It is clinically important to predict the conversion of major depression (MD) to bipolar disorder (BD). Therefore, we sought to identify related conversion rates and risk factors.

This cohort study included the Swedish population born from 1941 onward. Data were collected from Swedish population-based registers. Potential risk factors, including family genetic risk scores (FGRS), which were calculated based on the phenotypes of relatives in the extended family and not molecular data, and demographic/clinical characteristics from these registers were retrieved. Those with first MD registrations from 2006 were followed up until 2018. The conversion rate to BD and related risk factors were analyzed using Cox proportional hazards models. Additional analyses were performed for late converters and with stratification by sex.

The cumulative incidence of conversion was 5.84% [95% confidence interval (95% CI) 5.72–5.96] for 13 years. In the multivariable analysis, the strongest risk factors for conversion were high FGRS of BD [hazard ratio (HR) = 2.73, 95% CI 2.43–3.08], inpatient treatment settings (HR = 2.64, 95% CI 2.44–2.84), and psychotic depression (HR = 2.58, 95% CI 2.14–3.11). For late converters, the first registration of MD during the teenage years was a stronger risk factor when compared with the baseline model. When the interactions between risk factors and sex were significant, stratification by sex revealed that they were more predictive in females.

Family history of BD, inpatient treatment, and psychotic symptoms were the strongest predictors of conversion from MD to BD.

– Comorbidity between psychiatric disorders is extensive but, from a genetic perspective, still poorly understood. Modern molecular genetic approaches to this problem are limited by a reliance on case–control designs.

– In 5 828 760 individuals born in Sweden from 1932–1995 with a mean (s.d.) age at follow-up of 54.4 (18.1), we examined family genetic risk score (FGRS) profiles including internalizing, psychotic, substance use and developmental disorders in 10 pairs of psychiatric and substance use disorders diagnosed from population registries. We examined these profiles in three groups of patients: disorder A only, disorder B only and comorbid cases with both disorders.

– The most common pattern of findings, seen in five pairings, was simple and quantitative. Comorbid cases had higher FGRS than both non-comorbid cases for all (or nearly all) disorders. However, the pattern was more complex in the remaining five pairings and included qualitative changes where the comorbid cases showed no increases in FGRS for certain disorders and in a few cases significant decreases. Several comparisons showed an asymmetric pattern of findings with increases, in comorbidity compared to single disorder cases, of the FGRS for only one of the two disorders.

– The examination of FGRS profiles in general population samples where all disorders are assessed in all subjects provides a fruitful line of inquiry to understand the origins of psychiatric comorbidity. Further work will be needed, with an expansion of analytic approaches, to gain deeper insights into the complex mechanisms likely involved.