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Background: Mood disorders such as major depressive and bipolar disorders, along with posttraumatic stress disorder (PTSD), schizophrenia (SCZ), and other psychotic disorders, constitute serious mental illnesses (SMI) and often lead to inpatient psychiatric care for adults. Risk factors associated with increased hospitalization rate in SMI (H-SMI) are largely unknown but likely involve a combination of genetic, environmental, and socio-behavioral factors. We performed a genome-wide association study in an African American cohort to identify possible genes associated with hospitalization due to SMI (H-SMI)., Methods: Patients hospitalized for psychiatric disorders (H-SMI; n=690) were compared with demographically matched controls (n=4467). Quality control and imputation of genome-wide data were performed following the Psychiatric Genetic Consortium (PGC)-PTSD guidelines. Imputation of the Human Leukocyte Antigen (HLA) locus was performed using the HIBAG package., Results: Genome-wide association analysis revealed a genome-wide significant association at 6p22.1 locus in the ubiquitin D ( UBD/FAT10 ) gene (rs362514, p=9.43x10 -9 ) and around the HLA locus. Heritability of H-SMI (14.6%) was comparable to other psychiatric disorders (4% to 45%). We observed a nominally significant association with 2 HLA alleles: HLA-A*23:01 (OR=1.04, p=2.3x10 -3 ) and HLA-C*06:02 (OR=1.04, p=1.5x10 -3 ). Two other genes ( VSP13D and TSPAN9 ), possibly associated with immune response, were found to be associated with H-SMI using gene-based analyses., Conclusion: We observed a strong association between H-SMI and a locus that has been consistently and strongly associated with SCZ in multiple studies (6p21.32-p22.1), possibly indicating an involvement of the immune system and the immune response in the development of severe transdiagnostic SMI., Competing Interests: KR has performed scientific consultation for Acer Therapeutics, Bickel, Bionomics, Boehringer Ingelheim, Takeda, and Jazz Pharma; serves on Scientific Advisory Boards for Sage, the Brain Research Foundation, and the National Center for PTSD, he has received sponsored research support from Brains way and Alto Neuroscience. He also receives research funding from the NIH and the Welcome Leap. ED receives or has received research support for work unrelated to this project from NIMH 1R01MH117315-01A1; 5R21MH117512-02, the Department of Veterans Affairs CSP2016; CSP590; MHBA-016-15S; 1I01CX000974-01A1, Auspex Pharmaceuticals, Inc. and Teva Pharmaceuticals, Inc. ED is a full-time attending psychiatrist in the Mental Health Service Line at the Atlanta Veterans Affairs Health Care System, Decatur, GA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor GB declared a past co-authorship with author APW., (Copyright © 2024 Lori, Pearce, Katrinli, Carter, Gillespie, Bradley, Wingo, Jovanovic, Michopoulos, Duncan, Hinrichs, Smith and Ressler.)