hepatic, and immune systems that were both genetically and phenotypically associated with PTSD, with five markers demonstrating potential unidirectional causal effects of PTSD liability. MeaningOur findings reveal associations between PTSD and laboratory markers across multiple physiological systems, with evidence suggesting possible unidirectional causal effects of PTSD liability on cardiometabolic, hematologic, and hepatic markers.