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1.
  • Docherty, Anna R, et al. (author)
  • GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
  • 2023
  • In: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
  • Journal article (peer-reviewed)abstract
    • Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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2.
  • Mullins, Niamh, et al. (author)
  • Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
  • 2022
  • In: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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3.
  • Salvatore, Jessica E., et al. (author)
  • Parental alcohol use disorder and offspring marital outcomes
  • 2019
  • In: Addiction. - : Wiley. - 0965-2140. ; 114:1, s. 81-91
  • Journal article (peer-reviewed)abstract
    • Aims: We tested whether parental alcohol use disorder (AUD) predicted adult offspring's likelihood of marriage and marriage to an AUD-affected spouse; whether effects differed as a function of the sex or number of affected parents; and whether they were robust to confounders. Design: Sex-stratified Cox and logistic regression models. Setting: Sweden. Participants: A total of 1 171 070 individuals (51.40% male) born 1965–75. Measurements: Obtained from legal, medical and pharmacy registries. Predictor was parent AUD. Outcomes were marriage and spouse AUD. Adjustments included offspring birth year and AUD; and parental education, marriage, divorce, criminal behavior and drug abuse. Findings: Male and female offspring of AUD-affected parents were more likely to marry at younger ages (< 25), illustrative unadjusted hazard ratio (HR)age 20 = 1.22 (1.17, 1.28) and 1.34 (1.20, 1.39) and were less likely to marry at older ages (> 25), HRage 30 = 0.79 (0.78, 0.81) and 0.82 (0.81, 0.84). Parental AUD was associated with higher odds of having an affected spouse for males and females, odds ratio (OR) = 1.47 (1.38, 1.57) and 1.63 (1.56, 1.70). Effects were more pronounced for those with two versus one AUD-affected parent and adjustments attenuated effects negligibly. Daughters of affected mothers (versus fathers) were more likely to have AUD-affected husbands, OR = 1.68 (1.54, 1.84) versus 1.56 (1.48, 1.64), while there was no difference in sons. Conclusions: In Sweden, parental alcohol use disorder (AUD) is associated with a higher probability of marriage at younger ages, a lower probability of marriage at older ages and a higher likelihood of marriage to an affected spouse compared with no parental AUD. Most of these effects become stronger when the number of AUD-affected parents increases from one to two, and most effects hold after controlling for parents’ socio-economic status, marital history, other externalizing disorders and offspring's own AUD status. Daughters of affected mothers are more likely to have an affected spouse.
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4.
  • Crump, Casey, et al. (author)
  • Comparative risk of suicide by specific substance use disorders : A national cohort study
  • 2021
  • In: Journal of Psychiatric Research. - : Elsevier BV. - 0022-3956. ; 144, s. 247-254
  • Journal article (peer-reviewed)abstract
    • Substance use disorders (SUDs) are important risk factors for suicide, yet little is known about how suicide risks vary by specific SUDs. We examined these risks for the first time in a large general population to facilitate comparisons across SUDs. A national cohort study was conducted of all 6,947,191 adults in Sweden. SUDs (opioid, sedative/hypnotic, hallucinogen, cannabis, amphetamine, cocaine, and alcohol use disorders) were identified using inpatient, outpatient, and crime data, and suicide deaths using nationwide death data with follow-up during 2003–2016. Cox regression was used to compute hazard ratios (HRs) for suicide death while adjusting for sociodemographic factors and psychiatric, SUD, and somatic comorbidities. Co-sibling analyses assessed for confounding by unmeasured shared familial (genetic and/or environmental) factors. In 79.8 million person-years of follow-up, 15,616 (0.2%) suicide deaths were identified. All SUDs were associated with significantly increased risks, with HRs ranging from 12- to 26-fold and 2.5- to 6.4-fold before and after adjusting for covariates, respectively. After adjusting for all covariates, opioid use disorder was the strongest risk factor (HR, 6.39; 95% CI, 5.53–7.38) (P ≤ 0.002 compared with any other SUD), followed by sedative/hypnotic use disorder (4.62; 4.06–5.27) (P ≤ 0.009 compared with any other SUD except opioid or hallucinogen). Most associations persisted after controlling for shared familial factors, consistent with causal effects. In this large national cohort, all SUDs were associated with significantly increased risks of suicide death, especially opioid and sedative/hypnotic use disorders. These findings may improve risk stratification and inform interventions to prevent suicide in the highest-risk subgroups with SUDs.
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5.
  • Crump, Casey, et al. (author)
  • Health care utilization prior to suicide in adults with drug use disorders
  • 2021
  • In: Journal of Psychiatric Research. - : Elsevier BV. - 0022-3956. ; 135, s. 230-236
  • Journal article (peer-reviewed)abstract
    • Drug use disorders (DUD) are associated with psychiatric illness and increased risks of suicide. We examined health care utilization prior to suicide in adults with DUD, which may reveal opportunities to prevent suicide in this high-risk population. A national cohort study was conducted of all 6,947,191 adults in Sweden, including 166,682 (2.4%) with DUD, who were followed up for suicide during 2002–2015. A nested case-control design examined health care utilization among persons with DUD who died by suicide and 10:1 age- and sex-matched controls from the general population. In 86.7 million person-years of follow-up, 15,662 (0.2%) persons died by suicide, including 1946 (1.2%) persons with DUD. Unadjusted and adjusted relative risks of suicide associated with DUD were 11.03 (95% CI, 10.62–11.46) and 2.84 (2.68–3.00), respectively. 30.4% and 52.3% of DUD cases who died by suicide had a health care encounter within 2 weeks or 3 months before the index date, respectively, compared with 5.9% and 24.3% of controls (unadjusted prevalence ratio and difference, <2 weeks: 5.20 [95% CI, 4.76–5.67] and 24.6 percentage points [22.5–26.6]; <3 months: 2.15 [2.05–2.26] and 27.9 [25.6–30.2]). However, after adjusting for psychiatric comorbidities, these differences were much attenuated. Among DUD cases, 72.5% of last encounters within 2 weeks before suicide were in outpatient clinics, mostly for non-psychiatric diagnoses. In this large national cohort, suicide among adults with DUD was often shortly preceded by outpatient clinic encounters. Clinical encounters in these settings are important opportunities to identify suicidality and intervene accordingly in patients with DUD.
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6.
  • Crump, Casey, et al. (author)
  • Healthcare utilisation prior to suicide in persons with alcohol use disorder : National cohort and nested case-control study
  • 2020
  • In: British Journal of Psychiatry. - : Royal College of Psychiatrists. - 0007-1250 .- 1472-1465. ; 217:6, s. 710-716
  • Journal article (peer-reviewed)abstract
    • Background Alcohol use disorder (AUD) is common and associated with increased risk of suicide. Aims To examine healthcare utilisation prior to suicide in persons with AUD in a large population-based cohort, which may reveal opportunities for prevention. Method A national cohort study was conducted of 6 947 191 adults in Sweden in 2002, including 256 647 (3.7%) with AUD, with follow-up for suicide through 2015. A nested case-control design examined healthcare utilisation among people with AUD who died by suicide and 10:1 age- and gender-matched controls. Results In 86.7 million person-years of follow-up, 15 662 (0.2%) persons died by suicide, including 2601 (1.0%) with AUD. Unadjusted and adjusted relative risks for suicide associated with AUD were 8.15 (95% CI 7.86-8.46) and 2.22 (95% CI 2.11-2.34). Of the people with AUD who died by suicide, 39.7% and 75.6% had a healthcare encounter <2 weeks or <3 months before the index date respectively, compared with 6.3% and 25.4% of controls (adjusted prevalence ratio (PR) and difference (PD), <2 weeks: PR = 3.86, 95% CI 3.50-4.25, PD = 26.4, 95% CI 24.2-28.6; <3 months: PR = 2.03, 95% CI 1.94-2.12, PD = 34.9, 95% CI 32.6-37.1). AUD accounted for more healthcare encounters within 2 weeks of suicide among men than women (P = 0.01). Of last encounters, 48.1% were in primary care and 28.9% were in specialty out-patient clinics, mostly for non-psychiatric diagnoses. Conclusions Suicide among persons with AUD is often shortly preceded by healthcare encounters in primary care or specialty out-patient clinics. Encounters in these settings are important opportunities to identify active suicidality and intervene accordingly in patients with AUD.
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7.
  • Crump, Casey, et al. (author)
  • Preterm birth, low fetal growth and risk of suicide in adulthood : A national cohort and co-sibling study
  • 2021
  • In: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 50:5, s. 1604-1614
  • Journal article (peer-reviewed)abstract
    • Background: Adverse perinatal exposures have been associated with psychiatric disorders and suicidal behaviours later in life. However, the independent associations of gestational age at birth or fetal growth with suicide death, potential sex-specific differences, and causality of these associations are unclear. Methods: A national cohort study was conducted of all 2 440 518 singletons born in Sweden during 1973-98 who survived to age 18 years, who were followed up through 2016. Cox regression was used to compute hazard ratios (HRs) for suicide death associated with gestational age at birth or fetal growth while mutually adjusting for these factors, sociodemographic characteristics and family history of suicide. Co-sibling analyses assessed the influence of unmeasured shared familial (genetic and/or environmental) factors. Results: In 31.2 million person-years of follow-up, 4470 (0.2%) deaths by suicide were identified. Early preterm birth (22-33 weeks) was associated with an increased risk of suicide among females [adjusted hazard ratio (HR), 1.97; 95% confidence interval CI), 1.29, 3.01; P = 0.002) but not males (0.90; 0.64, 1.28; P = 0.56), compared with full-term birth (39-41 weeks). Small for gestational age was associated with a modestly increased risk of suicide among females (adjusted HR, 1.27; 95% CI, 1.08, 1.51; P = 0.005) and males (1.14; 1.03, 1.27; P = 0.02). However, these associations were attenuated and non-significant after controlling for shared familial factors. Conclusions: In this large national cohort, preterm birth in females and low fetal growth in males and females were associated with increased risks of suicide death in adulthood. However, these associations appeared to be non-causal and related to shared genetic or prenatal environmental factors within families.
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8.
  • Crump, Casey, et al. (author)
  • Response to Lao, Guan, Wang, et al.
  • 2024
  • In: Journal of the National Cancer Institute. - 0027-8874. ; 116:5, s. 770-770
  • Journal article (peer-reviewed)
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9.
  • Crump, Casey, et al. (author)
  • Risks of alcohol and drug use disorders in prostate cancer survivors : a national cohort study
  • 2023
  • In: JNCI CANCER SPECTRUM. - : Oxford University Press (OUP). - 2515-5091. ; 7:4
  • Journal article (peer-reviewed)abstract
    • Background: Prostate cancer (PC) survivors may potentially use substances to cope with psychological distress or poorly controlled physical symptoms. Little is known, however, about the long-term risks of alcohol use disorder (AUD) or drug use disorders in men with PC.Methods: A national cohort study was conducted in Sweden of 180 189 men diagnosed with PC between 1998 and 2017 and 1 801 890 age-matched population-based control men. AUD and drug use disorders were ascertained from nationwide records through 2018. Cox regression was used to compute hazard ratios (HRs) while adjusting for sociodemographic factors and prior psychiatric disorders. Subanalyses examined differences by PC treatment from 2005 to 2017.Results: Men with high-risk PC had increased risks of both AUD (adjusted HR = 1.44, 95% confidence interval [CI] = 1.33 to 1.57) and drug use disorders (adjusted HR = 1.93, 95% CI = 1.67 to 2.24). Their AUD risk was highest in the first year and was no longer significantly elevated 5 years after PC diagnosis, whereas their drug use disorders risk remained elevated 10 years after PC diagnosis (adjusted HR = 2.26, 95% CI = 1.45 to 3.52), particularly opioid use disorder (adjusted HR = 3.07, 95% CI = 1.61 to 5.84). Those treated only with androgen-deprivation therapy had the highest risks of AUD (adjusted HR = 1.91, 95% CI = 1.62 to 2.25) and drug use disorders (adjusted HR = 2.23, 95% CI = 1.70 to 2.92). Low- or intermediate-risk PC was associated with modestly increased risks of AUD (adjusted HR = 1.38, 95% CI = 1.30 to 1.46) and drug use disorders (adjusted HR = 1.19, 95% CI = 1.06 to 1.34).Conclusions: In this large cohort, men with PC had significantly increased risks of both AUD and drug use disorders, especially those with high-risk PC and treated only with androgen-deprivation therapy. PC survivors need long-term psychosocial support and timely detection and treatment of AUD and drug use disorders.
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10.
  • Crump, Casey, et al. (author)
  • Risks of Depression and Suicide After Diagnosis With Heart Failure : A National Cohort Study
  • 2022
  • In: JACC: Heart Failure. - : Elsevier BV. - 2213-1779. ; 10:11, s. 819-827
  • Journal article (peer-reviewed)abstract
    • Background: Heart failure (HF) has been associated with psychosocial distress, but other long-term mental health sequelae are unclear. Objectives: In this study, the authors sought to determine risks of major depression and suicide, susceptible time periods, and sex-specific differences after HF diagnosis in a large population-based cohort. Methods: A national cohort study was conducted of all 154,572 persons diagnosed with HF at ages 18-75 years during 2002-2017 in Sweden and 1,545,720 age- and sex-matched population-based control subjects who were followed up for major depression and suicide ascertained from nationwide inpatient, outpatient, and death records through 2018. Poisson regression was used to compute incidence rate ratios (IRRs) while adjusting for sociodemographic factors and comorbidities. Results: HF was associated with increased risks of major depression and death by suicide in both men and women, with highest risks in the first 3 months, then declining to modest risks at ≥12 months after HF diagnosis. Within 3 months after HF diagnosis, adjusted IRRs for new-onset major depression were 3.34 (95% CI: 3.04-3.68) in men and 2.78 (95% CI: 2.51-3.09) in women, and for suicide death were 4.47 (95% CI: 2.62-7.62) in men and 2.82 (95% CI: 1.11-7.12) in women. These risks were elevated regardless of age at HF diagnosis. HF was associated with significantly more depression cases in women (P < 0.001). Conclusions: In this large national cohort, HF was associated with substantially increased risks of depression and suicide in men and women, with highest risks occurring within 3 months after HF diagnosis. Men and women with HF need timely detection and treatment of depression and suicidality.
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11.
  • Crump, Casey, et al. (author)
  • Risks of depression, anxiety, and suicide in partners of men with prostate cancer : a national cohort study
  • 2024
  • In: Journal of the National Cancer Institute. - 0027-8874. ; 116:5, s. 745-752
  • Journal article (peer-reviewed)abstract
    • Background: A diagnosis of prostate cancer (PC) may cause psychosocial distress not only in a man but also in his intimate partner. However, long-term risks of depression, anxiety, or suicide in partners of men with PC are largely unknown. Methods: A national cohort study was conducted of 121 530 partners of men diagnosed with PC during 1998-2017 and 1 093 304 population-based controls in Sweden. Major depression, anxiety disorder, and suicide death were ascertained through 2018. Cox regression was used to compute hazard ratios (HRs) while adjusting for sociodemographic factors. Results: Partners of men with high-risk PC had increased risks of major depression (adjusted HR ¼ 1.34, 95% confidence interval [CI] ¼ 1.30 to 1.39) and anxiety disorder (adjusted HR ¼ 1.25, 95% CI ¼ 1.20 to 1.30), which remained elevated 10 or more years later. Suicide death was increased in partners of men with distant metastases (adjusted HR ¼ 2.38, 95% CI ¼ 1.08 to 5.22) but not other high-risk PC (adjusted HR ¼1.14, 95% CI ¼ 0.70 to 1.88). Among partners of men with high-risk PC, risks of major depression and anxiety disorder were highest among those 80 years of age or older (adjusted HR ¼ 1.73; 95% CI ¼ 1.53 to 1.96; adjusted HR ¼ 1.70, 95% CI ¼ 1.47 to 1.96, respectively), whereas suicide death was highest among those younger than 60 years of age (adjusted HR ¼ 7.55, 95% CI ¼ 2.20 to 25.89). In contrast, partners of men with low- or intermediate-risk PC had modestly or no increased risks of these outcomes. Conclusions: In this large cohort, partners of men with high-risk PC had increased risks of major depression and anxiety disorder, which persisted for 10 or more years. Suicide death was increased 2-fold in partners of men with distant metastases. Partners as well as men with PC need psychosocial support and close follow-up for psychosocial distress.
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12.
  • Dahlman, Disa, et al. (author)
  • Socioeconomic correlates of incident and fatal opioid overdose among Swedish people with opioid use disorder
  • 2021
  • In: Substance Abuse: Treatment, Prevention, and Policy. - : Springer Science and Business Media LLC. - 1747-597X. ; 16:1
  • Journal article (peer-reviewed)abstract
    • Background: Opioid overdose (OD) and opioid OD death are major health threats to people with opioid use disorder (OUD). Socioeconomic factors are underexplored potential determinants of opioid OD. In this study, we assessed socioeconomic and other factors and their associations with incident and fatal opioid OD, in a cohort consisting of 22,079 individuals with OUD. Methods: We performed a retrospective, longitudinal study based on Swedish national register data for the period January 2005–December 2017. We used Cox proportional hazard models to investigate the risk of incident and fatal opioid OD as a function of several individual, parental and neighborhood covariates. Results: Univariate analysis showed that several covariates were associated with incident and fatal opioid OD. In the multivariate analysis, incident opioid OD was associated with educational attainment (Hazard ratio [HR] 0.96; 95% confidence interval [CI] 0.94–0.97), having received social welfare (HR 1.31; 95% CI 1.22–1.39), and criminal conviction (HR 1.53; 95% CI 1.42–1.65). Fatal opioid OD was also associated with criminal conviction (HR 1.93; 95% CI 1.61–2.32). Conclusion: Individuals with low education and receipt of social welfare had higher risks of incident opioid OD and individuals with criminal conviction were identified as a risk group for both incident and fatal opioid OD. Our findings should raise attention among health prevention policy makers in general, and among decision-makers within the criminal justice system and social services in particular.
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13.
  • Edwards, Alexis C., et al. (author)
  • Alcohol use disorder and non-fatal suicide attempt : findings from a Swedish National Cohort Study
  • 2022
  • In: Addiction. - : Wiley. - 0965-2140 .- 1360-0443. ; 117:1, s. 96-105
  • Journal article (peer-reviewed)abstract
    • Background and Aims: Alcohol use disorder (AUD) is associated with increased risk of non-fatal suicide attempt. We aimed to measure the strength and mechanistic nature of the association between AUD and increased suicide attempt and determine any causal pathways and/or shared risk factors. Design: We used Cox proportional hazards models in population-level and co-relative analyses to evaluate the risk of first non-fatal suicide attempt as a function of previous AUD. Setting and Participants: We used continuously updated longitudinal nationwide Swedish registry data on native Swedes born from 1950 to 1970 (n = 2 229 619) and followed from age 15 until 2012. Measurements: AUD and suicide attempt were identified using International Classification of Diseases (ICD)-8, ICD-9, and ICD-10 codes. AUD was also identified using pharmacy and criminal records. Genetic and family environmental risks were derived based on relatedness via the Multi-Generation Register and shared residency via the Population and Housing Census and the Total Population Register. Findings: AUD was robustly associated with suicide attempt in crude models (hazard ratio [HR] = 15.24 [95% CI: 14.92, 15.56]). In models adjusted for sociodemographic factors and psychiatric comorbidity, the association was attenuated: for women, HRs declined gradually across time, ranging from 5.55 (3.72, 8.29) during the observation period that ranged from age 15 to 19 years to 1.77 (1.65, 1.90) at age 40 or older. For men, the corresponding figures were 6.12 (4.07, 9.19) and 1.83 (1.72, 1.94); in contrast to women, risk of suicide attempt among men increased from age 15 to 29 before declining. In co-relative models, a residual association remained, consistent with a causal path from AUD to suicide attempt. Conclusions: In Sweden, alcohol use disorder appears to be an important predictor of suicide attempt even in the context of other psychiatric disorders. The observed association is likely the result of features that jointly impact risk of alcohol use disorder and suicide attempts (genetic liability, psychiatric illness, and childhood stressors) and a potentially causal pathway, acting independently or in conjunction with one another.
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14.
  • Edwards, Alexis C., et al. (author)
  • Alcohol use disorder and risk of specific methods of suicide death in a national cohort
  • 2024
  • In: Acta Psychiatrica Scandinavica. - 0001-690X. ; 149:6, s. 479-490
  • Journal article (peer-reviewed)abstract
    • Introduction: Alcohol use disorder (AUD) is among the strongest correlates of suicide death, but it is unclear whether AUD status is differentially associated with risk of suicide by particular methods. Methods: The authors used competing risks models to evaluate the association between AUD status and risk of suicide by poisoning, suffocation, drowning, firearm, instruments, jumping, or other means in a large Swedish cohort born 1932–1995 (total N = 6,581,827; 48.8% female). Data were derived from Swedish national registers, including the Cause of Death Register and a range of medical registers. Results: After adjusting for sociodemographic factors and familial liability to suicidal behavior, AUD was positively associated with risk of suicide for each method evaluated (cumulative incidence differences: 0.006–1.040 for females, 0.046–0.680 for males), except the association with firearm suicide in females. AUD was most strongly associated with risk of suicide by poisoning. Sex differences in the effects of AUD and family liability were observed for some, but not all, methods. Furthermore, high familial liability for suicidal behavior exacerbated AUD's impact on risk for suicide by poisoning (both sexes) and suffocation and jumping (males only), while the inverse interaction was observed for firearm suicide (males only). Conclusions: AUD increases risk of suicide by all methods examined and is particularly potent with respect to risk of suicide by poisoning. Differences in risk related to sex and familial liability to suicidal behavior underscore AUD's nuanced role in suicide risk. Future research should investigate targeted means restriction effectiveness among persons with AUD.
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15.
  • Edwards, Alexis C., et al. (author)
  • Alcohol Use Disorder and Risk of Suicide in a Swedish Population-Based Cohort
  • 2020
  • In: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 177:7, s. 627-634
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: The authors examined the association between alcohol use disorder (AUD) and risk of suicide, before and after accounting for psychiatric comorbidity, and assessed the extent to which the observed association is due to a potentially causal mechanism or genetic and familial environmental confounding factors that increase risk for both. METHODS: Longitudinal population-wide Swedish medical, criminal, and pharmacy registries were used to evaluate the risk of death by suicide as a function of AUD history. Analyses employed prospective cohort and co-relative designs, including data on 2,229,880 native Swedes born between 1950 and 1970 and observed from age 15 until 2012. RESULTS: The lifetime rate of suicide during the observation period was 3.54% for women and 3.94% for men with AUD, compared with 0.29% and 0.76% of women and men, respectively, without AUD. In adjusted analyses, AUD remained robustly associated with suicide: hazard ratios across observation periods ranged from 2.61 to 128.0 among women and from 2.44 to 28.0 among men. Co-relative analyses indicated that familial confounding accounted for some, but not all, of the observed association. A substantial and potentially causal relationship remained after accounting for a history of other psychiatric diagnoses. CONCLUSIONS: AUD is a potent risk factor for suicide, with a substantial association persisting after accounting for confounding factors. These findings underscore the impact of AUD on suicide risk, even in the context of other mental illness, and implicate the time frame shortly after a medical or criminal AUD registration as critical for efforts to reduce alcohol-related suicide.
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16.
  • Edwards, Alexis C., et al. (author)
  • Associations between Divorce and Onset of Drug Abuse in a Swedish National Sample
  • 2018
  • In: American Journal of Epidemiology. - : Oxford University Press (OUP). - 0002-9262 .- 1476-6256. ; 187:5, s. 1010-1018
  • Journal article (peer-reviewed)abstract
    • Rates of drug abuse are higher among divorced individuals than among those who are married, but it is not clear whether divorce itself is a risk factor for drug abuse or whether the observed association is confounded by other factors. We examined the association between divorce and onset of drug abuse in a population-based Swedish cohort born during 1965-1975 (n = 651,092) using Cox proportional hazards methods, with marital status as a time-varying covariate. Potential confounders (e.g., demographics, adolescent deviance, and family history of drug abuse) were included as covariates. Parallel analyses were conducted for widowhood and drug-Abuse onset. In models with adjustments, divorce was associated with a substantial increase in risk of drug-Abuse onset in both sexes (hazard ratios > 5). Co-relative analyses (among biological relatives) were consistent with a partially causal role of divorce on drug-Abuse onset. Widowhood also increased risk of drug-Abuse onset, although to a lesser extent. Divorce is a potent risk factor for onset of drug abuse, even after adjusting for deviant behavior in adolescence and family history of drug abuse. The somewhat less-pronounced association with widowhood, particularly among men, suggests that the magnitude of association between divorce and drug abuse may not be generalizable to the end of a relationship.
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17.
  • Edwards, Alexis C., et al. (author)
  • Divorce and risk of suicide attempt : A Swedish national study
  • In: Psychological Medicine. - 0033-2917.
  • Journal article (peer-reviewed)abstract
    • 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.
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18.
  • Edwards, Alexis C., et al. (author)
  • Early environmental influences contribute to covariation between internalizing symptoms and alcohol intoxication frequency across adolescence
  • 2011
  • In: Addictive Behaviours. - Oxford, United Kingdom : Elsevier. - 0306-4603 .- 1873-6327. ; 36:3, s. 175-182
  • Journal article (peer-reviewed)abstract
    • The association between alcohol use and internalizing symptoms during adolescence varies across studies, and the causes underlying this association remain unclear. The current study examines the relationship between symptoms of anxiety and depression and intoxication frequency in a sample of Swedish twins assessed longitudinally from ages 13-14 to 19-20. The objectives of the study were to assess the stability of genetic and environmental influences on each trait across adolescence; to investigate whether these traits share genetic and/or environmental liabilities; and to explore quantitative changes in the shared liability over time. We found that the magnitude of genetic influences on internalizing symptoms remained relatively stable across adolescence, while their impact on intoxication frequency was dynamic. Symptoms of anxiety and depression were influenced by unique environmental factors, while both shared and unique environmental factors influenced intoxication frequency. Genetic and environmental innovation and attenuation were observed for both traits. While no significant genetic correlation was observed between traits, unique environmental factors did contribute to a shared liability. This environmental correlation was positive and moderate (r(E)=0.41) in the early assessment, but decreased and changed direction at later waves (r(E)=-.04 to -.01). The genetic and environmental factors underlying internalizing symptoms and intoxication frequency appear to be developmentally dynamic. Early environmental factors contribute to the association between these traits, but this shared liability diminishes across adolescence.
  •  
19.
  • Edwards, Alexis C., et al. (author)
  • Exposure to alcohol outlets and risk of suicidal behavior in a Swedish cohort of young adults
  • 2023
  • In: Alcoholism: Clinical and Experimental Research. - 0145-6008. ; 47:5, s. 930-939
  • Journal article (peer-reviewed)abstract
    • 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.
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20.
  • Edwards, Alexis C., et al. (author)
  • Genetic and environmental influences on the progression from alcohol use disorder to alcohol-related medical conditions
  • 2021
  • In: Alcoholism: Clinical and Experimental Research. - : Wiley. - 0145-6008 .- 1530-0277. ; 45:12, s. 2528-2535
  • Journal article (peer-reviewed)abstract
    • 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.
  •  
21.
  • Edwards, Alexis C., et al. (author)
  • Genetic differences between suicide deaths and deaths of undetermined intent
  • 2023
  • In: Suicide and Life-Threatening Behavior. - : Wiley. - 0363-0234 .- 1943-278X. ; 53:1, s. 100-109
  • Journal article (peer-reviewed)abstract
    • Introduction: Few, if any, prior studies have considered whether undetermined intent (UDI) deaths and suicide deaths differ with respect to genetic liability for suicidal behavior or psychopathology. Methods: The authors used Swedish national registry data to identify suicide deaths (N = 31,835) and UDI deaths (N = 10,623); sociodemographic covariates; and registrations for psychopathology. Family genetic risk scores (FGRS) were derived for each form of psychopathology. The authors used LASSO models to assess genetic and phenotypic differences across outcomes. Results: In the multivariate LASSO regressions, higher FGRS for major depression, bipolar disorder, and suicide death were associated with lower odds of UDI relative to unambiguous suicide (OR = 0.91–0.95), while those for alcohol and drug use disorders, ADHD, and criminal behavior were associated with higher odds of UDI relative to unambiguous suicide (OR = 1.04–1.12). When the corresponding phenotypic registration status for these outcomes was included in a subsequent model, the associations were attenuated and of small magnitude, but many remained different from OR = 1. Conclusions: Aggregate genetic differences between unambiguous suicide decedents and UDI deaths are small, particularly when accounting for psychiatric comorbidity, but in some cases, statistically significant. These findings suggest that different analytic treatment of UDI deaths may be warranted depending on the research question. Replication in other samples, and using molecular genetic data, is necessary.
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22.
  • Edwards, Alexis C., et al. (author)
  • Long-term Risks of Depression and Suicide Among Men with Prostate Cancer : A National Cohort Study
  • 2023
  • In: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 84:3, s. 263-272
  • Journal article (peer-reviewed)abstract
    • Background: A diagnosis of prostate cancer (PC) may cause psychosocial distress that worsens quality of life; however, long-term mental health outcomes are unclear.Objective: To determine the long-term risks of major depression and death by suicide in a large population-based cohort. Design, setting, and participants: This was a national cohort study of 180 189 men diagnosed with PC during 1998-2017 and 1 801 890 age-matched, population-based, control men in Sweden.Outcome measurements and statistical analysis: Major depression and death by suicide were ascertained from nationwide outpatient, inpatient, and death records up to 2018. Cox regression was used to compute hazard ratios (HRs) adjusted for sociodemographic factors and comorbidities. Subanalyses assessed differences by PC treatment during 2005-2017.Results and limitations: Men diagnosed with high-risk PC had higher relative rates of major depression (adjusted HR [aHR] 1.82, 95% confidence interval [CI] 1.75-1.89) and death by suicide (aHR 2.43, 95% CI 2.01-2.95). These associations persisted for >= 10 yr after PC diagnosis. The relative increase in major depression was lower among those treated with radiation (aHR 1.44, 95% CI 1.31-1.57) or surgery (aHR 1.60, 95% CI 1.311.95) in comparison to androgen deprivation therapy (ADT) alone (aHR 2.02, 95% CI 1.89-2.16), whereas the relative rate of suicide death was higher only among those treated solely with ADT (aHR 2.83, 95% CI 1.80-4.43). By contrast, men with low- or intermediate-risk PC had a modestly higher relative rate of major depression (aHR 1.19, 95% CI 1.16-1.23) and higher relative rate of suicide death at 3-12 mo after PC diagnosis (aHR 1.88, 95% CI 1.11-3.18) but not across the entire follow-up period aHR 1.02, 95% CI 0.84-1.25). This study was limited to Sweden and will need replication in other populations.Conclusions: In this large cohort, high-risk PC was associated with substantially higher relative rates of major depression and death by suicide, which persisted for >= 10 yr after PC diagnosis. PC survivors need close follow-up for timely detection and treatment of psychosocial distress. Patient summary: In a large Swedish population, men with aggressive prostate cancer had higher long-term relative rates of depression and suicide. (c) 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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23.
  • Edwards, Alexis C., et al. (author)
  • Military service and risk of subsequent drug use disorders among Swedish men
  • 2023
  • In: Social Psychiatry and Psychiatric Epidemiology. - : Springer Science and Business Media LLC. - 0933-7954 .- 1433-9285. ; 58:7, s. 1039-1048
  • Journal article (peer-reviewed)abstract
    • Purpose: Environmental factors contribute substantially to risk for drug use disorders (DUD). The current study applies multiple methods to empirically test whether military service is associated with subsequent DUD, as previous findings are inconsistent. Methods: Longitudinal Swedish national registry data on a cohort of male conscripts born 1972–1987 (maximum N = 485,900) were used to test the association between military service and subsequent registration for DUD. Cox proportional hazard models were used in preliminary analyses, followed by three methods that enable causal inference: propensity score models, co-relative models, and instrumental variable analysis. Results: Across all methods, military service was causally associated with lower risk of DUD. Hazard ratios ranged from HR = 0.43 (95% confidence intervals [CI] 0.37; 0.50) in the instrumental variable analysis to 0.77 (0.75; 0.79) in the multivariate propensity score matching analysis. This effect diminished across time. In the model including a propensity score, HRs remained below 1 across the observation period, while confidence intervals included 1 after ~ 11 years in the co-relative analysis and after ~ 21 years in the instrumental variable analysis. Conclusions: In this cohort of Swedish men, complementary methods indicate that military service conferred substantial but time-limited protection against subsequent DUD. The observed effect could be due to reduced opportunity for substance use during service, social cohesion experienced during and after service, and/or socioeconomic advantages among veterans. Additional research is necessary to clarify these protective mechanisms and determine how other environmental contexts can provide similar benefits.
  •  
24.
  • Edwards, Alexis C., et al. (author)
  • Oral contraceptive use and risk of suicidal behavior among young women
  • 2022
  • In: Psychological Medicine. - 0033-2917. ; 52:9, s. 1710-1717
  • Journal article (peer-reviewed)abstract
    • 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.
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25.
  • Edwards, Alexis C., et al. (author)
  • Protective Effects of Pregnancy on Risk of Alcohol Use Disorder
  • 2019
  • In: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 176:2, s. 138-145
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE:: The authors sought to clarify the etiology of the association between pregnancy and reduced risk of alcohol use disorder. METHODS:: The authors used data from longitudinal population-wide Swedish medical, pharmacy, and criminal registries to evaluate whether rates of alcohol use disorder are lower during pregnancy. They compared pregnant women born between 1975 and 1992 (N=322,029) with matched population controls, with female relatives discordant for pregnancy, and with pre- and postpregnancy periods within individuals. They further compared rates of alcohol use disorder between pregnant women and their partners. RESULTS:: Pregnancy was inversely associated with alcohol use disorder across all analyses (odds ratios, 0.17-0.32). In co-relative analyses, the strength of the association increased among more closely related individuals. Within individuals, rates of alcohol use disorder were substantially decreased during pregnancy relative to the prepregnancy period (odds ratios, 0.25-0.26), and they remained reduced during postpartum periods (odds ratios, 0.23-0.31). Results were similar for second pregnancies (odds ratio, 0.23). The partners of pregnant women also exhibited reductions in alcohol use disorder (odds ratio, 0.45). Among women who became pregnant at earlier ages and those with a history of criminal behavior, the negative association between pregnancy and alcohol use disorder was especially pronounced, but no moderation was observed for a personal or maternal parental history of alcohol use disorder. CONCLUSIONS:: The findings suggest that pregnancy plays a critical, and likely causal, motivational role in reducing alcohol use disorder risk among women and, to a lesser extent, their partners. These results extend our understanding of the relationship between pregnancy and alcohol use, demonstrating that even a severe condition such as alcohol use disorder is subject to the protective effects of pregnancy.
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26.
  • Edwards, Alexis C., et al. (author)
  • Shared genetic and environmental etiology between substance use disorders and suicidal behavior
  • 2023
  • In: Psychological Medicine. - 0033-2917. ; 53:6, s. 2380-2388
  • Journal article (peer-reviewed)abstract
    • 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.
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27.
  • Edwards, Alexis C., et al. (author)
  • Socioeconomic position indicators and risk of alcohol-related medical conditions : A national cohort study from Sweden
  • 2024
  • In: PLoS Medicine. - 1549-1277. ; 21:3
  • Journal article (peer-reviewed)abstract
    • Background AAUlco:hPollecaosencsounmfirpmtitohnatcaollnhteraibduintegsletvoelesxacreersesprmesoernbtiedditcyorarnedctmly:ortality 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.
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28.
  • Edwards, Alexis C., et al. (author)
  • Socioeconomic sequelae of drug abuse in a Swedish national cohort
  • 2020
  • In: Drug and Alcohol Dependence. - : Elsevier BV. - 0376-8716. ; 212
  • Journal article (peer-reviewed)abstract
    • Background: Drug abuse is frequently associated with negative sequelae such as reduced socioeconomic functioning. The extent to which these associations are attributable to a causal role of the disorder versus confounding factors that increase risk for both drug abuse and negative socioeconomic outcomes is unclear. Methods: Drug abuse cases were identified using Swedish national medical, pharmacy, and criminal registers. Applying Cox proportional hazard models, we tested the association between drug abuse and four outcomes: early retirement, social assistance, unemployment, and income at age 50. We used co-relative models to determine whether familial confounding factors accounted for observed associations. Results: In models adjusted for birth year, education, and early onset externalizing behavior, drug abuse was strongly associated with early retirement (hazard ratios [HR] = 5.13–6.28), social assistance (HR = 6.74–7.89), and income at age 50 (beta = −0.19 to −0.12); it was more modestly associated with unemployment (HR = 1.05–1.20). For social assistance and income (both sexes), and early retirement (women only), a model in which the association was partly attributable to familial factors fit the data well; residual associations support a partially causal role of drug abuse. For unemployment and early retirement among men, there was little evidence of familial confounding. Conclusions: The negative socioeconomic sequelae of drug abuse are likely due in part to familial confounding factors in conjunction with a causal relationship and/or unmeasured non-familial confounders. Relative contributions from distinct mechanisms differed across socioeconomic outcomes, which could have implications for understanding the potential impact of prevention and intervention efforts.
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29.
  • Edwards, Alexis C., et al. (author)
  • The role of substance use disorders in the transition from suicide attempt to suicide death : a record linkage study of a Swedish cohort
  • 2024
  • In: Psychological Medicine. - 1469-8978. ; 54:1, s. 90-97
  • Journal article (peer-reviewed)abstract
    • 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.
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30.
  • Edwards, Alexis C., et al. (author)
  • Time-specific and cumulative effects of exposure to parental externalizing behavior on risk for young adult alcohol use disorder
  • 2017
  • In: Addictive Behaviors. - : Elsevier BV. - 0306-4603. ; 72, s. 8-13
  • Journal article (peer-reviewed)abstract
    • Background Previous studies indicate that parental externalizing behavior (EB) is a robust risk factor for alcohol use disorder (AUD) in their children, and that this is due to both inherited genetic liability and environmental exposure. However, it remains unclear whether the effects of exposure to parental EB vary as a function of timing and/or chronicity. Methods We identified biological parents with an alcohol use disorder, drug abuse, or criminal behavior, during different periods of their child's upbringing, using Swedish national registries. Logistic regression was used to determine whether the effect of parental EB exposure during different developmental periods differentially impacted children's risk for young adult AUD (ages 19–24). In addition, we tested how multiply affected parents and/or sustained exposure to affected parents impacted risk. Results While parental EB increased risk for young adult AUD, timing of exposure did not differentially impact risk. Having a second affected parent increased the risk of AUD additionally, and sustained exposure to parental EB across multiple periods resulted in a higher risk of young adult AUD than exposure in only one period. Conclusions In this well-powered population study, there was no evidence of “sensitive periods” of exposure to national registry-ascertained parental EB with respect to impact on young adult AUD, but sustained exposure was more pathogenic than limited exposure. These findings suggest developmental timing does not meaningfully vary the impact, but rather there is a pervasive risk for development of young adult AUD for children and adolescents exposed to parental EB.
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31.
  • Homman, Lina E., et al. (author)
  • Gender and Direction of Effect of Alcohol Problems and Internalizing Symptoms in a Longitudinal Sample of College Students
  • 2017
  • In: Substance Use & Misuse. - : Taylor & Francis. - 1082-6084 .- 1532-2491. ; 52:4, s. 429-438
  • Journal article (peer-reviewed)abstract
    • Background: Alcohol problems and internalizing symptoms are consistently found to be associated but how they relate to each other is unclear. Objective: The present study aimed to address limitations in the literature of comorbidity of alcohol problems and internalizing symptoms by investigating the direction of effect between the phenotypes and possible gender differences in college students. Method: We utilized data from a large longitudinal study of college students from the United States (N = 2607). Three waves of questionnaire-based data were collected over the first two years of college (in 2011–2013). Cross-lagged models were applied to examine the possible direction of effect of internalizing symptoms and alcohol problems. Possible effects of gender were investigated using multigroup modeling. Results: There were significant correlations between alcohol problems and internalizing symptoms. A direction of effect was found between alcohol problems and internalizing symptoms but differed between genders. A unidirectional relationship varying with age was identified for males where alcohol problems initially predicted internalizing symptoms followed by internalizing symptoms predicting alcohol problems. For females, a unidirectional relationship existed wherein alcohol problems predicted internalizing symptoms. Conclusions/Importance: We conclude that the relationship between alcohol problems and internalizing symptoms is complex and differ between genders. In males, both phenotypes are predictive of each other, while in females the relationship is driven by alcohol problems. Importantly, our study examines a population-based sample, revealing that the observed relationships between alcohol problems and internalizing symptoms are not limited to individuals with clinically diagnosed mental health or substance use problems.
  •  
32.
  • Kendler, Kenneth S., et al. (author)
  • A developmental etiological model for drug abuse in men
  • 2017
  • In: Drug and Alcohol Dependence. - : Elsevier BV. - 0376-8716. ; 179, s. 220-228
  • Journal article (peer-reviewed)abstract
    • Background We attempt to develop a relatively comprehensive structural model of risk factors for drug abuse (DA) in Swedish men that illustrates developmental and mediational processes. Methods We examined 20 risk factors for DA in 48,369 men undergoing conscription examinations in 1969–70 followed until 2011 when 2.34% (n = 1134) of them had DA ascertained in medical, criminal and pharmacy registries. Risk factors were organized into four developmental tiers reflecting i) birth, ii) childhood/early adolescence, iii) late adolescence, and iv) young adulthood. Structural equational model fitting was performed using Mplus. Results The best fitting model explained 47.8% of the variance in DA. The most prominent predictors, in order, were: early adolescent externalizing behavior, early adult criminal behavior, early adolescent internalizing behavior, early adult unemployment, early adult alcohol use disorder, and late adolescent drug use. Two major inter-connecting pathways emerged reflecting i) genetic/familial risk and ii) family dysfunction and psychosocial adversity. Generated on a first and tested on a second random half of the sample, a model from these variables predicted DA with an ROC area under the curve of 83.6%. Fifty-nine percent of DA cases arose from subjects in the top decile of risk. Conclusions DA in men is a highly multifactorial syndrome with risk arising from familial-genetic, psychosocial, behavioral and psychological factors acting and interacting over development. Among the multiple predisposing factors for DA, a range of psychosocial adversities, externalizing psychopathology and lack of social constraints in early adulthood are predominant.
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33.
  • Kendler, Kenneth S., et al. (author)
  • A National Swedish Twin-Sibling Study of Alcohol Use Disorders
  • 2016
  • In: Twin Research and Human Genetics. - : Cambridge University Press (CUP). - 1832-4274 .- 1839-2628. ; 19:5, s. 430-437
  • Journal article (peer-reviewed)abstract
    • The relationship between the genetic and environmental risk factors for alcohol use disorders (AUD) detected in Swedish medical, pharmacy, and criminal registries has not been hitherto examined. Prior twin studies have varied with regard to the detection of shared environmental effects and sex differences in the etiology of AUD. In this report, structural equation modeling in OpenMx was applied to (1) the three types of alcohol registration in a population-based sample of male–male twins and reared-together full and half siblings (total 208,810 pairs), and (2) AUD, as a single diagnosis, in male–male, female–female, and opposite-sex (OS) twins and reared-together full and half siblings (total 787,916 pairs). An independent pathway model fit best to the three forms of registration and indicated that between 70% and 92% of the genetic and 63% and 98% of the shared environmental effects were shared in common with the remainder unique to each form of AUD registration. Criminal registration had the largest proportion of unique genetic and environmental factors. The best fit model for AUD estimated the heritability to be 22% and 57%, respectively, in females and males. Both shared (12% vs. 6%) and special twin environment (29% vs. 2%) were substantially more important in females versus males. In conclusion, AUD ascertained from medical, pharmacy, and criminal Swedish registries largely share the same genetic and environmental risk factors. Large sex differences in the etiology of AUD were seen in this sample, with substantially stronger familial environmental and weaker genetic effects in females versus males.
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34.
  • Kendler, Kenneth S, et al. (author)
  • An Extended Swedish National Adoption Study of Alcohol Use Disorder.
  • 2015
  • In: JAMA Psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 72:3, s. 211-218
  • Journal article (peer-reviewed)abstract
    • Alcohol use disorder (AUD) runs strongly in families. It is unclear to what extent the cross-generational transmission of AUD results from genetic vs environmental factors.
  •  
35.
  • Kendler, Kenneth S., et al. (author)
  • Clinical features of registry-ascertained alcohol use disorders that reflect familial risk
  • 2016
  • In: Drug and Alcohol Dependence. - : Elsevier BV. - 0376-8716. ; 164, s. 135-142
  • Journal article (peer-reviewed)abstract
    • Background: Alcohol Use Disorder (AUD) is clinically heterogeneous. Using a large epidemiological sample ascertained via public registries, is it possible to identify clinical and historical features of AUD that reflect familial risk? Methods: Using registration in national medical, legal or pharmacy registries, we identified four kinds of relative pairs (n = 683,223) starting with a proband with AUD: cousins, half-siblings, full-siblings and monozygotic cotwins. Using linear hazard regression, we examined the interaction between five clinical/historical features of AUD in the proband and risk for AUD in these relatives. Results: Increased risk for AUD in relatives was predicted by the proband's early age at first registration, total number of registrations, recurrence, history of drug abuse and ascertainment in the medical versus the legal or pharmacy registry. In multivariate models, age at first registration, number of registrations, recurrence and history of drug abuse remained significant and in aggregate strongly predicted the risk for AUD in relatives. The risk for AUD in siblings of AUD probands in the highest decile of genetic risk predicted by these four indices was more than twice as great as that predicted in siblings of probands in the lowest risk decile. Conclusions: In an epidemiological sample, familial risk for AUD can be assessed by simple clinical and historical variables.
  •  
36.
  • Kendler, Kenneth S., et al. (author)
  • Genetic liability to suicide attempt, suicide death, and psychiatric and substance use disorders on the risk for suicide attempt and suicide death : A Swedish national study
  • 2023
  • In: Psychological Medicine. - 0033-2917. ; 53:4, s. 1639-1648
  • Journal article (peer-reviewed)abstract
    • 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.
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37.
  • Kendler, Kenneth S., et al. (author)
  • Geographical proximity and the transmission of drug abuse among siblings : Evaluating a contagion model in a Swedish National Sample
  • 2020
  • In: Epidemiology and Psychiatric Sciences. - 2045-7960. ; 29
  • Journal article (peer-reviewed)abstract
    • AimsCan drug abuse (DA) be transmitted psychologically between adult siblings consistent with a social contagion model?MethodsWe followed Swedish sibling pairs born in 1932-1990 until one of them, sibling1 (S1), had a first DA registration. We then examined, using Cox regression, the hazard rate for a first registration for DA in sibling2 (S2) within 3 years of a first DA registration in S1 as a function of their geographical proximity. We examined 153 294 informative pairs. To control for familial confounding, we repeated these analyses in sibships containing multiple pairs, comparing risk in different siblings with their proximity to S1. DA was recorded in medical, criminal or pharmacy registries.ResultsThe best-fit model predicted risk for DA in S2 as a function of the log of kilometres between S1 and S2 with parameter estimates (±95% confidence intervals) of 0.94 (0.92; 0.95). Prediction of DA included effects of cohabitation and an interaction of proximity and time since S1 registration with stronger effects of proximity early in the follow-up period. Proximity effects were stronger for smaller S1-S2 age differences and for same-v. opposite-sex pairs. Sibship analyses confirmed sibling-pair results.ConclusionsConsistent with a social contagion model, the probability of transmission of a first registration for DA in sibling pairs is related to their geographical proximity and similarity in age and sex. Such effects for DA are time-dependent and include cohabitation effects. These results illustrate the complexity of the familial aggregation of DA and support efforts to reduce their contagious spread within families in adulthood.
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38.
  • Kendler, Kenneth S., et al. (author)
  • Mediational pathways from genetic risk to alcohol use disorder in swedish men and women
  • 2021
  • In: Journal of Studies on Alcohol and Drugs. - : Alcohol Research Documentation, Inc.. - 1937-1888 .- 1938-4114. ; 82:3, s. 431-438
  • Journal article (peer-reviewed)abstract
    • Objective: The purpose of this study was to clarify the mediational pathways from genetic risk for alcohol use disorder (AUD) to AUD itself. Method: Using information on AUD status from first-through fourth-degree relatives obtained from national registries, we created a genetic risk score for AUD for the Swedish population. We first tested a simple mediational path model in males and females separately, with early onset externalizing psychopathology (EPP), internalizing psychopathology (IPP), and poor educational attainment (EA). We then tested a more complex model in a smaller, older sample of males that contained additional self-report measures from late ado-lescence. Results: In our basic model, the largest mediational pathway from AUD genetic risk to AUD in both sexes was via high EPP followed by low EA and high IPP. The EPP pathway was considerably stronger in males, the low EA pathway was modestly stronger in females, and the IPP pathway was identical in both sexes. Our more complex model replicated the strong externalizing pathway to AUD, showing that it connected to key downstream risk factors such as early drug and alcohol use and low resilience. Conclusions: Our models concurred in showing that the strongest mediational pathway for genetic risk to AUD includes externalizing symptoms and disorders, which in turn predict further key downstream risk factors. Pathways through lower EA and IPP had smaller effects. IPP had mixed effects (partly predisposing and partly protective) on downstream risk factors. The largest sex difference was a stronger externalizing pathway to genetic risk to AUD in males than in females. (J. Stud. Alcohol Drugs, 82, 431–438, 2021).
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39.
  • Kendler, Kenneth S., et al. (author)
  • The sources of parent-child transmission of risk for suicide attempt and deaths by suicide in swedish national samples
  • 2020
  • In: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 177:10, s. 928-935
  • Journal article (peer-reviewed)abstract
    • Objective: The authors aimed to clarify the sources of parent-child transmission for suicide attempt and death by suicide. Methods: Three sources of parent-child resemblance (genes plus rearing, genes only, and rearing only) were examined in parents and offspring from four family types from Swedish national samples: intact nuclear families, families with a not-lived-with biological father, families with a stepfather, and adoptees and their biological and adoptive parents. Parent-child resemblance was assessed primarily by tetrachoric correlation. Results: For suicide attempt to suicide attempt transmission, best-estimate tetrachoric correlations for genes plus rearing, genes only, and rearing only were 0.23 (95% CI=0.23, 0.24), 0.13 (95% CI=0.11, 0.15), and 0.14 (95% CI=0.11, 0.16), respectively. Suicide attempt was more strongly transmitted to male offspring compared with female offspring. Parental psychiatric disorders accounted for 40% of the genetic transmission but had no impact on rearing effects. For suicide death to suicide death transmission, best estimates of tetrachoric correlations for genes plus rearing, genes only, and rearing only were 0.16 (95% CI=0.15, 0.18), 0.07 (95% CI=0.02, 0.12), and 20.05 (95% CI=20.17, 0.07), respectively. Although the suicide attempt-suicide death genetic correlation was high (0.84), the hypothesis that they reflect behaviors only differing in severity on the same continuum of genetic liability could be rejected. Conclusions: The transmission of suicide attempt across generations is moderately strong and arises equally from genetic and rearing effects. Parental psychiatric illness explains almost half of the genetic transmission of suicide attempt but none of the rearing effect. Suicide death is modestly transmitted across generations, probably via genetic effects, although rearing may play a role. While suicide attempt and suicide death share a substantial proportion of their hereditary risk, they do not, from a genetic perspective, simply reflect milder and more severe forms of the same diathesis.
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40.
  • Lannoy, Séverine, et al. (author)
  • A Swedish population-based study to evaluate the usefulness of resting heart rate in the prediction of suicidal behavior among males
  • In: Suicide and Life-Threatening Behavior. - 0363-0234.
  • Journal article (peer-reviewed)abstract
    • 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.
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41.
  • Lannoy, Séverine, et al. (author)
  • Mediational pathways between aggregate genetic liability and nonfatal suicide attempt : A Swedish population-based cohort
  • In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics. - 1552-4841.
  • Journal article (peer-reviewed)abstract
    • 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.
  •  
42.
  • Lannoy, Séverine, et al. (author)
  • Risk of non-fatal suicide attempt in individuals with substance use disorder : the roles of aggregate genetic liability and environmental exposures in a Swedish population-based cohort
  • 2022
  • In: Addiction. - : Wiley. - 0965-2140 .- 1360-0443. ; 117:11, s. 2943-2952
  • Journal article (peer-reviewed)abstract
    • Background and Aims: Substance use disorder (SUD) is related to widespread adverse consequences, including higher suicidality. Shared genetic liability has been demonstrated between SUD and suicidality. Here, we measured the factors that contribute to increased risk of non-fatal suicide attempt among individuals with SUD by focusing upon aggregate genetic risks and both childhood and past-year environmental factors. Design: Longitudinal study. Family genetic risk scores and environmental factors (childhood, aged from 0 to 15 years, and the year preceding SUD registration) were used to predict the relative risk of non-fatal suicide attempt using Cox proportional hazards models. Additional analyses employed a co-relative design, accounting for genetic factors and shared familial environment, to test for potential causality. Setting and participants: Based on longitudinal Swedish registry data, 228 617 individuals with SUD registrations from 1991 to 2015 were included. Measurements: SUD and suicide attempts were identified using medical records (International Classification of Diseases codes). SUD was also identified using pharmacy and criminal registries. Findings: In multivariable analyses that jointly accounted for all the selected potential predictors, individuals with SUD were at higher risk for non-fatal suicide attempt if they had experienced a parental death [hazard ratio (HR) = 1.58; 95% confidence interval (CI) = 1.30, 1.93], were female (HR = 1.53, 95% CI = 1.49, 1.57), had low educational attainment (HR = 1.50, 95% CI = 1.46, 1.55), received social welfare (HR = 1.21, 95% CI = 1.17, 1.25) or had lived in a non-intact family (HR = 1.11, 95% CI = 1.08, 1.14). In co-relative analyses, low education was supported as a possible causal factor for suicide attempt. Aggregate genetic risks interacted with low education and being raised in a non-intact family, with increased prevalence of suicide attempt in people with high genetic risks and unfavorable environmental exposures. Conclusions: Aggregate genetic liability, childhood environmental experiences and specific socio-economic indicators are important risk factors for non-fatal suicide attempt among individuals with substance use disorder.
  •  
43.
  • Lannoy, Séverine, et al. (author)
  • Risk of suicidal behavior as a function of alcohol use disorder typologies : A Swedish population-based study
  • 2024
  • In: Addiction. - 0965-2140. ; 119:2, s. 281-290
  • Journal article (peer-reviewed)abstract
    • 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.
  •  
44.
  • Lannoy, Séverine, et al. (author)
  • Roles of alcohol use disorder and resilience in risk of suicide attempt in men : A Swedish population-based cohort
  • 2022
  • In: Suicide and Life-Threatening Behavior. - : Wiley. - 0363-0234 .- 1943-278X. ; 52:2, s. 341-351
  • Journal article (peer-reviewed)abstract
    • Introduction: Alcohol use disorder (AUD) has been identified as a strong risk factor for suicide attempt. However, few studies have considered protective factors that may moderate this association, such as resilience. Methods: We used longitudinal nationwide Swedish data of 903,333 males born 1960–1980 and 48,285 males born 1949–1951. We performed Cox proportional hazards models to test the role of AUD, resilience, and their interaction on risk for suicide attempt. We used co-relative models to account for familial factors. Results: Alcohol use disorder was strongly associated with increased risk of suicide attempt [hazard ratio (HR) = 12.22], while resilience was associated with reduced risk (HR = 0.73). Multiplicative interaction (HR = 1.21) showed that, in the context of AUD, the protective role of resilience on risk of suicide attempt was somewhat attenuated. Co-relative analyses supported both familial liability and a possible causal pathway between AUD, resilience, and suicide attempt. In the cohort born 1949–1951, resilience subcomponents—social maturity, interests, psychological energy, home conditions, and emotional control—were all associated with reduced suicide attempt risk (HRs between 0.63 and 0.74). Conclusion: While resilience is associated with reduced risk of suicide attempt, this effect is less pronounced in the context of AUD. These associations are potentially causal.
  •  
45.
  • Lannoy, Séverine, et al. (author)
  • The causal effect of education and cognitive performance on risk for suicide attempt : A combined instrumental variable and co-relative approach in a Swedish national cohort
  • 2022
  • In: Journal of Affective Disorders. - : Elsevier BV. - 0165-0327. ; 305, s. 115-121
  • Journal article (peer-reviewed)abstract
    • Background: The aim of this study was to clarify the possible causal associations between education phenotypes and non-fatal suicide attempts. In particular, we evaluated the roles of academic achievement (school grades), cognitive performance (IQ), and educational attainment (education level). Methods: Based on longitudinal Swedish registry data, we included 2,335,763 individuals (48.7% female) with available school grades, 1,448,438 men with IQ measures, and 4,352,989 individuals (48.4% female) with available data on education level. We combined two different approaches to aid in causal inference: 1) instrumental variables analysis, using month of birth as an instrument related to education but not suicide attempt, to control for measured and unmeasured confounders, and 2) co-relative analysis, comparing pairs of different genetic relatedness (cousins, half, and full siblings) to control for genetic and environmental influences. Results: High education was associated with reduced risk of suicide attempt. Instrumental variable analysis indicated evidence of a likely causal association between higher school grades and lower risk of suicide attempts (HR = 0.71). Co-relative analyses supported the causality between the three predictors and suicide attempt risk (school grades, HR = 0.80, IQ, HR = 0.83, education level, HR = 0.76). Finally, we examined the specificity of education phenotypes and found that both cognitive (IQ) and non-cognitive (school grades, education level) processes were involved in suicide attempt risk. Limitations: IQ was only available in men, limiting the generalizability of this analysis in women. Conclusions: Efforts to support causal associations in psychiatric research are needed to offer better intervention. Programs improving education during adolescence would decrease suicide attempt risk.
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46.
  • Patel, Vishal C., et al. (author)
  • Rifaximin-alpha reduces gut-derived inflammation and mucin degradation in cirrhosis and encephalopathy : RIFSYS randomised controlled trial
  • 2022
  • In: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 76:2, s. 332-342
  • Journal article (peer-reviewed)abstract
    • Background & Aims: Rifaximin-alpha is efficacious for the prevention of recurrent hepatic encephalopathy (HE), but its mechanism of action remains unclear. We postulated that rifaximin-alpha reduces gut microbiota-derived endotoxemia and systemic inflammation, a known driver of HE. Methods: In a placebo-controlled, double-blind, mechanistic study, 38 patients with cirrhosis and HE were randomised 1:1 to receive either rifaximin-alpha (550 mg BID) or placebo for 90 days. Primary outcome: 50% reduction in neutrophil oxidative burst (OB) at 30 days. Secondary outcomes: changes in psychometric hepatic encephalopathy score (PHES) and neurocognitive functioning, shotgun metagenomic sequencing of saliva and faeces, plasma and faecal metabolic profiling, whole blood bacterial DNA quantification, neutrophil toll-like receptor (TLR)-2/4/9 expression and plasma/faecal cytokine analysis. Results: Patients were well-matched: median MELD (11 rifaximin-alpha vs. 10 placebo). Rifaximin-alpha did not lead to a 50% reduction in spontaneous neutrophil OB at 30 days compared to baseline (p = 0.48). However, HE grade normalised (p = 0.014) and PHES improved (p = 0.009) after 30 days on rifaximin-alpha. Rifaximin-alpha reduced circulating neutrophil TLR-4 expression on day 30 (p = 0.021) and plasma tumour necrosis factor-alpha (TNF-alpha) (p <0.001). Rifaximin-a suppressed oralisation of the gut, reducing levels of mucin-degrading sialidase-rich species, Streptococcus spp, Veillonella atypica and parvula, Akkermansia and Hungatella. Rifaximin-alpha promoted a TNF-alpha-and interleukin17E-enriched intestinal microenvironment, augmenting antibacterial responses to invading pathobionts and promoting gut barrier repair. Those on rifaximin-alpha were less likely to develop infection (odds ratio 0.21; 95% CI 0.05-0.96). Conclusion: Rifaximin-alpha led to resolution of overt and covert HE, reduced the likelihood of infection, reduced oralisation of the gut and attenuated systemic inflammation. Rifaximin-alpha plays a role in gut barrier repair, which could be the mechanism by which it ameliorates bacterial translocation and systemic endotoxemia in cirrhosis.
  •  
47.
  • Stephenson, Mallory, et al. (author)
  • Clarifying the relationship between physical injuries and risk for suicide attempt in a Swedish national sample
  • In: Acta Psychiatrica Scandinavica. - 0001-690X.
  • Journal article (peer-reviewed)abstract
    • 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.
  •  
48.
  • Stephenson, Mallory E., et al. (author)
  • Sibling Alcohol Use Disorder Is Associated With Increased Risk for Suicide Attempt
  • 2022
  • In: Clinical Psychological Science. - : SAGE Publications. - 2167-7026 .- 2167-7034. ; 10:2, s. 374-382
  • Journal article (peer-reviewed)abstract
    • 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, even after we accounted for the proband’s AUD status, the proband’s risk for suicide attempt was significantly elevated when the proband’s sibling was affected by AUD. Furthermore, the proband’s risk for 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.
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