Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans

Tim B. Bigdeli, Ayman H. Fanous, Yuli Li, Nallakkandi Rajeevan, Frederick Sayward, Giulio Genovese, Rishab Gupta, Krishnan Radhakrishnan, Anil K. Malhotra, Ning Sun, Qiongshi Lu, Yiming Hu, Boyang Li, Quan Chen, Shrikant Mane, Perry Miller, Kei Hoi Cheung, Raquel E. Gur, Tiffany A. Greenwood, David L. BraffEric D. Achtyes, Peter F. Buckley, Michael A. Escamilla, Douglas Lehrer, Dolores P. Malaspina, Steven A. McCarroll, Mark H. Rapaport, Marquis P. Vawter, Michele T. Pato, Carlos N. Pato, Hongyu Zhao, Thomas R. Kosten, Mary Brophy, Saiju Pyarajan, Yunling Shi, Timothy J. O'Leary, Theresa Gleason, Ronald Przygodzki, Sumitra Muralidhar, J. Michael Gaziano, Grant D. Huang, John Concato, Larry J. Siever, Mihaela Aslan, Philip D. Harvey

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)517-529
Number of pages13
JournalSchizophrenia bulletin
Volume47
Issue number2
DOIs
StatePublished - Mar 1 2021
Externally publishedYes

Keywords

  • US veterans
  • bipolar disorder
  • genome-wide association studies (GWAS)
  • schizophrenia

ASJC Scopus subject areas

  • Psychiatry and Mental health

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