Schizophrenia polygenic risk scores, urbanicity and treatment-resistant schizophrenia

Introduction To investigate the impact of a polygenic risk score for schizophrenia (PRS-SZ) and urbanicity on the risk of treatment-resistant schizophrenia in people with a diagnosis of schizophrenia and to evaluate the association between PRS-SZ and TRS across areas of urbanicity. Methods Cohort study of people born after 1981 with a first time diagnosis of schizophrenia between 1996 and 2012 using Danish population registry data. Through linkage to genome-wide data, we calculated PRS-SZ based on a Psychiatric Genomics Consortium meta-analysis. We assessed urbanicity at birth (capital, provincial and rural areas). TRS was defined using prescription and hospital data. Performing Cox regression analysis, we calculated hazard rate ratios (HRs) and 95% confidence intervals (CI). Results Among 4,475 people with schizophrenia, we identified 593 (13.3%) with TRS during 17 558 person years of follow-up. The adjusted HR for TRS associated with 1 standard deviation (SD) increase in the PRS-SZ was 1.11 (95% CI: 1.00–1.24). The adjusted HRs for urbanicity and TRS were 1.20 (95% CI: 0.98–1.47) for provincial areas and 1.19 (95% CI 0.96–1.47) for rural areas compared with the capital area. Across strata of urbanicity, the adjusted HR for TRS was 1.39 (95% CI: 1.14–1.70) in the capital area with 1 SD increase in the PRS-SZ, 0.99 (95% CI 0.84–1.17) in provincial areas, and 1.03 (95% CI: 0.86–1.25) in rural areas. Conclusion The risk of TRS associated with genetic liability varied across urbanicity areas and was highest in people with schizophrenia who resided in the capital areas at birth.