High-impact rare genetic variants in severe schizophrenia
Anthony W. Zoghbi, Ryan S. Dhindsa, Terry E. Goldberg, Aydan Mehralizade, Joshua E. Motelow, Xinchen Wang, Anna Alkelai, Matthew Harms, Jeffrey A. Lieberman, Sander Markx, David B. Goldstein
Abstract
Significance In this study, we found that selecting individuals with extremely severe forms of schizophrenia led to a significantly improved ability to detect disease-associated rare variants. The high prevalence of rare variant risk factors in individuals with severe, extremely treatment-resistant schizophrenia suggests future clinical opportunities for risk prediction, prognostic stratification, and genetic counseling. These findings have implications for the design of future genetic studies in schizophrenia and highlight a strategy to reduce phenotypic heterogeneity and improve gene discovery efforts in other neuropsychiatric disorders.