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This genetic association study uses electronic health record data to investigate the association between polygenic score of posttraumatic stress disorder symptom severity and clinical diagnoses and laboratory tests. Key Points: Question: Which clinical diagnoses and laboratory tests are associated with a polygenic score of posttraumatic stress disorder (PTSD)? Findings: The polygenic score of PTSD symptom severity was associated with circulatory system, respiratory traits, and metabolic laboratory measures in the electronic health records of 496 317 individuals across 4 independent biobanks. Genomic causal inference analyses suggest that genetic liability to PTSD was associated with various digestive disorders, alcoholism, tachycardia, and cardiac dysrhythmias, among others. Meaning: Results suggest shared genetics between PTSD and several physical health conditions that may explain previously reported comorbid associations in observational studies. Importance: Posttraumatic stress disorder (PTSD) has been reported to be a risk factor for several physical and somatic symptoms. However, the genetics of PTSD and its potential association with medical outcomes remain unclear. Objective: To examine disease categories and laboratory tests from electronic health records (EHRs) that are associated with PTSD polygenic scores. Design, Setting, and Participants: This genetic association study was conducted from July 15, 2021, to January 24, 2023, using EHR data from participants across 4 biobanks. The polygenic scores of PTSD symptom severity (PGS-PTSD) were tested with all available phecodes in Vanderbilt University Medical Center's biobank (BioVU), Mass General Brigham (MGB), Michigan Genomics Initiative (MGI), and UK Biobank (UKBB). The significant medical outcomes were tested for overrepresented disease categories and subsequently tested for genetic correlation and 2-sample mendelian randomization (MR) to determine genetically informed associations. Multivariable MR was conducted to assess whether PTSD associations with health outcomes were independent of the genetic effect of body mass index and tobacco smoking. Exposures: Polygenic score of PTSD symptom severity. Main Outcomes and Measures: A total of 1680 phecodes (ie, International Classification of Diseases, Ninth Revision– and Tenth Revision–based phenotypic definitions of health outcomes) across 4 biobanks and 490 laboratory tests across 2 biobanks (BioVU and MGB). Results: In this study including a total of 496 317 individuals (mean [SD] age, 56.8 [8.0] years; 263 048 female [53%]) across the 4 EHR sites, meta-analyzing associations of PGS-PTSD with 1680 phecodes from 496 317 individuals showed significant associations to be overrepresented from mental health disorders (fold enrichment = 3.15; P = 5.81 × 10−6), circulatory system (fold enrichment = 3.32; P = 6.39 × 10−12), digestive (fold enrichment = 2.42; P = 2.16 × 10−7), and respiratory outcomes (fold enrichment = 2.51; P = 8.28 × 10−5). The laboratory measures scan with PGS-PTSD in BioVU and MGB biobanks revealed top associations in metabolic and immune domains. MR identified genetic liability to PTSD symptom severity as an associated risk factor for 12 health outcomes, including alcoholism (β = 0.023; P = 1.49 × 10−4), tachycardia (β = 0.045; P = 8.30 × 10−5), cardiac dysrhythmias (β = 0.016, P = 3.09 × 10−5), and acute pancreatitis (β = 0.049, P = 4.48 × 10−4). Several of these associations were robust to genetic effects of body mass index and smoking. We observed a bidirectional association between PTSD symptoms and nonspecific chest pain and C-reactive protein. Conclusions and Relevance: Results of this study suggest the broad health repercussions associated with the genetic liability to PTSD across 4 biobanks. The circulatory and respiratory systems association was observed to be overrepresented in all 4 biobanks. [ABSTRACT FROM AUTHOR]