Tim B Bigdeli1,2, Ayman H Fanous1,2, Yuli Li3,4, Nallakkandi Rajeevan3,4, Frederick Sayward3,4, Giulio Genovese5,6, Rishab Gupta2, Krishnan Radhakrishnan3,7, Anil K Malhotra8,9,10, Ning Sun3,4, Qiongshi Lu4,11, Yiming Hu4, Boyang Li4, Quan Chen3,4, Shrikant Mane4, Perry Miller3,4, Kei-Hoi Cheung3,4, Raquel E Gur12, Tiffany A Greenwood13, David L Braff13,14, Eric D Achtyes15, Peter F Buckley16, Michael A Escamilla17, Douglas Lehrer18, Dolores P Malaspina19, Steven A McCarroll5,6, Mark H Rapaport20, Marquis P Vawter21, Michele T Pato2, Carlos N Pato2, Hongyu Zhao3,4, Thomas R Kosten22, Mary Brophy23,24, Saiju Pyarajan23, Yunling Shi23, Timothy J O'Leary25, Theresa Gleason25, Ronald Przygodzki25, Sumitra Muralidhar25, J Michael Gaziano23,26, Grant D Huang25, John Concato3,4, Larry J Siever19,27, Mihaela Aslan3,4, Philip D Harvey28,29. 1. VA New York Harbor Healthcare System, Brooklyn, NY. 2. Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY. 3. Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), VA Connecticut Healthcare System, West Haven, CT. 4. Department of Medicine, Yale School of Medicine, New Haven, CT. 5. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA. 6. Department of Genetics, Harvard Medical School, Boston, MA. 7. College of Medicine, University of Kentucky, Lexington, KY. 8. Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY. 9. Division of Psychiatry Research, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY. 10. Department of Psychiatry, Hofstra Northwell School of Medicine, Hempstead, NY. 11. Department of Biostatistics & Medical Informatics, University of Wisconsin-Madison, Madison, WI. 12. Departments of Psychiatry and Child & Adolescent Psychiatry and Lifespan Brain Institute, University of Pennsylvania Perelman School of Medicine and Children's Hospital of Philadelphia, Philadelphia, PA. 13. Department of Psychiatry, University of California, La Jolla, San Diego, CA. 14. VISN-22 Mental Illness, Research, Education and Clinical Center (MIRECC), VA San Diego Healthcare System, San Diego, CA. 15. Cherry Health and Michigan State University College of Human Medicine, Grand Rapids, MI. 16. School of Medicine, Virginia Commonwealth University, Richmond, VA. 17. Department of Psychiatry, School of Medicine, University of Texas Rio Grande Valley, Harlingen, TX. 18. Department of Psychiatry, Wright State University, Dayton, OH. 19. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY. 20. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA. 21. Department of Psychiatry and Human Behavior, University of California, Irvine, CA. 22. Departments of Psychiatry, Neuroscience, Pharmacology, and Immunology and Rheumatology, Baylor College of Medicine, Houston, TX. 23. Massachusetts Area Veterans Epidemiology, Research, and Information Center (MAVERIC), Jamaica Plain, MA. 24. Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA. 25. Office of Research and Development, Veterans Health Administration, Washington, DC. 26. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. 27. University of Miami Miller School of Medicine, James J. Peters Veterans Affairs Medical Center, Bronx, NY. 28. Research Service Bruce W. Carter VA Medical Center, Miami, FL. 29. Department of Psychiatry, University of Miami Miller School of Medicine, Miami, FL.
Abstract
BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world's population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. METHODS: We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. RESULTS: Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10-30) and African American (P < .0005) participants in CSP #572. CONCLUSIONS: We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2020.
BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world's population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. METHODS: We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. RESULTS: Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10-30) and African American (P < .0005) participants in CSP #572. CONCLUSIONS: We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2020.
Entities:
Keywords:
US veterans; bipolar disorder; genome-wide association studies (GWAS); schizophrenia
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