Structure of the Genetic Risks for Psychiatric Disorders in Swedish Population-Based Registries

Importance: Recent efforts to clarify the structure of the genetic risks for psychiatric disorders have been limited to disorders with large molecular samples. These heterogeneous samples have typically been ascertained from diverse sources and use a widening range of diagnostic approaches including single-item self-reports. Objective: To assess the structure of genetic risk factors for 18 diverse psychiatric and substance use disorders in a single population, using high-quality population-based registries. Design, Setting, and Participants: This cohort study included individuals born between 1960 and 2000 in Sweden to Swedish-born parents who were followed up to a mean (SD) age of 40.9 (10.5) years in 2018. Registries included the Swedish Multigeneration Register and Swedish National Patient Register. Data were analyzed from September to December 2025. Exposures: The family genetic risk scores (FGRSs) for 18 disorders in all individuals calculated from first- through fifth-degree relatives, controlling for cohabitation. Main Outcomes and Measures: Exploratory and confirmatory factor analysis (EFA and CFA, respectively) of these FGRSs performed on split-half samples. Results: Among 3 021 948 individuals (1 549 159 [51.3%] male), EFA found a 6-factor structure consisting of psychotic disorders, externalizing disorders, anxiety disorders, neurodevelopmental disorders, mood disorders, and eating disorders. The mean (SD) interfactor correlation was 0.29. The CFA fit well and set 70.3% of the loadings to 0. Interesting features included identification of separate mood and anxiety disorder factors, with major depression loading on both; bipolar disorder, schizoaffective disorder, and acute psychoses all loading on the mood and psychotic disorder factors, with loadings on the mood disorder factor stronger for bipolar disorder than the psychotic disorder factor and the reverse seen for schizoaffective and acute psychotic disorder; posttraumatic stress disorder having the most diverse loadings on the mood, anxiety, and externalizing disorder factors; and attention-deficit/hyperactivity disorder loading on both the neurodevelopmental and externalizing factors. Because FGRSs are skewed, especially for rare disorders, a range of transformations was performed to reduce skewness, which produced results similar to those obtained on the original data. Conclusions and Relevance: Using a complete epidemiological ascertainment frame for treated psychiatric disorders in a large population sample with high-quality registries, this cohort study uncovered a structure of genetic risks that, compared to prior efforts, was similar in many ways but also had important differences.