Polygenic Risk Score Contribution to Psychosis Prediction in a Target Population of Persons at Clinical High Risk

• Type of Material: Article
• Authors: Diana O. Perkins, University of North Carolina, Chapel Hill; Loes Olde Loohuis, University of North Carolina, Chapel Hill; Jenna Barbee, University of North Carolina, Chapel Hill; John Ford, University of North Carolina, Chapel Hill; Clark D. Jeffries, University of North Carolina, Chapel Hill; Jean Addington, University of Calgary; Carrie E. Bearden, University of California, Los Angeles; Kristin S. Cadenhead, University of California, San Diego; Tyrone D. Cannon, Yale University; Barbara A. Cornblatt, Zucker HIllside Hospital; Daniel H. Mathalon, University of California, San Francisco; Thomas H. McGlashan, Yale University; Larry J. Seidman, Harvard University; Ming Tsuang, University of California, San Diego; Elaine F. Walker, Emory University; Scott W. Woods, Yale University
• Language: English
• Date: 2019-11-12
• Publisher: American Psychiatric Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 American Psychiatric Association
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1176/appi.ajp.2019.18060721
• Title of Journal or Parent Work: The American Journal of Psychiatry
• Volume: 177
• Issue: 2
• Start Page: 155
• End Page: 163
• Grant/Funding Agency: Commonwealth of Massachusetts; Broad Institute; NIMH
• Grant/Funding Information: Supported by NIMH grant U01 MH081984 (to Dr. Addington); grant U01 MH081902 (to Dr. Cannon), grant P50 MH066286 (Prodromal Core) (to Dr. Bearden); grants R01 MH60720, U01 MH082022, and K24 MH76191 (to Dr. Cadenhead); grant U01 MH081857 (to Dr. Cornblatt); grant K99 MH116115 (to Dr. Olde Loohuis); grant U01 MH082004 (to Dr. Perkins); grants U01 MH081928, P50 MH080272, and Commonwealth of Massachusetts grant SCDMH82101008006 (to Dr. Seidman); grant U01 MH081988 (to Dr. Walker); and grant U01 MH082022 (to Dr. Woods). The Broad Institute funded the costs of performing the Illumina assays.
• Keywords: Clinical High Risk; Polygenic Risk Score; psychosis
• Subject - Topics: Clinical psychiatry; Precision medicine; Psychiatry

Abstract

Objective: The 2-year risk of psychosis in persons who meet research criteria for a high-risk syndrome is about 15%–25%; improvements in risk prediction accuracy would benefit the development and implementation of preventive interventions. The authors sought to assess polygenic risk score (PRS) prediction of subsequent psychosis in persons at high risk and to determine the impact of adding the PRS to a previously validated psychosis risk calculator. Methods: Persons meeting research criteria for psychosis high risk (N=764) and unaffected individuals (N=279) were followed for up to 2 years. The PRS was based on the latest schizophrenia and bipolar genome-wide association studies. Variables in the psychosis risk calculator included stressful life events, trauma, disordered thought content, verbal learning, information processing speed, and family history of psychosis. Results: For Europeans, the PRS varied significantly by group and was higher in the psychosis converter group compared with both the nonconverter and unaffected groups, but was similar for the nonconverter group compared with the unaffected group. For non-Europeans, the PRS varied significantly by group; the difference between the converters and nonconverters was not significant, but the PRS was significantly higher in converters than in unaffected individuals, and it did not differ between nonconverters and unaffected individuals. The R2 (R2 adjusted for the rate of disease risk in the population being studied, here assuming a 2-year psychosis risk between 10% and 30%) for Europeans varied between 9.2% and 12.3% and for non-Europeans between 3.5% and 4.8%. The amount of risk prediction information contributed by the addition of the PRS to the risk calculator was less than severity of disordered thoughts and similar to or greater than for other variables. For Europeans, the PRS was correlated with risk calculator variables of information processing speed and verbal memory. Conclusions: The PRS discriminates psychosis converters from nonconverters and modestly improves individualized psychosis risk prediction when added to a psychosis risk calculator. The schizophrenia PRS shows promise in enhancing risk prediction in persons at high risk for psychosis, although its potential utility is limited by poor performance in persons of non-European ancestry.