Relationship of Family Genetic Risk Score With Diagnostic Trajectory in a Swedish National Sample of Incident Cases of Major Depression, Bipolar Disorder, Other Nonaffective Psychosis, and Schizophrenia

Importance Since its inception under Kraepelin in the modern era, diagnostic stability and familial/genetic risk have been among the most important psychiatric nosologic validators. Objective To assess the interrelationships of family genetic risk score (FGRS) with diagnostic stability or diagnostic change in major depression (MD), bipolar disorder (BD), other nonaffective psychosis (ONAP), and schizophrenia. Design, Setting, and Participants This longitudinal population-based cohort (N = 4 171 120) included individuals with incident cases of MD (n = 235 095), BD (n = 11 681), ONAP (n = 16 009), and schizophrenia (n = 6312) who had at least 1 further diagnosis of the 4 disorders during follow-up, as assessed from Swedish national medical registries, observed over a mean (SD) of 13.1 (5.9) years until a mean (SD) age of 48.4 (12.3) years. Data were collected from January 1973 to December 2018, and data were analyzed from August to September 2022. Exposures FGRS for MD, BD, ONAP, and schizophrenia, calculated from morbidity risks for disorders in first-degree through fifth-degree relatives, controlling for cohabitation effects. Main Outcomes and Measures Final diagnostic outcome of MD, BD, ONAP, or schizophrenia. Results Of 269 097 included individuals, 173 061 (64.3%) were female, and the mean (SD) age at first registration was 35.1 (11.9) years. Diagnostic stability was highest for MD (214 794 [91.4%]), followed by schizophrenia (4621 [73.2%]), BD (7428 [63.6%]), and ONAP (6738 [42.1%]). The second most common final diagnosis for each of these MD, schizophrenia, BD, and ONAP were BD (15 506 [6.6%]), ONAP (1110 [17.6%]), MD (2681 [23.0%]), and schizophrenia (4401 [27.5%]), respectively. A high FGRS for the incident diagnosis was consistently associated with diagnostic stability, while a high FGRS for the final diagnosis and a low FGRS for the incident diagnosis was associated with diagnostic change. In multivariate models, those in the upper 5% of genetic risk had an odds ratio (OR) of 1.75 or greater for the following diagnostic transition: for MD FGRS, ONAP to MD (OR, 1.91; 95% CI, 1.59-2.29) and schizophrenia to MD (OR, 2.45; 95% CI, 1.64-3.68); for BD FGRS, MD to BD (OR, 2.60; 95% CI, 2.47-2.73), ONAP to BD (OR, 2.16; 95% CI, 1.85-2.52), and schizophrenia to BD (OR, 2.20; 95% CI, 1.39-3.49); for ONAP FGRS, MD to ONAP (OR, 1.80; 95% CI, 1.62-2.02), MD to schizophrenia (OR, 1.95; 95% CI, 1.58-2.41), and BD to schizophrenia (OR, 1.89; 95% CI, 1.39-2.56); and for schizophrenia FGRS, MD to schizophrenia (OR, 1.80; 95% CI, 1.46-2.23), and BD to schizophrenia (OR, 1.75; 95% CI, 1.25-2.45). FGRS profiles for incident cases confirmed at final diagnosis were more homogenous than genetic profiles for those who changed diagnoses. Conclusions and Relevance In a large population-based longitudinal cohort, the genetic risk factors for MD, BD, ONAP, and schizophrenia were meaningfully and systematically associated with the diagnostic trajectories of these 4 disorders. Over time, clinical diagnosis and genetic risk profiles became increasingly consilient, thereby providing genetic validation of these diagnostic constructs. Diagnostically unstable incident cases were more genetically heterogeneous than those who were diagnostically stable over time.