One potential cause of comorbidity is the direct causal effect of one disorder – A – on risk for subsequent onset of disorder B. Could genetic risk scores be utilized to test for such an effect? If disorder A causally impacts on risk for disorder B, then genetic risk for disorder A should be lower in cases of disorder A with v. without a prior onset of B.

In all individuals (n = 905 736) born in Sweden from 1980 to 1990, from six psychiatric and drug use disorders (major depression, anxiety disorders, alcohol use disorder, drug use disorder, bipolar disorder, and schizophrenia), we formed 14 pairs of disorders A and B. In these pairs, we compared, using Cox proportional hazards models, the predictive effect of the familial-genetic risk score (FGRS) for disorder B in those who had v. had not had a prior onset of disorder A.

In all pairs, the impact of the FGRS for disorder B was significantly stronger in cases without v. with a prior history of disorder A. These effects were similar across sex, stable across levels of FGRS and not likely due to clinician bias. In many of our disorder pairs, previous clinical studies suggest a mechanism for a causal effect of disorder A on B.

Our findings provide indirect evidence that the occurrence of one psychiatric or substance use disorder often has a causal effect on risk for subsequent disorders. This mechanism may substantially contribute to the widespread comorbidity among psychiatric conditions.

Alcohol use disorder (AUD) is clinically heterogeneous. We examine its potential genetic heterogeneity as a function of sex, age, clinical features and mode of ascertainment.

In the Swedish population born 1932–1995 (n = 5 829 952), we examined the genetic risk profiles for AUD, major depression (MD), anxiety disorders, bipolar disorder, drug use disorder (DUD), attention deficit-hyperactivity disorder (ADHD) and criminal behavior (CB) in 361 124 cases of AUD subdivided by sex, age at onset (AAO), recurrence, mode of ascertainment and medical complications. Family genetic risk scores (FGRS), calculated from 1st to 5th-degree relatives controlling of cohabitation, assesses genetic risk from phenotypes in the family, not from DNA variants.

FGRS profiles differed modestly across sex with all scores higher in females. Differences were more pronounced for AAO and recurrence with the FGRS for AUD, DUD, ADHD and CB substantially higher in cases with early AAO or high recurrence rates. Genetic profiles differed considerably by mode of ascertainment, with higher FGRS for AUD and most other disorders in patients seen in hospital v. primary care settings. Cases of AUD with medical complications had higher FGRS for AUD. AUD cases comorbid with MD and DUD had higher FGRS risk for AUD, but this genetic may be less specific given increases in FGRS for multiple other disorders.

From a genetic perspective, AUD differs substantially as a function of AAO, recurrence, mode of ascertainment and patterns of comorbidity, suggesting caution in cross-sample comparisons of AUD cohorts that differ in these features.