We utilize a novel contrastive genetic-epidemiological method, the Maternal Half-Sibling Families with Discordant Fathers (MHSFDF) design, to examine cross-generational genetic transmission of posttraumatic stress disorder (PTSD) and related internalizing major depression (MD), and externalizing disorders: alcohol use disorder (AUD) and drug use disorder (DUD).

Using Swedish national registries, we identified 72,467 maternal half-sibling pairs reared together whose biological fathers were discordant for the diagnoses of PTSD, MD, AUD, and DUD. Offspring selected had to have less than 1 year of contact with their affected fathers. We examined the differences in outcome for within- and cross-disorder risk of diagnosis in the half-siblings with an affected versus unaffected father.

Paternal PTSD increased the risk of PTSD (HR: 1.43, 95% CI: 1.05–1.96) and MD (HR: 1.55, CI: 1.28–1.88) in offspring. It did not, however, elevate the risk of externalizing disorders (AUD or DUD). Offspring of fathers with AUD, DUD, or MD had increased risk of PTSD, suggesting sharing of vertically transmitted genetic risk between these disorders. No sex effects were found for any studied diagnosis.

This study is the first to show cross-generation genetic transmission for PTSD using the MHSFDF design. The pattern of cross-disorder genetic risk broadly supported an internalizing versus externalizing disorder split.

We seek to clarify how changes in the prevalence of drug use disorder (DUD) in Sweden in the 1950–1990 birth cohort impact the aggregation and co-aggregation in siblings of DUD and alcohol use disorder (AUD).

We examined risk for DUD and AUD in siblings of 102,624 DUD cases and matched control probands and 123,837 AUD case and matched control probands identified using Swedish registries. Flexible parametric survival models assessed the difference in disorder risk in siblings of case versus control probands.

Over birthyears 1950–1990, rates of DUD increased substantially in the Swedish population. In siblings of DUD cases versus controls, the risk for DUD increased dramatically starting in birthyear 1965 while their risk for AUD fell moderately. A similar, but less pronounced pattern, was seen in the siblings of AUD versus control probands. These differences were much larger in male than in female siblings.

The factors that drove upward population rates of DUD in Sweden (e.g. increased availability, reduced stigma) produced much stronger effects in high-risk subjects (siblings of DUD and AUD probands) than in normal risk groups (siblings of controls), thereby increasing familial aggregation of DUD. However, parallel declines in AUD rates in high-risk versus normal-risk siblings were observed, likely due to ‘competitive effects’ reducing coaggregation of DUD and AUD. Results of genetic studies of substance use disorders can be substantially impacted by changes in availability and stigma of psychoactive substance use and indirectly by ‘competition’ as predicted by behavioral economic models, between abusable substances.

Among individuals with alcohol use disorder (AUD) and drug use disorder (DUD), is their genetic liability and its specificity moderated by substance availability?

Offspring (born 1960–1995) and their biological parents from three family types [not-lived-with (NLW) biological father, mother and adoptive] and their AUD and DUD diagnoses were ascertained from Swedish national registers. Parent–offspring resemblance was calculated by tetrachoric correlation.

In Swedes born from 1960 to 1995, prevalence rates of AUD were stable while DUD rates increased substantially. Best-estimate tetrachoric correlations (±95% confidence intervals) between AUD in biological parents and AUD and DUD in their offspring were, respectively, +0.19 (0.18–0.20) and +0.18 (0.17–0.20). Parallel results from DUD in parents to AUD and DUD in children were +0.12 (0.10–0.13) and +0.27 (0.26–0.28). When divided into older and younger cohorts, the specificity of DUD transmission increased substantially over time, while the genetic correlation between AUD and DUD significantly decreased.

Raised when alcohol was the preferred substance of abuse and illicit drugs highly stigmatized, AUD in parents reflected a general liability to substance use disorders, as they transmitted similar genetic risk for AUD and DUD to their children raised when both substances were widely available and relatively acceptable. DUD in parents, by contrast, reflected a more specific liability to DUD and, when transmitted to offspring, produced a considerably stronger risk for DUD than for AUD that increased over time. The magnitude and specificity of the genetic liability to psychoactive substances can be influenced by the availability of that substance.