A Swedish population-based study to evaluate the usefulness of resting heart rate in the prediction of suicidal behavior among males.

INTRODUCTION: Resting heart rate has been distinctly related to both internalizing (high pulse) and externalizing (low pulse) disorders. We aimed to explore the associations between resting heart rate and suicidal behavior (nonfatal suicide attempt [SA] and suicide death [SD]) and evaluate if such associations exist beyond the effects of internalizing/externalizing symptomatology. METHOD: We used Cox proportional hazards models to evaluate the associations between resting heart rate (age 19) and later SA/SD in 357,290 Swedish men. Models were controlled for internalizing disorders, externalizing disorders, and resilience (the ability to deal with adversity). Co-relative analysis (comparing pairs of different genetic relatedness) was used to control for unmeasured family confounders and improve causal inference. RESULTS: In baseline models, low resting heart rate was associated with SA (HR = 0.96; 95% CI: 0.95,0.98) and high resting heart rate with SD (HR = 1.04; 95% CI: 1.002,1.07). The association with SA remained after adjustment for all confounders (HR = 0.98). However, the association with SD did not persist after controlling for covariates. Co-relative analysis did not support causal associations. CONCLUSIONS: Our findings raise interesting etiological questions for the understanding of suicidal behaviors but do not support the usefulness of resting heart rate in suicide prediction.

The predictive effect of family genetic risk scores as an indirect measure of causal effects of one disorder on another.

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.

The genetic epidemiology of schizotypal personality disorder.

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.

Mediational pathways between aggregate genetic liability and nonfatal suicide attempt: A Swedish population-based cohort.

Despite recent progress in the genetics of suicidal behavior, the pathway by which genetic liability increases suicide attempt risk is unclear. We investigated the mediational pathways from family/genetic risk for suicide attempt (FGRSSA ) to suicide attempt by considering the roles of psychiatric illnesses. In a Swedish cohort, we evaluated time to suicide attempt as a function of FGRSSA and the mediational effects of alcohol use disorder, drug use disorder, attention-deficit/hyperactivity disorder, major depression, anxiety disorder, bipolar disorder, and non-affective psychosis. Analyses were conducted by sex in three age periods: 15-25 years (Nfemales = 850,278 and Nmales = 899,366), 26-35 years (Nfemales = 800,189 and Nmales = 861,774), and 36-45 years (Nfemales = 498,285 and Nmales = 535,831). The association between FGRSSA and suicide attempt was mediated via psychiatric disorders. The highest mediation effects were observed for alcohol use disorder in males (15-25 years, HRtotal = 1.60 [1.59; 1.62], mediation = 14.4%), drug use disorder in females (25-36 years, HRtotal = 1.46 [1.44; 1.49], mediation = 11.2%), and major depression (25-36 years) in females (HRtotal = 1.46 [1.44; 1.49], mediation = 7%) and males (HRtotal = 1.50 [1.47;1.52], mediation = 4.7%). While the direct effect of FGRSSA was higher at ages of 15-25, the mediation via psychiatric disorders was more prominent in later adulthood. Our study informs about the psychiatric illnesses via which genetic liability operates to impact suicide attempt risk, with distinct contributions according to age and sex.

Clarifying the relationship between physical injuries and risk for suicide attempt in a Swedish national sample.

INTRODUCTION: The Interpersonal-Psychological Theory of Suicide proposes that capability for suicide is acquired through exposure to painful and provocative events (PPEs). Although there is robust evidence for a positive association between aggregate measures of PPEs and risk for suicidal behavior, little is known about the contributions of physical injuries. The present study investigated the relationship between injuries and risk of subsequent suicide attempt (SA). METHODS: Data were from Swedish population-based registers. All individuals born in Sweden between 1970 and 1990 were included (N = 1,011,725 females and 1,067,709 males). We used Cox regression models to test associations between 10 types of injuries (eye injury; fracture; dislocation/sprain/strain; injury to nerves and spinal cord; injury to blood vessels; intracranial injury; crushing injury; internal injury; traumatic amputation; and other or unspecified injuries) and risk for later SA. Analyses were stratified by sex and adjusted for year of birth and parental education. Additional models tested for differences in the pattern of associations based on age group and genetic liability for SA. In co-relative models, we tested the association between each injury type and risk for SA in relative pairs of varying genetic relatedness to control for unmeasured familial confounders. RESULTS: All 10 injury types were associated with elevated risk for SA (hazard ratios [HRs] = 1.2-7.0). Associations were stronger in the first year following an injury (HRs = 1.8-7.0), but HRs remained above 1 more than 1 year after injury exposure (HRs = 1.2-2.6). The strength of associations varied across injury type, sex, age, and genetic liability for SA. For example, the magnitude of the association between crushing injury and risk for SA was larger in females than males, whereas other injuries showed a similar pattern of associations across sex. Moreover, there was evidence to support positive additive interaction effects between several injury types and aggregate genetic liability for SA (relative excess risk due to interaction [RERI] = 0.1-0.3), but the majority of these interactions became non-significant or changed direction after accounting for comorbid psychiatric and substance use disorders. In co-relative models, the pattern of associations differed by injury type, such that there was evidence to support a potential causal effect of eye injury, fracture, dislocation/sprain/strain, intracranial injury, and other and unspecified injuries on risk for SA. For the remaining injury types, HRs were not significantly different from 1 in monozygotic twins, which is consistent with confounding by familial factors. CONCLUSIONS: Injuries are associated with increased risk for subsequent SA, particularly in the first year following an injury. While genetic and familial environmental factors may partly explain these associations, there is also evidence to support a potential causal effect of several injury types on future risk for SA.

Risk for psychiatric and substance use disorders as a function of transitions in Sweden's public educational system: a national study.

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.

The risk for venous thromboembolism and cardiometabolic disorders in offspring from thrombosis-prone pedigrees.

BACKGROUND: Most family studies on venous thromboembolism (VTE) have focused on first-degree relatives. OBJECTIVES: We took a pedigree-based approach and examined the risk of VTE and cardiometabolic disorders in offspring from extended pedigrees according to the densities of VTE in pedigrees. METHODS: From the Swedish population, we identified a total of 482 185 pedigrees containing a mean of 14.2 parents, aunts/uncles, grandparents, and cousins of a core full sibship that we termed the pedigree offspring (n = 751 060). We then derived 8 empirical classes of these pedigrees based on the density of cases of VTE. The risk was determined in offspring for VTE and cardiometabolic disorders as a function of VTE density in their pedigrees. Bonferroni correction for multiple comparisons was performed. RESULTS: VTE was unevenly distributed in the population; the Gini coefficient was 0.59. Higher VTE density in pedigrees was associated in the offspring with a higher risk of different VTE manifestations (deep venous thrombosis, pulmonary embolism, pregnancy-related VTE, unusual thrombosis, and superficial thrombophlebitis), thrombophilia, and lower age of first VTE event. Moreover, VTE density in pedigrees was significantly associated in the offspring with obesity, diabetes, gout, varicose veins, and arterial embolism and thrombosis (excluding brain and heart). No significant associations were observed for retinal vein occlusion, hypercholesterolemia, hypertension, coronary heart disease, myocardial infarction, ischemic stroke, atrial fibrillation, heart failure, primary pulmonary hypertension, cerebral hemorrhage, aortic aneurysm, peripheral artery disease, and overall mortality. CONCLUSION: Offspring of pedigrees with a high density of VTE are disadvantaged regarding VTE manifestations and certain cardiometabolic disorders.

Risk of suicidal behavior as a function of alcohol use disorder typologies: A Swedish population-based study.

BACKGROUND AND AIMS: Alcohol use disorder (AUD) is one of the strongest predictors of suicidal behavior. Here, we measured risk of suicide attempt and death as a function of AUD typologies. DESIGN: We used AUD typologies from previous latent class analysis: (i) externalizing subtype (characterized by externalizing symptomatology and early age of onset; individuals in this group have lower education and higher familial/social difficulties); (ii) subtype described by minimal psychopathology; and (iii) internalizing subtype (characterized by internalizing symptomatology and later age of onset; individuals in this group have higher education). We used class membership to predict distal outcomes (attempt and death) and performed regressions to evaluate whether differences in suicidal behavior were explained by the group characteristics (sex, age of onset, number and type of AUD registrations, familial/genetic risk for AUD, externalizing and internalizing behaviors, socio-economic indicators, marital status and childhood family status). We also evaluated the effect of suicide attempt prior to AUD. SETTING AND PARTICIPANTS: Based on longitudinal Swedish registry data, we included 217 074 individuals with AUD born 1950-80. MEASUREMENTS: Suicide attempts were identified using medical registers and deaths using the mortality register. FINDINGS: Individuals with the externalizing subtype had higher risks of suicidal behavior than other groups [attempt: externalizing versus minimal psychopathology: odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.35, 1.35; externalizing versus internalizing: OR = 1.47, 95% CI = 1.46, 1.48; death: externalizing versus minimal psychopathology: OR = 1.57, 95% CI = 1.57, 1.58; externalizing versus internalizing: OR = 1.99, 95% CI = 1.93, 2.06]. Individuals with minimal psychopathology had higher risks than those with internalizing symptomatology (attempt: OR = 1.09, 95% CI = 1.08, 1.10, death: OR = 1.26, 95% CI = 1.23, 1.30). These differences were explained by age at registration and were related to the number of registrations, sex, education, family disruption and suicide attempt prior to AUD. CONCLUSIONS: Among people in Sweden, considering alcohol use disorder (AUD) heterogeneity appears to be a meaningful way to evaluate suicide risk. The highest risk of suicide attempt and death occurs in the externalizing subtype of AUD, followed by the minimal psychopathology subtype, and then the internalizing subtype.

Divorce and risk of suicide attempt: a Swedish national study.

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.

The relationship between familial-genetic risk and pharmacological treatment in a Swedish national sample of patients with major depression, bipolar disorder, and schizophrenia.

Using Swedish registers, we examine whether the prescription of and the response to antidepressants (AD), mood stabilizers (MS), and antipsychotics (AP) in the treatment of, respectively, major depression (MD), bipolar disorder (BD), and schizophrenia (SZ), are influenced by familial-genetic risk. We examined individuals born in Sweden 1960-1995 with a first diagnosis of MD (n = 257,177), BD (n = 23,032), and SZ (n = 4248) from 2006 to 2018. Drug classes and Defined Daily Dose (DDD) were obtained from the Pharmacy register using the Anatomical Therapeutic Chemical system. We utilized the Familial Genetic Risk Scores (FGRS) calculated from morbidity risks in first- through fifth degree relatives. Treatment with antidepressants (AD) in MD, mood-stabilizers (MS) in BD, and antipsychotics (AP) in SZ were associated with significantly higher disorder-specific familial-genetic risks. Using dosage trajectory analysis of AD, MS, and AP treatment for MD, BD, and SZ, respectively, familial-genetic risk was positively associated with higher and/or increasing drug dosages over time. For MD and BD, examining cases started on the most common pharmacologic treatment class (SSRIs for MD and "other anti-epileptics" for BD), familial-genetic risks were significantly lower in those who did not versus did later receive treatment from other AD and MS classes, respectively. Higher familial-genetic risk for BD predicted switching AD medication in cases of MD. Among pharmacologically treated cases of BD, familial-genetic risk was significantly higher for those treated with lithium. In a large population-based patient cohort, we found evidence of a wide-spread association between higher familial-genetic risk and i) increased likelihood of receiving pharmacologic treatment but 2) responding more poorly to it-as indicated by a switching of medications -- and/or requiring higher doses. Further investigations into the clinical utility of genetic risk scores in the clinical managements of MD, BD, and SZ are warranted.

Trajectories of primary health care utilization: a 10-year follow-up after the Swedish Patient Choice Reform of primary health care.

BACKGROUND: In January 2010, the choice reform was instituted in Swedish primary health care establishing free entry for private primary health care providers and enabling patients to choose freely among primary health care centers. The motivation behind the reform was to improve access to primary care and responsiveness to patient expectations. Reform effects on health care utilization have previously been investigated by using subgroup analyses assuming a pattern of homogeneous subgroups of the population. By using a different methodological approach, the aim of this study was to, from an equity perspective, investigate long term trends of primary health care utilization following the choice reform. METHOD: A closed cohort was created based on register data from Region Skåne, the third most populated region in Sweden, describing individuals' health care utilization between 2007-2017. Using a novel approach, utilization data, measured as primary health care visits, was matched with socioeconomic and geographic determinants, and analyzed using logistic regression models. RESULTS: A total of 659,298 individuals were included in the cohort. Sex differences in utilization were recorded to decrease in the older age group and to increase in the younger age group. Multivariable logistic regression showed increasing utilization in older men to be associated with higher socioeconomic position, while in women it was associated with lower socioeconomic position. Furthermore, groups of becoming high utilizers were all associated with lower socioeconomic position and with residence in urban areas. CONCLUSION: The impact of demographic, socioeconomic and geographic determinants on primary health care utilization varies in magnitude and direction between groups of the population. As a result, the increase in utilization as observed in the general population following the choice reform is unevenly distributed between different population groups.

Exposure to alcohol outlets and risk of suicidal behavior in a Swedish cohort of young adults.

BACKGROUND: Greater alcohol accessibility, for example in the form of a high density of alcohol outlets or low alcohol taxation rates, may be associated with increased risk of suicidal behavior. However, most studies have been conducted at the aggregate level, and some have not accounted for potential confounders such as socioeconomic position or neighborhood quality. METHODS: In a Swedish cohort of young adults aged 18 to 25, we used logistic regressions to evaluate whether living in a neighborhood that included bars, nightclubs, and/or government alcohol outlets was associated with risk of suicide attempt (SA) or suicide death (SD) during four separate 2-year observation periods. Neighborhoods were defined using pre-established nationwide designations. We conducted combined-sex and sex-stratified analyses, and included as covariates indicators of socioeconomic position, neighborhood deprivation, and aggregate genetic liability to suicidal behavior. RESULTS: Risk of SA was increased in some subsamples of individuals living in a neighborhood with a bar or government alcohol outlet (odds ratios [ORs] = 1.05 to 1.15). Risk of SD was also higher among certain subsamples living in a neighborhood with a government outlet (ORs = 1.47 to 1.56), but lower for those living near a bar (ORs = 0.89 to 0.91). Significant results were driven by, but not exclusive to, the male subsample. Individuals with higher aggregate genetic risk for SA were more sensitive to the effects of a neighborhood government alcohol outlet, pooled across observation periods, in analyses of the sexes combined (relative excess risk due to interaction [RERI] = 0.05; 95% confidence intervals [CI] 0.01; 0.09) and in the male subsample (RERI = 0.06; 95% CI 0.001; 0.12). CONCLUSIONS: Although effect sizes are small, living in a neighborhood with bars and/or government alcohol outlets may increase suicidal behavior among young adults. Individuals with higher genetic liability for SA are slightly more susceptible to these exposures.

Selecting cases of major psychiatric and substance use disorders in Swedish national registries on the basis of clinical features to maximize the strength or specificity of the genetic risk.

We investigate how selection of psychiatric cases by phenotypic criteria can alter the strength and specificity of their genetic risk by examining samples from national Swedish registries for five disorders: major depression (MD, N = 158,557), drug use disorder (DUD, N = 69,841), bipolar disorder (BD, N = 13,530)) ADHD (N = 54,996) and schizophrenia (N = 11,227)). We maximized the family genetic risk score (FGRS) for each disorder and then the specificity of the FGRS in six disorder pairs by univariable and multivariable regression. We use split-half methods to divide our cases for each disorder into deciles for prediction of genetic risk magnitude and quintiles for prediction of specificity by FGRS differences between two disorders. We utilized seven predictor groups: demography/sex, # registrations, site of diagnosis, severity, comorbidity, treatment, and educational/social variables. The ratio of the FGRS in the upper vs two lower deciles from our multivariable prediction model was, in order, DUD - 12.6, MD - 4.9, BD - 4.5, ADHD - 3.3 and schizophrenia 1.4. From the lowest to highest quintile, our measures of genetic specificity increased more than five-fold for i) MD vs. Anxiety Disorders, ii) MD vs BD, iii) MD versus alcohol use disorder (AUD), iv) BD vs schizophrenia and v) DUD vs AUD. This increase was nearly two-fold for ADHD vs DUD. We conclude that the level of genetic liability for our psychiatric disorders could be substantially enriched by selection of cases with our predictors. Specificity of genetic risk could also be substantially impacted by these same predictors.

The moderation of the genetic risk for alcohol and drug use disorders in a Swedish national sample by the genetic aptitude for educational attainment.

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.

Predictors of diagnostic conversion from major depression to bipolar disorder: a Swedish national longitudinal study.

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.

Workplace socioeconomic characteristics and coronary heart disease: a nationwide follow-up study.

OBJECTIVES: Important gaps in previous research include a lack of studies on the association between socioeconomic characteristics of the workplace and coronary heart disease (CHD).We aimed to examine two contextual factors in association with individuals' risk of CHD: the mean educational level of all employees at each individual's workplace (educationwork) and the neighbourhood socioeconomic characteristics of each individual's workplace (neighbourhood SESwork). DESIGN: Nationwide follow-up/cohort study. SETTING: Nationwide data from Sweden. PARTICIPANTS: All individuals born in Sweden from 1943 to 1957 were included (n=1 547 818). We excluded individuals with a CHD diagnosis prior to 2008 (n=67 619), individuals without workplace information (n=576 663), individuals lacking residential address (n=4139) and individuals who had unknown parents (n=7076). A total of 892 321 individuals were thus included in the study (426 440 men and 465 881 women). PRIMARY AND SECONDARY OUTCOME MEASURES: The outcome variable was incident CHD during follow-up between 2008 and 2012. The association between educationwork and neighbourhood SESwork and the outcome was explored using multilevel and cross-classified logistic regression models to determine ORs and 95% CIs, with individuals nested within workplaces and neighbourhoods. All models were conducted in both men and women and were adjusted for age, income, marital status, educational attainment and neighbourhood SESresidence. RESULTS: Low (vs high) educationwork was significantly associated with increased CHD incidence for both men (OR 1.29, 95% CI 1.23 to 1.34) and women (OR 1.38, 95% CI 1.29 to 1.47) and remained significant after adjusting for potential confounders. These findings were not replicable for the variable neighbourhood SESwork. CONCLUSIONS: Workplace socioeconomic characteristics, that is, the educational attainment of an individual's colleagues, may influence CHD risk, which represents new knowledge relevant to occupational health management at workplaces.

Impact of comorbidity on family genetic risk profiles for psychiatric and substance use disorders: a descriptive analysis.

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.

Shared genetic and environmental etiology between substance use disorders and suicidal behavior.

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.

Contagious Transmission in a Swedish National Sample of Alcohol Use Disorders as a Function of Geographical Proximity Among Siblings and Propinquity-of-Rearing Defined Acquaintances.

OBJECTIVE: The purpose of this study was to determine whether alcohol use disorder (AUD) can be transmitted contagiously in siblings and likely acquaintances growing up close to one another (Propinquity-of-Rearing Defined Acquaintances [PRDAs]). METHOD: PRDAs were pairs of same-age subjects growing up within 1 km of each other and sharing the same school class, where one of whom (PRDA1) was first registered for AUD at age 15 or older. Using adult residential location, we predicted proximity-dependent risk for an AUD first registration in a second PRDA within 3 years of PRDA1's registration. RESULTS: In 150,195 informative siblings, cohabitation status (hazard ratio [HR] = 1.22, 95% confidence interval [CI] [1.08, 1.37]), but not proximity, predicted risk for AUD onset. In 114,375 informative PRDA pairs, a log model fit best, predicting lower risk the greater the distance (HR = 0.88, 95% CI [0.84, 0.92]) with risks for AUD at 10, 50, and 100 km from affected PRDA1 cases equaling, respectively: 0.73 [0.66, 0.82], 0.60 [0.51, 0.72], and 0.55 [0.45, 0.68]. Within PRDA acquaintanceships, results resembled those found among PRDA pairs. The proximity-dependent contagious risk for AUD among PRDA pairs was attenuated by increasing age, lower genetic risk, and higher educational attainment. CONCLUSIONS: Cohabitation but not distance predicted transmission of AUD between siblings. However, contagious transmission of AUD among acquaintances growing up and attending school together was present and attenuated by increasing distance in adulthood. The impact of adult proximity on transmission was moderated by age, educational attainment, and genetic risk for AUD. Our results provide support for the validity of contagion models for AUD.