Socioeconomic position indicators and risk of alcohol-related medical conditions: A national cohort study from Sweden.

BACKGROUND: Alcohol consumption contributes to excess morbidity and mortality in part through the development of alcohol-related medical conditions (AMCs, including alcoholic cardiomyopathy, hepatitis, cirrhosis, etc.). The current study aimed to clarify the extent to which risk for these outcomes differs as a function of socioeconomic position (SEP), as discrepancies could lead to exacerbated health disparities. METHODS AND FINDINGS: We used longitudinal Swedish national registries to estimate the individual and joint associations between 2 SEP indicators, educational attainment and income level, and risk of AMC based on International Classification of Diseases codes, while controlling for other sociodemographic covariates and psychiatric illness. We conducted Cox proportional hazards models in sex-stratified analyses (N = 1,162,679 females and N = 1,196,659 males), beginning observation at age 40 with follow-up through December 2018, death, or emigration. By the end of follow-up, 4,253 (0.37%) females and 11,183 (0.93%) males had received an AMC registration, corresponding to overall AMC incidence rates among females and males of 2.01 and 5.20, respectively. In sex-stratified models adjusted for birth year, marital status, region of origin, internalizing and externalizing disorder registrations, and alcohol use disorder (AUD) registration, lower educational attainment was associated with higher risk of AMC in both females (hazard ratios [HRs] = 1.40 to 2.46 for low- and mid-level educational attainment across 0 to 15 years of observation) and males (HRs = 1.13 to 1.48). Likewise, risk of AMC was increased for those with lower income levels (females: HRs = 1.10 to 5.86; males: HRs = 1.07 to 6.41). In secondary analyses, we further adjusted for aggregate familial risk of AUD by including family genetic risk scores for AUD (FGRSAUD), estimated using medical, pharmacy, and criminal registries in extended families, as covariates. While FGRSAUD were associated with risk of AMC in adjusted models (HR = 1.17 for females and HR = 1.21 for males), estimates for education and income level remained largely unchanged. Furthermore, FGRSAUD interacted with income level, but not education level, such that those at higher familial liability to AUD were more susceptible to the adverse effect of low income. Limitations of these analyses include the possibility of false negatives for psychiatric illness registrations, changes in income after age 40 that were not accounted for due to modeling restrictions, restriction to residents of a high-income country, and the inability to account for individual-level alcohol consumption using registry data. CONCLUSIONS: Using comprehensive national registry data, these analyses demonstrate that individuals with lower levels of education and/or income are at higher risk of developing AMC. These associations persist even when accounting for a range of sociodemographic, psychiatric, and familial risk factors. Differences in risk could contribute to further health disparities, potentially warranting increased screening and prevention efforts in clinical and public health settings.

The joint effects of genetic liability and the death of close relatives on risk for major depression and alcohol use disorder in a Swedish national sample.

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.

Post-traumatic stress disorder and drug use disorder: examination of aetiological models in a Swedish population-based cohort.

Background: There are two primary phenotypic models of comorbidity between post-traumatic stress disorder (PTSD) and drug use disorder (DUD), i.e. self-medication (PTSD precedes and causes DUD) and susceptibility (DUD precedes and causes PTSD). We sought to clarify the longitudinal relationship between PTSD and DUD, while examining sex differences.Method: We used approximately 23 years of longitudinal data from Swedish population registries to conduct two complementary statistical models: Cox proportional hazard models (N ≈ 1.5 million) and a cross-lagged panel model (N ≈ 3.8 million).Results: Cox proportional hazards models, adjusting for cohort and socioeconomic status, found strong evidence for the self-medication hypothesis, as PTSD predicted increased risk for DUD among both women [hazard ratio (HR) = 5.34, 95% confidence interval (CI) 5.18, 5.51] and men (HR = 3.65, 95% CI 3.54, 3.77), and moreover, that the PTSD to DUD association was significantly higher among women (interaction term 0.68, 95% CI 0.65, 0.71). The results of the susceptibility model were significant, but not as strong as the self-medication model. DUD predicted risk for PTSD among both women (HR = 2.43, 95% CI 2.38, 2.50) and men (HR = 2.55, 95% CI 2.50, 2.60), and HR was significantly higher in men (interaction term 1.05, 95% CI 1.02, 1.08). Investigating the pathways simultaneously in the cross-lagged model yielded support for both pathways of risk. The cross-paths instantiating the susceptibility model (0.10-0.22 in females, 0.12-0.19 in males) were mostly larger than those capturing the self-medication model (0.01-0.16 in females, 0.04-0.22 in males).Conclusions: We demonstrate that the relationship between PTSD and DUD is bidirectional, with evidence that future research should prioritize examining specific pathways of risk that may differ between men and women.

Post-traumatic stress disorder (PTSD) and drug use disorder (DUD) are highly comorbid, and few large population-based longitudinal studies have been conducted to better understand why these disorders co-occur at a rate far greater than chance.We used approximately 23 years of longitudinal data from the Swedish National Registries, in a sample of over 1.5 million people, to look at the prospective relationships between PTSD and DUD, and vice versa.We found evidence for bidirectional risk such that having one disorder increased the future risk for the other disorder, although the effect sizes were higher for PTSD's risk on future DUD, and some patterns differed by sex.

The Impact of the Good Behavior Game on Risk for Drug Use Disorder in an Agent-Based Model of Southern Sweden.

OBJECTIVE: Drug use disorder (DUD) is a worldwide problem, and strategies to reduce its incidence are central to decreasing its burden. This investigation seeks to provide a proof of concept for the ability of agent-based modeling to predict the impact of the introduction of an effective school-based intervention, the Good Behavior Game (GBG), on reducing DUD in Scania, Sweden, primarily through increasing school achievement. METHOD: We modified an existing agent-based simulation model of opioid use disorder to represent DUD in Scania County, southern Sweden. The model represents every individual in the population and is calibrated with the linked individual data from multiple sources including demographics, education, medical care, and criminal history. Risks for developing DUD were estimated from the population in Scania. Scenarios estimated the impact of introducing the GBG in schools located in disadvantaged areas. RESULTS: The model accurately reflected the growth of DUD in Scania over a multiyear period and reproduced the levels of affected individuals in various socioeconomic strata over time. The GBG was estimated to improve school achievement and lower DUD registrations over time in males residing in disadvantaged areas by 10%, reflecting a decrease of 540 cases of DUD. Effects were considerably smaller in females. CONCLUSIONS: This work provides support for the impact of improving school achievement on long-term risks of developing DUD. It also demonstrated the value of using simulation modeling calibrated with data from a real population to estimate the impact of an intervention applied at a population level.

The effects of sociodemographic factors and comorbidities on sepsis: A nationwide Swedish cohort study.

Sepsis is a severe condition, representing a significant public health concern, especially in the elderly. There is, however, little insight into the potential effects of sociodemographic factors and comorbidities on sepsis incidence and how these factors interact. This was a nationwide open cohort study including individuals (N = 6 746 010) in Sweden ≥ 18 years of age spanning from 1997 to 2018, with 116 175 995 person years of follow-up. The outcome was time to first occurrence of sepsis. The following variables were included in the analysis: sociodemographic factors (age, sex, income, education, marital status, region of residency, and country of origin), severe mental disorders (schizophrenia and bipolar disorders), and Charlson Comorbidity Index. Interaction tests were conducted. A total of 161 558 individuals were diagnosed with sepsis during the study period, corresponding to an incidence rate of 13.9 per 10 000 person years (95% CI: 13.8 - 14.0). The main findings were that male sex, high age, low education, and comorbid conditions were positively associated with sepsis, after adjustments for the other covariates. Being aged 80 years and above yielded a HR of 18.19 (95% CI: 17.84 - 18.55) and the effect of high age was more than twice as high in men than in women. In conclusion, this large nationwide cohort found that several sociodemographic factors and comorbid conditions were independently associated with sepsis and men were more affected by higher age than women. These findings can help improve sepsis awareness and preventive work in risk groups.

Life is pain: Fibromyalgia as a nexus of multiple liability distributions.

Fibromyalgia is a complex disease of unclear etiology that is complicated by difficulties in diagnosis, treatment, and clinical heterogeneity. To clarify this etiology, healthcare-based data are leveraged to assess the influences on fibromyalgia in several domains. Prevalence is less than 1% of females in our population register data, and about 1/10th that in males. Fibromyalgia often presents with co-occurring conditions including back pain, rheumatoid arthritis, and anxiety. More comorbidities are identified with hospital-associated biobank data, falling into three broad categories of pain-related, autoimmune, and psychiatric disorders. Selecting representative phenotypes with published genome-wide association results for polygenic scoring, we confirm genetic predispositions to psychiatric, pain sensitivity, and autoimmune conditions show associations with fibromyalgia, although these may differ by ancestry group. We conduct a genome-wide association analysis of fibromyalgia in biobank samples, which did not result in any genome-wide significant loci; further studies with increased sample size are necessary to identify specific genetic effects on fibromyalgia. Overall, fibromyalgia appears to have strong clinical and likely genetic links to several disease categories, and could usefully be understood as a composite manifestation of these etiological sources.

Death of parent, sibling, spouse, and child in a Swedish national sample and risk of subsequent stress reaction, major depression, alcohol-use disorder, and drug-use disorder.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Testing Phenotypic Models of Posttraumatic Stress Disorder and Alcohol Use Disorder Comorbidity Using Longitudinal Registry Data.

OBJECTIVE: Two predominant phenotypic models of causality exist to explain the high co-occurrence of posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD): the self-medication and susceptibility models. Population-based longitudinal studies that simultaneously examine both models are needed. Thus, the goal of the present study is to test these models using the Swedish National Registries. METHOD: Registries were used to conduct longitudinal Cox proportional hazard models (n ≈ 1.5 million) and cross-lagged panel models (N ≈ 3.8 million) with follow-up periods of ~23 years. RESULTS: Covarying for cohort and socioeconomic status, Cox proportional hazards model results found strong support for the self-medication model. Results showed that PTSD predicted increased risk for AUD among both men (HR = 4.58 [4.42, 4.74]) and women (HR = 4.14 [3.99, 4.30]), significantly more so for men (interaction HR = 1.11 [1.05, 1.16]). Support was also found for the susceptibility model, although the effects were lower in magnitude than those for the self-medication model. AUD increased risk for PTSD among men (HR = 2.53 [2.47, 2.60]) and women (HR = 2.06 [2.01, 2.12]), and significantly more so for men (interaction term HR = 1.23 [1.18, 1.28]). Cross-lagged model results of simultaneously testing both models found support for bidirectionality. The PTSD-to-AUD paths and the AUD-to-PTSD paths were of modest effect for men and women. CONCLUSIONS: The results from both complementary statistical approaches demonstrate that the models of comorbidity are not mutually exclusive. Although the Cox model results evidenced more support for the self-medication pathway, the cross-lagged model results suggest that the prospective relationships between these disorders are nuanced across development.

Risk factors for the development of opioid use disorder after first opioid prescription: a Swedish national study.

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.

Origins of spousal cross-concordance for psychiatric disorders: a test of the social stress theory for alcohol use disorder.

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.

Social genetic effects for drug use disorder among spouses.

AIMS: Preclinical and human studies suggest that a social partner's genotype may be associated with addiction-related outcomes. This study measured whether spousal genetic makeup is associated with risk of developing drug use disorder (DUD) during marriage and whether the risk associated with a spouse's genotype could be disentangled from potentially confounding rearing environmental effects. DESIGN: Univariable and multivariable logistic regression analyses. SETTING: Sweden. PARTICIPANTS: Men and women born between 1960 and 1990 and in opposite-sex first marriages before age 35 (n = 294 748 couples). MEASUREMENTS: Outcome was DUD diagnosis (inclusive of opioids, sedatives/hypnotics/anxiolytics, cocaine, cannabis, amphetamine and other psychostimulants, hallucinogens, other drugs of abuse and combinations thereof) obtained from legal, medical and pharmacy registries. The focal predictor was family genetic risk scores for DUD (FGRS-DUD), which were inferred from diagnoses in first- through fifth-degree relatives and weighted by degree of genetic sharing. FGRS-DUD were calculated separately for each partner in a couple. FINDINGS: Marriage to a spouse with a high FGRS-DUD was associated with increased risk of developing DUD during marriage, ORmales = 1.68 (95% CI = 1.50, 1.88) and ORfemales = 1.35 (1.16, 1.56), above and beyond the risk associated with one's own FGRS-DUD. The risk associated with a spouse's FGRS-DUD remained statistically significant after covarying for parental education. As indicated by a series of null interaction effects, there was no evidence that the risk associated with a spouse's FGRS-DUD differed depending on whether the spouse was DUD-affected, probands' probable contact with in-laws and whether the spouse was raised by his/her biological parents or in another home. CONCLUSIONS: There is relatively robust evidence that a person's risk for developing drug use disorder is associated with the genetic makeup of the person's spouse.

The actions and interactions of family genetic risk scores for alcohol use disorder and major depression on the risk for these two disorders.

We know little about how genetic risk factors for two disorders jointly act and interact in predisposing to illness. Therefore, in the Swedish population, born 1970-1990 (n = 2,116,082) and followed through 2015, we examine, using additive Cox models, the impact of the family genetic risk scores (FGRS) for alcohol use disorder (AUD) and major depression (MD), their interaction with each other and with the relevant comorbid disorder on risk for AUD and MD. FGRS scores are constructed using rates of illness in first-fourth degree relatives. FGRS for AUD and MD interacted in predicting of both disorders and one FRGS (e.g., for AUD) interacted with the phenotype of MD to predict that disorder (e.g., AUD). These FGRS interactions were not substantially attenuated by adding interactions with the disorders. These results replicated across sexes. In predicting risk for a given disorder, we rarely consider genetic liabilities for other disorders. But such effects were here significant and interactive. Furthermore, the primary disorder genetic risk interacts with comorbid disorders. The pathways to risk for disorders from their and other disorders' genetic liability may be more complex than commonly considered.

Predicting the Onset of Opioid Use Disorder in the Swedish General Population.

OBJECTIVE: Given the public health importance of opioid use disorder (OUD), we sought to understand better its risk predictors in the Swedish general population. METHOD: We examined the Swedish population, born 1950-1970 (n = 2,092,359), and followed through 2018. Using Cox, logistic, and co-sibling models, we explored associations between a wide range of putative risk factors and a first onset of OUD--assessed through medical, criminal, and pharmacy registers--in the entire cohort and in the cohort wherein prior cases of drug use disorder (DUD) were censored. RESULTS: OUD was predicted by the following four risk factor domains: (a) externalizing syndromes, especially prior non-opioid DUD; (b) psychopathology; (c) psychosocial factors, including social class and immigrant and marital status; and (d) serious injuries and pain diagnoses. When predicting OUD as the first form of DUD, the importance of pain diagnoses as a predictor increased. Co-sibling analyses suggested that the association of some of these risk factors with OUD onset was likely largely causal, whereas others were a mixture of causal effects and familial confounding. An aggregate risk score from these individual risk factors had reasonable receiver operating characteristic (ROC) curve performance. CONCLUSIONS: OUD is a multifactorial syndrome for which risk can be meaningfully predicted by prior externalizing syndromes, internalizing and psychotic psychopathology, indicators of psychosocial status, and predictors of pain diagnoses. Some important differences were seen in the prediction of any OUD onset versus OUD onset as the first form of DUD. Much of the effect of these predictors appear, in co-sibling analyses, to likely reflect causal influences.

Sibling alcohol use disorder is associated with increased risk for suicide attempt.

The association between having a sibling diagnosed with alcohol use disorder (AUD) and risk for suicide attempt may be attributable to shared genetic liability between AUD and suicidal behavior, effects of environmental exposure to a sibling's AUD, or both. To distinguish between these alternatives, we conducted a series of Cox regression models using data derived from Swedish population-based registers with national coverage. Among full sibling pairs (656,807 males and 607,096 females), we found that proband risk for suicide attempt was significantly elevated when their sibling was affected by AUD, even after accounting for the proband's AUD status. Further, risk for proband suicide attempt was consistently higher when the sibling's AUD registration had occurred more recently. Our findings provide evidence for exposure to sibling AUD as an environmental risk factor for suicide attempt and suggest that clinical outreach may be warranted following a sibling's diagnosis with AUD.

Oral contraceptive use and risk of suicidal behavior among young women.

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.

Insulin action and secretion independent of traditional risk factors predict new-onset type 2 diabetes in Iraqi and Swedish born citizens - The MEDIM cohort study.

AIMS: Our aim was to study the incidence of type 2 diabetes in a population-based cohort of Swedish and Iraqi born individuals, focussing on traditional risk factors, insulin action, insulin secretion and ethnicity. MATERIALS AND METHODS: The cohort consisted of 1164 Iraqi and 693 Swedish-born citizens. We investigated the association between new-onset type 2 diabetes and the predictors including lifestyle factors, metabolic risk markers, country of birth, insulin sensitivity and secretion assessed by Matsuda index with Cox regression. RESULTS: Eighty-nine individuals were diagnosed with type 2 diabetes with a mean follow-up of 7.5 years. Both lower insulin sensitivity (ISI, HR 0.02 [0.01-0.08]) as well as insulin secretion (CIR, HR 0.13 [0.07-0.24]) at baseline predicted type 2 diabetes onset, independent of traditional risk factors. Our results were not modified by country of birth. Regarding traditional risk factors, WHR (1.05 [1.00-1.09]), blood glucose (3.27 [2.35-4.55]), LDL/HDL (1.46 [1.20-1.78]) and diastolic blood pressure (1.04 [1.00-1.07]) predicted diabetes incidence in the full model. CONCLUSIONS: Both impaired insulin sensitivity index and corrected insulin response predicted type 2 diabetes onset, independent of traditional risk factors. We conclude that insulin secretion and action might be useful additional predictors for type 2 diabetes in populations of European and Middle Eastern ethnicities.

Genetic and environmental influences on the progression from alcohol use disorder to alcohol-related medical conditions.

BACKGROUND: Medical conditions related to alcohol use disorders (AUD) represent a substantial public health concern. However, only a subset of individuals with AUD develop these conditions and the extent to which genetic and environmental factors that are shared with AUD, versus those distinct from it, contribute to this progression has not yet been determined. METHODS: Using data from Swedish national registries for a cohort born from 1932 to 1970 (N = 1,319,214, 48.9% women), we conducted twin-sibling biometric model fitting to examine the genetic and environmental sources of variance that contribute to the liability to alcohol-related medical conditions (AMC). Progression to AMC, determined using medical registry data, was contingent on an AUD registration, which was determined using medical and criminal registry data. RESULTS: We identified AUD registrations in 3.2% of women and 9.2% of men. Among individuals with an AUD registration, 14.4% of women and 15.4% of men had an AMC registration. In the final models, we constrained the beta pathway from AUD to AMC and the genetic and unique environmental paths to be equal across sexes. The beta path was estimated at 0.59. AMC was modestly heritable in women (A = 0.32) and men (A = 0.30). The proportion of total heritability unique to AMC was 39.6% among women and 41.3% among men. A higher proportion of total environmental variance was unique to AMC: 76.7% for women and 77.2% for men. In a sensitivity analysis limited to liver-related AMC, we observed similar results, with a slightly lower beta path from AUD to AMC (0.46) and higher proportions of AMC-specific genetic (70.0% in women; 71.7% in men) and environmental (84.5% in both sexes) variance. CONCLUSIONS: A moderate-to-substantial proportion of genetic and environmental variance that contributes to AMC risk is not shared with AUD, underscoring the need for additional gene identification efforts for AMC. Furthermore, the prominent influence of environmental factors specific to AMC provides a promising area for the identification of prevention targets. We did not observe significant sex differences in the etiology of AMC, although follow-up is warranted in other well-powered studies.

Young men's behavioral competencies and risk of alcohol use disorder in emerging adulthood: Early protective effects of parental education.

We investigate how early exposure to parental externalizing behaviors (EB) may contribute to development of alcohol use disorders (AUD) in young adulthood, testing a developmental cascade model focused on competencies in three domains (academic, conduct, and work) in adolescence and emerging adulthood, and examining whether high parental education can buffer negative effects of parental EB and other early risk factors. We use data from 451,054 Swedish-born men included in the national conscript register. Structural equation models showed parental EB was associated with academic and behavioral problems during adolescence, as well as with lower resilience, more criminal behavior, and reduced social integration during emerging adulthood. These pathways led to elevated rates of AUD in emerging and young adulthood. Multiple groups analysis showed most of the indirect pathways from parental EB to AUD were present but buffered by higher parental education, suggesting early life experiences and competencies matter more for young men from lower socioeconomic status (SES) families than from higher SES families. Developmental competencies in school, conduct, and work are important precursors to the development of AUD by young adulthood that are predicted by parental EB. Occupational success may be an overlooked source of resilience for young men from low-SES families.

The causal nature of the association between resting pulse in late adolescence and risk for internalizing and externalizing disorders: a co-relative analysis in a national male Swedish sample.

BACKGROUND: Resting pulse is robustly and inversely associated with the risk for externalizing disorders and may be positively associated with internalizing disorders. We know little about the causal nature of these associations. METHODS: We examined resting pulse at conscription examination in 369 301 males born 1960-80 with a mean (s.d.) follow-up of 29.1 (7.7) years. From pulse rates, we predicted, using Cox models, the risk for criminal behavior (CB), drug abuse (DA), alcohol use disorder (AUD), major depression (MD), and anxiety disorders (AD), assessed from medical, criminal, and pharmacy registries. Co-relative analyses were conducted on the general population, cousin, half-sibling, full-sibling, and monozygotic pairs discordant for the outcome. Twin/sibling modeling for pulse was performed using OpenMX. RESULTS: Familial resemblance for pulse resulted entirely from genetic factors. In the general population, the risk for externalizing disorders (CB, DA, and AUD) and internalizing disorders (MD and AD) were, respectively, significantly associated with low and high resting pulse rate. For CB, DA, and AUD, co-relative analyses showed that the inverse association with pulse resulted entirely from familial common causes (aka 'confounders'). By contrast, co-relative analyses found that the association between higher pulse and MD and AD resulted from direct causal effects. CONCLUSIONS: Resting pulse has a negative and positive association with, respectively, the risk for externalizing and for internalizing disorders. Co-relative analyses indicate that the nature of these associations differ, suggesting that elevated pulse appears to directly increase the risk for internalizing disorders while the reduced pulse is a risk index for underlying traits that predispose to externalizing disorders.

Does Neighborhood Alcohol Availability Moderate the Impact of Familial Liability and Marital Status on Risk for Alcohol Use Disorders? A Swedish National Study.

OBJECTIVE: The purpose of this study was to determine whether ease of access to alcohol at the neighborhood level moderates the impact of familial liability and marital status on risk for alcohol use disorder (AUD). METHOD: Individuals in Sweden were divided into those residing in a neighborhood with (n = 14.1%) versus without (n = 85.9%) an alcohol outlet (bars/nightclubs or government stores). AUD was detected through national medical, legal, and pharmacy registries. Using an additive model predicting AUD registration over 5 years in 1,624,814 individuals, we tested for interactions between the presence of outlets in the individuals' neighborhoods and familial risk for externalizing syndromes and marital status. RESULTS: In both males and females, we found positive and significant interactions in the prediction of AUD between the presence versus absence of a nearby alcohol outlet with (a) familial risk and (b) single and divorced versus married status. Similar but nonsignificant interactions were seen between nearby outlets and widowed versus married status. These results changed little when all cases with prior AUD were removed from the sample. For males, most of the interaction arose from the proximity of bars/nightclubs, whereas for females the results varied across different kinds of outlets. CONCLUSIONS: Environments that provide easy access to alcohol augment the impact of a range of risk factors for AUD, especially familial vulnerability and the reduced social constraints associated with single, divorced, and widowed marital status.