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.

Stressful life events (SLEs) increase the risk for subsequent major depression (MD) episodes. Most prior studies of SLEs utilized questionnaires or interview-based assessments. We sought to develop and evaluate an environmental risk score (ERS) for MD from multiple classes of SLEs obtained from national Swedish registries.

We assessed, in the entire adult population of Sweden (n = 7,105,712), the occurrence of 52 categories of SLEs derived from registry information for the 6 months prior to January 9, 2010 and the risk for MD registration over the subsequent 6 months. Weights for our ERS were obtained from a random half of our sample and ERS and its relationship to MD risk was evaluated in the second half.

The ERS was robustly related to risk for subsequent MD episodes. Women were more sensitive to the depressogenic effect of the ERS than men. Those with prior episodes of MD had larger absolute increases in MD risk from our ERS than those without previous episodes. Genetic risk for MD was associated with a greater sensitivity to the depressogenic effects of the ERS. A co-sibling control analysis suggested that most, but not all, of the association between ERS and subsequent risk for MD was causal.

Valid measures of SLEs that predispose to risk for MD can be assessed from high-quality registry data. While not all event categories (e.g. interpersonal or romantic difficulties) can be assessed, this method avoids problems with accurate dating and recall bias and can be performed in very large samples.

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.

Drug use Disorder (DUD), the risk for which is substantially influenced by both genetic and social factors, is geographically concentrated in high-risk regions. An important step toward understanding this pattern is to examine geographical distributions of the genetic liability to DUD and a key demographic risk factor – social deprivation.

We calculated the mean family genetic risk score (FGRS) for DUD ((FGRSDUD) and social deprivation for each of the 5983 areas Demographic Statistical Areas (DeSO) for all of Sweden and used geospatial techniques to analyze and map these factors.

Using 2018 data, substantial spatial heterogeneity was seen in the distribution of the genetic risk for DUD in Sweden as a whole and in its three major urban centers which was confirmed by hot-spot analyses. Across DeSOs, FGRSDUD and s.d. levels were substantially but imperfectly correlated (r = + 0.63), with more scattering at higher FGRSDUD and s.d. scores. Joint mapping across DeSOs for FGRSDUD and s.d. revealed a diversity of patterns across Sweden. The stability of the distributions of FGRSDUD and s.d. in DeSOs within Sweden over the years 2012–2018 was quite high.

The geographical distribution of the genetic risk to DUD is quite variable in Sweden. DeSO levels of s.d. and FRGSDUD were substantially correlated but also disassociated in a number of regions. The observed patterns were largely consistent with known trends in the human geography of Sweden. This effort lays the groundwork for further studies of the sources of geographic variation in rates of DUD.

Robust clinical indices of etiologic heterogeneity for psychiatric disorders are rare. We investigate whether age at onset (AAO) reflects genetic heterogeneity, utilizing Genetic Risk Ratios (GRR) derived from Family Genetic Risk Scores (FGRS).

We examined, in individuals born in Sweden 1940–2003, whether AAO for five primary disorders -- drug use disorder (DUD), alcohol use disorder (AUD), major depression (MD), bipolar disorder (BD), and schizophrenia (SZ)-- was associated with varying levels of GRRs with a range of informative secondary disorders and traits.

Our disorders displayed a varying pattern of change of GRRs with increasing AAO. At one end was SZ, where all GRRs rose with increasing AAO meaning that SZ became increasing genetically heterogeneous with later AAO. The most balanced disorder was AUD where, with increasing AAO, GRRs rose for AD, BD, and MD and declined for DUD, CB, and ADHD. That is, at young AAO, AUD had high levels of genetic risk for other externalizing disorders while at older AAO, high genetic risk for internalizing disorders were more prominent. MD was at the continuum's other end where all GRRs, except for AD, decreased with higher AAO, meaning that MD became increasingly genetically homogeneous with later AAO.

Genetic heterogeneity was robustly associated with AAO across our five primary disorders with substantial inter-disorder differences in the observed patterns. In particular, young AAO was associated with maximal genetic homogeneity for SZ and DUD while older AAO had greater genetic homogeneity for MD with AUD falling in between.

The concept of schizotypal personality disorder (SPD) emerged from observations of personality characteristics common in relatives of schizophrenic patients. While often studied in family designs, few studies and none with genetic measures, have examined SPD in epidemiological samples.

We studied individuals born in Sweden 1940–2000 with an ICD-10 diagnosis of SPD with no prior schizophrenia (SZ) diagnosis (n = 2292). Demographic features, patterns of comorbidity, and Family Genetic Risk Scores (FGRS) were assessed from multiple Swedish registries. Prediction of progression to SZ was assessed by Cox models.

SPD was rare, with a prevalence of 0.044%, and had high levels of comorbidity with autism spectrum disorder (ASD), OCD, ADHD, and major depression (MD), and increased rates of being single, unemployed and in receipt of welfare. Affected individuals had elevated levels of FGRS for SZ (+0.42), ASD (+0.30), MD (+0.29), and ADHD (+0.20). Compared to cases of schizophrenia, they had significantly lower rates of FGRSSZ, but significantly elevated rates of genetic risk for ASD, MD, and ADHD. Over a mean follow-up of 8.7 years, 14.6% of SPD cases received a first diagnosis of SZ, the risk for which was significantly increased by levels of FGRSSZ, male sex, young age at SPD diagnosis and an in-patient SPD diagnosis and significantly decreased by comorbidity with MD, ASD, and ADHD.

Our results not only support the designation of SPD as a schizophrenia spectrum disorder but also suggest potentially important etiologic links between SPD and ASD and, to a lesser extent, ADHD, OCD, and MD.

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.

To determine whether genetic risk factors for major depression (MD) and alcohol use disorder (AUD) interact with a potent stressor – death of spouse, parent, and sibling – in predicting episodes of, respectively, MD and AUD.

MD and AUD registrations were assessed from national Swedish registries. In individuals born in Sweden 1960–1970, we identified 7586, 388 459, and 34 370 with the loss of, respectively, a spouse, parent, and sibling. We started following subjects at age 18 or the year 2002 with end of follow-up in 2018. We examined time to event – a registration for MD within 6 months or AUD within a year – on an additive scale, using the Nelson–Aalen estimator. Genetic risk was assessed by the Family Genetic Risk Score (FGRS).

In separate models controlling for the main effects of death of spouse, parent, and sibling, FGRS, and sex, significant interactions were seen in all analyses between genetic risk for MD and death of relative in prediction of subsequent MD registration. A similar pattern of results, albeit with weaker interaction effects, was seen for genetic risk for AUD and risk for AUD registration. Genetic risk for bipolar disorder (BD) and anxiety disorders (AD) also interacted with event exposure in predicting MD.

Genetic risk for both MD and AUD act in part by increasing the sensitivity of individuals to the pathogenic effects of environmental stressors. For prediction of MD, similar effects are also seen for genetic risk for AD and BD.

Prior research has reported an association between divorce and suicide attempt. We aimed to clarify this complex relationship, considering sex differences, temporal factors, and underlying etiologic pathways.

We used Swedish longitudinal national registry data for a cohort born 1960–1990 that was registered as married between 1978 and 2018 (N = 1 601 075). We used Cox proportional hazards models to estimate the association between divorce and suicide attempt. To assess whether observed associations were attributable to familial confounders or potentially causal in nature, we conducted co-relative analyses.

In the overall sample and in sex-stratified analyses, divorce was associated with increased risk of suicide attempt (adjusted hazard ratios [HRs] 1.66–1.77). Risk was highest in the year immediately following divorce (HRs 2.20–2.91) and declined thereafter, but remained elevated 5 or more years later (HRs 1.41–1.51). Divorcees from shorter marriages were at higher risk for suicide attempt than those from longer marriages (HRs 3.33–3.40 and 1.20–1.36, respectively). In general, HRs were higher for divorced females than for divorced males. Co-relative analyses suggested that familial confounders and a causal pathway contribute to the observed associations.

The association between divorce and risk of suicide attempt is complex, varying as a function of sex and time-related variables. Given evidence that the observed association is due in part to a causal pathway from divorce to suicide attempt, intervention or prevention efforts, such as behavioral therapy, could be most effective early in the divorce process, and in particular among females and those whose marriages were of short duration.

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.

To determine, in a general population, how much rates of stress reactions (SR), major depression (MD), alcohol-use disorder (AUD) and drug-use disorder (DUD) increase after the death of close relatives.

SR, MD, AUD, and DUD registrations were assessed from national Swedish registries. From the population followed from 2000 to 2018, those exposed to death of a close relative in 2002–2016 were matched to unexposed controls and analyzed in males and females by a controlled pre-post design using a difference-in-difference method.

Substantial, brief increases in risk for SR and more modest prolonged increases in MD were observed after death of relatives in both men and women greatest with children, followed by spouses, parents, and siblings. Relatively long-lasting modest increases in AUD but not DUD were also observed following death of relatives. The absolute increases for SR and MD were greater in females than males and for AUD greater in males than females. However, logistic regression analyses showed most effects did not differ significantly by sex. Consistently larger increases in disorder risk were seen with the death of younger v. older parents, siblings, and spouses and with accidental v. non-accidental death in children.

Applying a matched cohort design to Swedish population registries, death of close relatives was associated with, and likely caused, substantial increases in rates of SR, MD, and AUD, consistent with smaller prior clinical investigations. Through such registries, we can, in large representative samples, integrate the impact of exposures to selected environmental adversities into disorder risk pathways.

To clarify, in a national sample, associations between risk for seven psychiatric and substance use disorders and five key transitions in Sweden's public educational system.

Swedish-born individuals (1972–1995, N = 1 997 910) were followed through 12-31-2018, at mean age 34.9. We predicted, from these educational transitions, risk for major depression (MD), obsessive-compulsive disorder (OCD), bipolar disorder (BD), schizophrenia (SZ), anorexia nervosa (AN), alcohol use disorder (AUD), and drug use disorder (DUD), assessed from Swedish national registers, by Cox regression, censoring individuals with onsets ⩽17. We also predicted risk from the deviation of grades from family-genetic expectations (deviation 1) and from changes in grades from ages 16 to 19 (deviation 2).

We observed four major risk patterns across transitions in our disorders: (i) MD and BD, (ii) OCD and SZ, (iii) AUD and DUD, and (iv) AN. Failing early educational transitions had the greatest impact on risk for OCD and SZ while for other disorders, not progressing from basic to upper high school had the largest effect. Completing vocational v. college-prep upper high school was strongly associated with risk for AUD and DUD, had little relation with MD, OCD, BD, and SZ risk, and was protective for AN. Deviation 1 predicted risk most strongly for SZ, AN, and MD. Deviation 2 predicted risk most strongly for SZ, AUD, and DUD.

The pattern of educational transitions and within family and within person development deviations are strongly and relatively specifically associated with future risk for seven psychiatric and substance-use disorders.

We need to better understand the frequency and predictors of opioid use disorder (OUD) after first opioid prescription (OP).

We followed 1 516 392 individuals from the Swedish population born 1980–2000, from 1 July 2007, until 31 Dec 2017. We examined putative risk predictors with univariable and multivariable Cox Models and the potential causal effects of predictors by propensity score and co-sibling analyses.

Of the individuals in our cohort, 24.8% (375 404) received a first OP, of whom 3034 (0.90%) developed a subsequent first OUD. The hazard ratio (HR) (± 95% CIs) for OUD after OP equaled 7.10 (6.75–7.46), with a mean time to onset of 3.41 (2.39) years. The strongest putative risk factors for development of OUD after OP were prior psychiatric and substance use disorders, criminal behavior, parental divorce/death, poor school performance, current community deprivation, divorce, and male sex. Few predictors differed across sexes. OP renewal was associated with a HR of 3.66 (3.41–3.93) for OUD. Co-sibling and propensity score analyses suggested that at least a moderate proportion of the risk factor-OUD association was likely causal. A risk score to predict OUD after OP had an AUC of 0.85, where nearly 60% of cases scoring in the top decile.

In a general population sample, an OP represents a substantial risk factor for subsequent OUD. Many of the risk factors for OUD after OP can be readily assessed at the time of potential OP, permitting clinicians to evaluate the risk of iatrogenic OUD.

Suicidal behavior and substance use disorders (SUDs) are important public health concerns. Prior suicide attempts and SUDs are two of the most consistent predictors of suicide death, and clarifying the role of SUDs in the transition from suicide attempt to suicide death could inform prevention efforts.

We used national Swedish registry data to identify individuals born 1960–1985, with an index suicide attempt in 1997–2017 (N = 74 873; 46.7% female). We assessed risk of suicide death as a function of registration for a range of individual SUDs. We further examined whether the impact of SUDs varied as a function of (i) aggregate genetic liability to suicidal behavior, or (ii) age at index suicide attempt.

In univariate models, risk of suicide death was higher among individuals with any SUD registration [hazard ratios (HRs) = 2.68–3.86]. In multivariate models, effects of specific SUDs were attenuated, but remained elevated for AUD (HR = 1.86 95% confidence intervals 1.68–2.05), opiates [HR = 1.58 (1.37–1.82)], sedatives [HR = 1.93 (1.70–2.18)], and multiple substances [HR = 2.09 (1.86–2.35)]. In secondary analyses, the effects of most, but not all, SUD were exacerbated by higher levels of genetic liability to suicide death, and among individuals who were younger at their index suicide attempt.

In the presence of a strong predictor of suicide death – a prior attempt – substantial predictive power is still attributable to SUDs. Individuals with SUDs may warrant additional suicide screening and prevention efforts, particularly in the context of a family history of suicidal behavior or early onset of suicide attempt.

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.

The authors sought to clarify the impact of spousal psychiatric disorders of differing severity [major depression or anxiety disorders (DAD) v. bipolar disorder or nonaffective psychosis (BPN)] on proband risk for alcohol use disorder (AUD) during marriage.

In a Swedish cohort (N = 744 628), associations between spousal DAD and BPN and proband AUD were estimated with Cox proportional hazards; associations between parental AUD, proband premarital AUD, and spousal lifetime DAD and BPN were estimated with logistic regression; and whether spousal DAD or BPN causally increased risk for AUD was evaluated with frailty models.

Spousal premarital DAD, spousal marital-onset DAD, and spousal BPN (premarital or marital-onset) were associated with proband AUD during marriage [hazard ratios (HR) range 1.44–3.72]. Those with a parental or premarital history of AUD (v. without) were more likely to marry a spouse with DAD or BPN (odds ratios 1.22–2.77). Moving from an unaffected first spouse to a DAD-affected second spouse increased AUD risk in males (HR 2.90). Moving from an unaffected first spouse to a BPN-affected second spouse increased AUD risk (HRmales 3.96; HRfemales 5.64). Moving to an unaffected second spouse from a DAD-affected first spouse decreased AUD risk, with stronger evidence in females compared to males (HRmales 0.59; HRfemales 0.28).

Associations between spousal DAD or BPN and proband AUD reflect both selection and causal effects. Marriage to a BPN-affected spouse has a particularly strong effect on AUD risk, with more modest effects for spousal DAD.

Despite a large descriptive literature linking creativity and risk for psychiatric illness, the magnitude and specificity of this relationship remain controversial.

We examined, in 1 137 354 native Swedes with one of 59 3-digit official and objective occupational codes in managerial and educated classes, their familial genetic risk score (FGRS) for ten major disorders, calculated from 1st through 5th degree relatives. Mean FGRS across disorders were calculated, in 3- and 4-digit occupational groups, and then controlled for those whose disorder onset preceded occupational choice. Using sequential analyses, p values were evaluated using Bonferroni correction.

3-digit professions considered to reflect creativity (e.g. ‘artists’ and ‘authors’) were among those with statistically significant elevations of FGRS. Among more specific 4-digit codes, visual artists, actors, and authors stood out with elevated genetic risks, highest for major depression (MD), anxiety disorders (AD) and OCD, more modest for bipolar disorders (BD) and schizophrenia and, for authors, for drug and alcohol use disorders. However, equal or greater elevations in FGRS across disorders were seen for religious (e.g. ministers), helping (e.g. psychologists, social workers), and teaching/academic occupations (e.g. professors). The potential pathway from FGRS → Disorder → Occupation accounts for a modest proportion of the signal, largely for MD and AD risk.

While traditional creative occupations were associated with elevated genetic risk for a range of psychiatric disorders, this association was not unique, as similar, or greater elevations were seen for religious, helping and teaching professions and was stronger for internalizing than psychotic disorders.

Functional somatic disorders (FSD) feature medical symptoms of unclear etiology. Attempts to clarify their origin have been hampered by a lack of rigorous research designs. We sought to clarify the etiology of the FSD by examining the genetic risk patterns for FSD and other related disorders.

This study was performed in 5 829 186 individuals from Swedish national registers. We quantified familial genetic risk for FSD, internalizing disorders, and somatic disorders in cases of chronic fatigue syndrome (CFS), fibromyalgia (FM), and irritable bowel syndrome (IBS), using a novel method based on aggregate risk in first to fifth degree relatives, adjusting for cohabitation. We compared these profiles with those of a prototypic internalizing psychiatric – major depression (MD) – and a somatic/autoimmune disorder: rheumatoid arthritis (RA).

Patients with FM carry substantial genetic risks not only for FM, but also for pain syndromes and internalizing, autoimmune and sleep disorders. The genetic risk profiles for IBS and CFS are also widely distributed although with lower average risks. By contrast, genetic risk profiles of MD and RA are much more restricted to related conditions.

Patients with FM have a relatively unique family genetic risk score profile with elevated genetic risk across a range of disorders that differs markedly from the profiles of a classic autoimmune disorder (RA) and internalizing disorder (MD). A similar less marked pattern of genetic risks was seen for IBS and CFS. FSD arise from a distinctive pattern of genetic liability for a diversity of psychiatric, autoimmune, pain, sleep, and functional somatic disorders.

Do genetic risk profiles for drug use disorder (DUD), major depression (MD), and attention-deficit hyperactivity disorder (ADHD) differ substantially as a function of sex, age at onset (AAO), recurrence, mode of ascertainment, and treatment?

Family genetic risk scores (FGRS) for MD, anxiety disorders, bipolar disorder, schizophrenia, alcohol use disorder, DUD, ADHD, and autism-spectrum disorder were calculated from 1st–5th degree relatives in the Swedish population born 1932–1995 (n = 5 829 952). Profiles of these FGRS were obtained and compared across various subgroups of DUD, MD, and ADHD cases.

Differences in FGRS profiles for DUD, MD, and ADHD by sex were modest, but they varied substantially by AAO, recurrence, ascertainment, and treatment with scores typically higher in cases with greater severity (e.g. early AAO, high recurrence, ascertainment in high intensity clinical settings, and treatment). However, severity was not always related to purer genetic profiles, as genetic risk for many disorders often increased together. However, some results, such as by mode of ascertainment from different Swedish registries, produced qualitative differences in FGRS profiles.

Differences in FGRS profiles for DUD, MD, and ADHD varied substantially by AAO, recurrence, ascertainment, and treatment. Replication of psychiatric studies, particularly those examining genetic factors, may be difficult unless cases are matched not only by diagnosis but by important clinical characteristics. Genetic correlations between psychiatric disorders could arise through one disorder impacting on the patterns of ascertainment for the other, rather than from the direct effects of shared genetic liabilities.

Does the genetic aptitude for educational attainment (GAEA) moderate the genetic risk for alcohol use disorder (AUD) and drug use disorder (DUD)?

In the native Swedish population, born 1960–1980 and followed through 2017 (n = 1 862 435), the family genetic risk score (FGRS) for AUD and DUD and GAEA were calculated from, respectively, the educational attainment and risk for AUD and DUD, of 1st through 5th degree relatives from Swedish national registers. Analyses utilized Aalen's linear hazards models.

Risk for AUD was robustly predicted by the main effects of FGRSAUD [b = 6.32 (95% CI 6.21–6.43), z = 64.9, p < 0.001) and GAEA [b = −2.90 (2.83–2.97), z = 44.1, p < 0.001] and their interaction [b = −1.93 (1.83–2.03), z = 32.9, p < 0.001]. Results were similar for the prediction of DUD by the main effects of FGRSDUD [b = 4.65 (CI 4.56–4.74), z = 59.4, p < 0.001] and GAEA [−2.08 (2.03–2.13), z = 46.4, p < 0.001] and their interaction [b = −1.58 (1.50–1.66)), z = 30.2, p < 0.001]. The magnitude of the interactions between GAEA and FGRSAUD and FGRSDUD in the prediction of, respectively, AUD and DUD was attenuated only slightly by the addition of educational attainment to the model.

The genetic propensity to high educational attainment robustly moderates the genetic risk for both AUD and DUD such that the impact of the genetic liability to AUD and DUD on the risk of illness is substantially attenuated in those with high v. low GAEA. This effect is not appreciably mediated by the actual level of educational attainment. These naturalistic findings could form the basis of prevention efforts in high-risk youth.