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BackgroundStudies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds.MethodsWe examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes.ResultsIn COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47-0.68%, p = 2.0 × 10-8-1.0 × 10-10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10-8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10-6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10-11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10-7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10-16).ConclusionsAUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.

BACKGROUND: The Psychiatric Genomics Consortium (PGC) has made major advances in the molecular etiology of MDD, confirming that MDD is highly polygenic. Pathway enrichment results from PGC meta-analyses can also be used to help inform molecular drug targets. Prior to any knowledge of molecular biomarkers for MDD, drugs targeting molecular pathways (MPs) proved successful in treating MDD. It is possible that examining polygenicity within specific MPs implicated in MDD can further refine molecular drug targets. METHODS: Using a large case-control GWAS based on low-coverage whole genome sequencing (N = 10 640) in Han Chinese women, we derived polygenic risk scores (PRS) for MDD and for MDD specific to each of over 300 MPs previously shown to be relevant to psychiatric diagnoses. We then identified sets of PRSs, accounting for critical covariates, significantly predictive of case status. RESULTS: Over and above global MDD polygenic risk, polygenic risk within the GO: 0017144 drug metabolism pathway significantly predicted recurrent depression after multiple testing correction. Secondary transcriptomic analysis suggests that among genes in this pathway, CYP2C19 (family of Cytochrome P450) and CBR1 (Carbonyl Reductase 1) might be most relevant to MDD. Within the cases, pathway-based risk was additionally associated with age at onset of MDD. CONCLUSIONS: Results indicate that pathway-based risk might inform etiology of recurrent major depression. Future research should examine whether polygenicity of the drug metabolism gene pathway has any association with clinical presentation or treatment response. We discuss limitations to the generalizability of these preliminary findings, and urge replication in future research.

Background: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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). Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background. This review tackles the question: 'Is bereavement related depression (BRD) the same or different from standard (non-bereavement-related) major depression (SMD)?' To answer this question, we examined published data on key characteristics that define and characterize SMD to assess whether they also characterize BRD.Method. We searched all English-language reports in Medline up to November 2006 to identify relevant studies. Bibliographies of located articles were searched for additional studies.Results. Consistent with the position that BRD is distinct from SMD, some, but not all, studies report that men are as likely as women to have BRD and that past or family histories of SMD do not predict BRD. With greater consistency, studies suggest that, like SMD, BRD is: more common in younger than in older adults, predicated by poor health or low social support, followed by recurrent episodes of major depressive episode (MDE), and associated with impaired immunological responses, altered sleep architecture, and responsivity to antidepressant treatment.Conclusions. Overall, the prevailing evidence more strongly supports similarities than differences between BRD and SMD. Because so few studies focus on BRD occurring within the first 2 months of bereavement, the period identified by the DSM to exclude the diagnosis of MDE, more research is needed specifically on this group to help us evaluate the validity of this important diagnostic convention.

Background: 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. Methods: 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). Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusions: Family history of BD, inpatient treatment, and psychotic symptoms were the strongest predictors of conversion from MD to BD. [ABSTRACT FROM AUTHOR]

Background: We need to better understand the frequency and predictors of opioid use disorder (OUD) after first opioid prescription (OP). Methods: 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. Result: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) is one of the growing human mental health challenges facing the global health care system. In this study, the structural connectivity between symptoms of MDD is explored using two different network modeling approaches. Methods: Data are from 'the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders (VATSPSUD)'. A cohort of N = 2163 American Caucasian female-female twins was assessed as part of the VATSPSUD study. MDD symptoms were assessed using personal structured clinical interviews. Two network analyses were conducted. First, an undirected network model was estimated to explore the connectivity between the MDD symptoms. Then, using a Bayesian network, we computed a directed acyclic graph (DAG) to investigate possible directional relationships between symptoms. Results: Based on the results of the undirected network, the depressed mood symptom had the highest centrality value, indicating its importance in the overall network of MDD symptoms. Bayesian network analysis indicated that depressed mood emerged as a plausible driving symptom for activating other symptoms. These results are consistent with DSM-5 guidelines for MDD. Also, somatic weight and appetite symptoms appeared as the strongest connections in both networks. Conclusions: We discuss how the findings of our study might help future research to detect clinically relevant symptoms and possible directional relationships between MDD symptoms defining major depression episodes, which would help identify potential tailored interventions. This is the first study to investigate the network structure of VATSPSUD data using both undirected and directed network models. [ABSTRACT FROM AUTHOR]

Background: Among individuals with alcohol use disorder (AUD) and drug use disorder (DUD), is their genetic liability and its specificity moderated by substance availability? Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: Despite a large descriptive literature linking creativity and risk for psychiatric illness, the magnitude and specificity of this relationship remain controversial. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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). Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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). Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: 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? Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: Does the genetic aptitude for educational attainment (GAEA) moderate the genetic risk for alcohol use disorder (AUD) and drug use disorder (DUD)? Methods: 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. Results: 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. Conclusions and relevance: 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. [ABSTRACT FROM AUTHOR]

Background: – 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. Methods: – 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. Results: – 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. Conclusions: – 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. [ABSTRACT FROM AUTHOR]

Background: Previous studies have demonstrated substantial associations between substance use disorders (SUD) and suicidal behavior. The current study empirically assesses the extent to which shared genetic and/or environmental factors contribute to associations between alcohol use disorders (AUD) or drug use disorders (DUD) and suicidal behavior, including attempts and death. Methods: The authors used Swedish national registry data, including medical, pharmacy, criminal, and death registrations, for a large cohort of twins, full siblings, and half siblings (N = 1 314 990) born 1960–1980 and followed through 2017. They conducted twin-sibling modeling of suicide attempt (SA) or suicide death (SD) with AUD and DUD to estimate genetic and environmental correlations between outcomes. Analyses were stratified by sex. Results: Genetic correlations between SA and SUD ranged from rA = 0.60–0.88; corresponding shared environmental correlations were rC = 0.42–0.89 but accounted for little overall variance; and unique environmental correlations were rE = 0.42–0.57. When replacing attempt with SD, genetic and shared environmental correlations with AUD and DUD were comparable (rA = 0.48–0.72, rC = 0.92–1.00), but were attenuated for unique environmental factors (rE = −0.01 to 0.31). Conclusions: These findings indicate that shared genetic and unique environmental factors contribute to comorbidity of suicidal behavior and SUD, in conjunction with previously reported causal associations. Thus, each outcome should be considered an indicator of risk for the others. Opportunities for joint prevention and intervention, while limited by the polygenic nature of these outcomes, may be feasible considering moderate environmental correlations between SA and SUD. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: How does genetic liability to suicide attempt (SA), suicide death (SD), major depression (MD), bipolar disorder (BD), schizophrenia (SZ), alcohol use disorder (AUD), and drug use disorder (DUD) impact on risk for SA and SD? Methods: In the Swedish general population born 1932–1995 and followed through 2017 (n = 7 661 519), we calculate family genetic risk scores (FGRS) for SA, SD, MD, BD, SZ, AUD, and DUD. Registration for SA and SD was assessed from Swedish national registers. Results: In univariate and multivariate models predicting SA, FGRS were highest for SA, AUD, DUD, and MD. In univariate models predicting SD, the strongest FGRS were AUD, DUD, SA, and SD. In multivariate models, the FGRS for SA and AUD were higher in predicting SA while the FGRS for SD, BD, and SZ were higher in predicting SD. Higher FGRS for all disorders significantly predicted both younger age at first SA and frequency of attempts. For SD, higher FGRS for MD, AUD, and SD predicted later age at SD. Mediation of FGRS effects on SA and SD was more pronounced for SD than SA, strongest for AUD, DUD, and SZ FGRS and weakest for MD. Conclusions: FGRS for both SA and SD and for our five psychiatric disorders impact on risk for SA and SD in a complex manner. While some of the impact of genetic risk factors for psychiatric disorders on risk for SA and SD is mediated through developing the disorders, these risks also predispose directly to suicidal behaviors. [ABSTRACT FROM AUTHOR]

Background: Most epidemiological studies show a decrease of internalizing disorders at older ages, but it is unclear how the prevalence exactly changes with age, and whether there are different patterns for internalizing symptoms and traits, and for men and women. This study investigates the impact of age and sex on the point prevalence across different mood and anxiety disorders, internalizing symptoms, and neuroticism. Methods: We used cross-sectional data on 146 315 subjects, aged 18–80 years, from the Lifelines Cohort Study, a Dutch general population sample. Between 2012 and 2016, five current internalizing disorders – major depression, dysthymia, generalized anxiety disorder, social phobia, and panic disorder – were assessed according to DSM-IV criteria. Depressive symptoms, anxiety symptoms, neuroticism, and negative affect (NA) were also measured. Generalized additive models were used to identify nonlinear patterns across age, and to investigate sex differences. Results: The point prevalence of internalizing disorders generally increased between the ages of 18 and 30 years, stabilized between 30 and 50, and decreased after age 50. The patterns of internalizing symptoms and traits were different. NA and neuroticism gradually decreased after age 18. Women reported more internalizing disorders than men, but the relative difference remained stable across age (relative risk ~1.7). Conclusions: The point prevalence of internalizing disorders was typically highest between age 30 and 50, but there were differences between the disorders, which could indicate differences in etiology. The relative gap between the sexes remained similar across age, suggesting that changes in sex hormones around the menopause do not significantly influence women's risk of internalizing disorders. [ABSTRACT FROM AUTHOR]

Background: Few factor analyses and no network analyses have examined the structure of DSM phobic fears or tested the specificity of the relationship between panic disorder and agoraphobic fears. Methods: Histories of 21 lifetime phobic fears, coded as four-level ordinal variables (no fear to fear with major interference) were assessed at personal interview in 7514 adults from the Virginia Twin Registry. We estimated Gaussian Graphical Models on individual phobic fears; compared network structures of women and men using the Network Comparison Test; used community detection to determine the number and nature of groups in which phobic fears hang together; and validated the anticipated specific relationship between panic disorder and agoraphobia. Results: All networks were densely and positively inter-connected; networks of women and men were structurally similar. Our most frequent and stable solution identified four phobic clusters: (i) blood-injection, (ii) social-agoraphobia, (iii) situational, and (iv) animal-disease. Fear of public restrooms and of diseases clustered with animal and not, respectively, social and blood-injury phobias. When added to the network, the three strongest connections with lifetime panic disorder were all agoraphobic fears: being in crowds, going out of the house alone, and being in open spaces Conclusions: Using network analyses applied to a large epidemiologic twin sample, we broadly validated the DSM-IV typography but did not entirely support the distinction of agoraphobic and social phobic fears or the DSM placements for fears of public restrooms and diseases. We found strong support for the specificity of the relationship between panic disorder and agoraphobic fears. [ABSTRACT FROM AUTHOR]

Background: Oral contraceptive use has been previously associated with an increased risk of suicidal behavior in some, but not all, samples. The use of large, representative, longitudinally-assessed samples may clarify the nature of this potential association. Methods: We used Swedish national registries to identify women born between 1991 and 1995 (N = 216 702) and determine whether they retrieved prescriptions for oral contraceptives. We used Cox proportional hazards models to test the association between contraceptive use and first observed suicidal event (suicide attempt or death) from age 15 until the end of follow-up in 2014 (maximum age 22.4). We adjusted for covariates, including mental illness and parental history of suicide. Results: In a crude model, use of combination or progestin-only oral contraceptives was positively associated with suicidal behavior, with hazard ratios (HRs) of 1.73–2.78 after 1 month of use, and 1.25–1.82 after 1 year of use. Accounting for sociodemographic, parental, and psychiatric variables attenuated these associations, and risks declined with increasing duration of use: adjusted HRs ranged from 1.56 to 2.13 1 month beyond the initiation of use, and from 1.19 to 1.48 1 year after initiation of use. HRs were higher among women who ceased use during the observation period. Conclusions: Young women using oral contraceptives may be at increased risk of suicidal behavior, but risk declines with increased duration of use. Analysis of former users suggests that women susceptible to depression/anxiety are more likely to cease hormonal contraceptive use. Additional studies are necessary to determine whether the observed association is attributable to a causal mechanism. [ABSTRACT FROM AUTHOR]