Genetics of environmental sensitivity to psychiatric and neurodevelopmental phenotypes: evidence from GWAS of monozygotic twins.

Individual sensitivity to environmental exposures may be genetically influenced. This genotype-by-environment interplay implies differences in phenotypic variance across genotypes. However, environmental sensitivity genetic variants have proven challenging to detect. GWAS of monozygotic twin differences is a family-based variance analysis method, which is more robust to systemic biases that impact population-based methods. We combined data from up to 21,792 monozygotic twins (10,896 pairs) from 11 studies to conduct the largest GWAS meta-analysis of monozygotic phenotypic differences in children and adolescents/adults for seven psychiatric and neurodevelopmental phenotypes: attention deficit hyperactivity disorder (ADHD) symptoms, autistic traits, anxiety and depression symptoms, psychotic-like experiences, neuroticism, and wellbeing. The SNP-heritability of variance in these phenotypes were estimated (h2: 0% to 18%), but were imprecise. We identified a total of 13 genome-wide significant associations (SNP, gene, and gene-set), including genes related to stress-reactivity for depression, growth factor-related genes for autistic traits and catecholamine uptake-related genes for psychotic-like experiences. Monozygotic twins are an important new source of evidence about the genetics of environmental sensitivity.

Health, behavior, and social outcomes among offspring of parents with criminal convictions: a register-based study from Sweden.

BACKGROUND: There is currently insufficient understanding of the health and behavior of children whose parents engage in criminal behavior. We examined associations between parental criminal convictions and wide range of offspring health, behavioral, and social outcomes by age 18 in a large, national sample, aiming to get a comprehensive picture of the risks among children of offending parents. METHODS: We studied 1,013,385 individuals born in Sweden between 1987 and 1995, and their parents. Using data from several longitudinal nationwide registers, we investigated parental convictions and 85 offspring outcomes until the end of 2013, grouped into birth-related conditions, psychiatric and somatic disorders, accidents and injuries, mortality, school achievement, violent victimization, and criminality. Cox proportional hazards regression and logistic regression models were used to examine the associations. The role of genetic factors in intergenerational associations was studied in children-of-siblings analyses. We also examined the co-occurrence of multiple outcomes using Poisson regression. RESULTS: A total of 223,319 (22.0%) individuals had one parent convicted and 31,241 (3.1%) had both parents convicted during the first 18 years of their life. The strongest associations were found between parental convictions and offspring behavioral problems, substance use disorders, poor school achievement, violent victimization, and criminality, with an approximately 2 to 2.5-fold increased risk in children with one convicted parent and 3- to 4-fold increased risk in children with two convicted parents. The risks were particularly elevated among children of incarcerated parents with a history of violent convictions. The associations appeared to be at least partly explained by genetic influences. Parental convictions were also associated with an increased likelihood of experiencing multiple outcomes. CONCLUSIONS: Our findings help to calibrate the risks of a wide range of adverse outcomes associated with parental convictions and may be used to guide prevention efforts and identify key areas for future research.

Effectiveness of substance use disorder treatment as an alternative to imprisonment.

INTRODUCTION: Drug courts are criminal justice programs to divert people with substance use disorders from incarceration into treatment. Drug courts have become increasingly popular in the US and other countries. However, their effectiveness in reducing important public health outcomes such as recidivism and substance-related health harms remains ambiguous and contested. We used nationwide register data from Sweden to evaluate the effectiveness of contract treatment sanction, the Swedish version of drug court, in reducing substance misuse, adverse somatic and mental health outcomes, and recidivism. METHODS: In this prospective cohort study, two quasi-experimental designs were used: difference-in-differences and the within-individual design. In the latter, we compared the risk of outcomes during time on contract treatment to, 1) parole after imprisonment and, 2) probation. RESULTS: The cohort included 11,893 individuals (13% women) who underwent contract treatment. Contract treatment was associated with a reduction of 7 percentage points (95% CI: -.088, -.055) in substance misuse, 5 percentage points (-.064, -.034) in adverse mental health events, 9 percentage points (-.113, -.076) in adverse somatic health events, and 3 fewer charges (-3.16, -2.85) for crime in difference-in-differences analyses. Within-individual associations suggested that the same individual had longer times-to-event for all outcomes during contract treatment than on parole or on probation. CONCLUSIONS: Contract treatment is an effective intervention from both public health and criminal justice perspective. Our findings suggest that it is a superior alternative to incarceration in its target group. Further, we find that an implementation approach that is less punitive and more inclusive than what is typical in the US can be successful.

Cohort Effects on Tobacco Consumption and its Genetic and Environmental Variance Among Finnish Adults born between 1880-1957.

INTRODUCTION: Population research indicates that smoking behaviors in Finland have varied over time by sex and birth cohort. Smoking behaviors are influenced by genes and the environment; like the behaviors themselves, these underlying influences are not necessarily stable over time and may be modifiable by national drug policy. METHODS: We utilized longitudinal mixed effects models and causal-common-contingent twin models to evaluate sex and cohort effects on tobacco consumption and the underlying genetic and environmental variance components in a birth cohort sample of same-sex twins born in Finland between 1880-1957, assessed in 1975, 1981, 1990, and 2011. RESULTS: We identified significant main effects of age, sex, and cohort on quantity of cigarette consumption, as well as significant age×cohort and sex×cohort interactions. We also identified sex and cohort effects on the liability to initiate regular smoking and the magnitude of variation underlying quantity of cigarette consumption. That said, heritability and environmental contributions to both traits were not different between the four sex×cohort groups. CONCLUSIONS: Our results indicate sex and cohort effects on the prevalence of smoking and its underlying variation. Our results on changing prevalence mirror existing population-level research in Finnish samples, but we did not identify differences in heritability found in other studies of cohort effects in tobacco use, potentially due to power issues. These results highlight the importance of considering age, cohort, and timing of policy changes when evaluating changes in substance consumption across time. IMPLICATIONS: This study identifies sex and cohort effects influencing tobacco consumption in a sample of Finnish adult twins born between 1880-1957. Our results are in line with other population level research in Finland and research on cohort effects influencing alcohol use in the same sample. Our results highlight the intertwining effects of age, cohort, sex, and substance policies on substance use.

Patterns and predictors of alcohol misuse trajectories from adolescence through early midlife.

We took a multilevel developmental contextual approach and characterized trajectories of alcohol misuse from adolescence through early midlife, examined genetic and environmental contributions to individual differences in those trajectories, and identified adolescent and young adult factors associated with change in alcohol misuse. Data were from two longitudinal population-based studies. FinnTwin16 is a study of Finnish twins assessed at 16, 17, 18, 25, and 35 years (N = 5659; 52% female; 32% monozygotic). The National Longitudinal Study of Adolescent to Adult Health (Add Health) is a study of adolescents from the United States, who were assessed at five time points from 1994 to 2018 (N = 18026; 50% female; 64% White, 21% Black, 4% Native American, 7% Asian, 9% Other race/ethnicity). Alcohol misuse was measured as frequency of intoxication in FinnTwin16 and frequency of binge drinking in Add Health. In both samples, trajectories of alcohol misuse were best described by a quadratic growth curve: Alcohol misuse increased across adolescence, peaked in young adulthood, and declined into early midlife. Individual differences in these trajectories were primarily explained by environmental factors. Several adolescent and young adult correlates were related to the course of alcohol misuse, including other substance use, physical and mental health, and parenthood.

Lower autonomic arousal as a risk factor for criminal offending and unintentional injuries among female conscripts.

BACKGROUND: Lower autonomic arousal is a well-known correlate of criminal offending and other risk-taking behaviors in men, but few studies have investigated this association in women. AIM: To test associations between autonomic arousal and criminal offending as well as unintentional injuries among female conscripts. METHODS: All women born 1958-1994 in Sweden who participated in voluntary military conscription (n = 12,499) were identified by linking Swedish population-based registers. Predictors were resting heart rate (RHR) and systolic blood pressure (SBP). Covariates were height, weight, and physical energy capacity. Main outcomes were criminal convictions (any, violent, and non-violent) from the National Crime Register. Secondary outcome was unintentional injuries requiring medical treatment or causing death. We used survival analyses to test for associations between predictors and outcomes. RESULTS: Low RHR, relative to high RHR, was associated with an increased risk of any criminal conviction, non-violent criminal convictions, and unintentional injuries. Low SBP, relative to high SBP, was associated with an increased risk of violent criminal convictions. CONCLUSIONS: Results support lower autonomic arousal, particularly lower RHR, as a correlate of criminal offending among women that warrants further examination, as the reported findings have potential implications for the prediction of future female crime.

Associations between sleep medication use and alcohol consumption over 36 years in Finnish twins.

BACKGROUND: Sleep medication use is an indicator of underlying sleep problems that might be induced by various factors such as alcohol use. However, the longitudinal relationship between drinking and sleep problems remains poorly understood. We investigated associations between sleep medication and alcohol use throughout adulthood, and examined the role of familial and potential confounding factors contributing to these associations. METHODS: We used information of zygosity and self-report questionnaire data over a follow-up period of 36 years from the Older Finnish Twin Cohort (N=13,851). RESULTS: Logistic regression analyses suggested consistent associations between sleep medication use and heavy/binge drinking at all four time points (OR range =1.36-3.18, P <0.05), implying that increased drinking is associated with increased sleep medication use over time. Cross-lagged path analyses suggested that moderate/heavy and binge drinking predict sleep medication use at most time points (OR range = 1.15-1.94, P <0.05), whilst sleep medication use predicts subsequent abstaining from alcohol (OR range =2.26-2.47, P <0.05). Within-pair analyses implied that familial factors play a role, and quantitative genetic modelling estimated genetic factors to explain approximately 80% of the lifetime association of sleep medication use with moderate/heavy and binge drinking. CONCLUSIONS: Drinking is associated with sleep medication use throughout adulthood. Further, our results suggest that drinking is likely to predict sleep medication use, thereby potentially constituting a risk factor for sleep problems, and that genetic factors contribute to the association. These findings are important in terms of better understanding the development of sleep and alcohol use disorders.

Parental substance use disorder and risk of intellectual disability in offspring in Sweden: a national register study.

Background: Intellectual disability (ID) is a disorder with unknown aetiology in many cases. Maternal alcohol use is a known risk factor for ID, but less is known about the importance of maternal and paternal substance use disorder (SUD) and risk of ID in offspring. Methods: Data from multiple nationwide registers were used to create a cohort of children born from January 01, 1978 to December 31, 2002. All participants were born in Sweden, had available parental identification information and did not emigrate or die before age 12 (n = 1,940,820). Logistic regression modelling was performed with exposure defined as having a parent who received any SUD diagnosis, including alcohol use disorder (AUD) and drug use disorder (DUD). The outcome was registration of diagnosis of any form of ID. First, we analysed the risk of ID if parental SUD was registered prior to childbirth with stepwise adjustment of multiple covariates. Second, the effect of timing of SUD diagnosis in relation to childbirth was analysed. Findings: Of 37,410 offspring with parental SUD registered prior to birth, 3.0% (n = 1110) had any form of ID compared to 1.2% (n = 23,168) of those 1,903,410 individuals without parental SUD prior birth. Parental SUD prior birth was associated with an increased risk of any form of ID (Odds Ratio [OR]: 2.3 [2.2-2.5]), with ORs similar for maternal (OR: 2.3 [2.1-2.5]) and paternal SUD (OR: 2.3 [2.1-2.5]). These ORs were reduced but remained statistically significant after adjusting for parental education, migration, psychiatric comorbidity, and co-parent SUD (OR parental SUD: 1.6 [1.5-1.8]; OR maternal SUD: 1.4 [1.2-1.5]; OR paternal SUD: 1.6 [1.5-1.7]). Parental SUD was associated with increased risk of ID in offspring irrespective of timing of diagnosis, but if mothers or fathers were diagnosed with AUD during pregnancy (OR maternal AUD: 5.0 [3.1-8.2]; OR paternal AUD: 2.8 [2.2-3.6]), the risk was significantly greater than if the AUD diagnosis was first registered after childbirth (OR maternal AUD: 1.9 [1.8-2.0]; OR paternal AUD: 1.6 [1.6-1.7]). Interpretation: Both paternal and maternal SUD were associated with an increased risk of ID in offspring, with greatest risk observed when AUD was diagnosed during pregnancy. Possible mechanisms may involve shared genetic and environmental factors, including toxic effects from alcohol intake. These findings have clinical implications in suggesting that parental SUD in either parent represents a possibly modifiable risk factor to consider when developing prevention, diagnostics and treatment programs for children with ID. Funding: Stockholm County Council, the Research Council of the Swedish Alcohol Retailing Monopoly, Fredrik and Ingrid Thurings stiftelse, Academy of Finland, the Swedish Research Council and the Swedish Research Council for Health, Working Life and Welfare, Nordforsk by the Nordic Council of Ministers and the Polish Medical Research Agency.

General and violent recidivism of former forensic psychiatric patients in Finland.

Background: Forensic psychiatric care in Finland is provided to individuals who have committed a crime due to a serious mental disorder and are in need of psychiatric care. The reconviction (recidivism) rates for this patient group vary in time and between countries, likely due to different treatment practices and requirements for forensic care. Materials and methods: We set out to study criminal recidivism in a national cohort of all patients released from forensic psychiatric care in Finland between 1999 and 2018. National registries were used to identify the patients and gain information on their criminal sentences. Forensic psychiatric examinations were used to record demographic information for the cohort. The cohort was followed up from hospital discharge to the end of 2019. Results: We identified a total of 501 patients who were released from forensic psychiatric care (mean age: 46.6 years [SD 13.4), 434 (86.6%) were male). The mean and median times spent in treatment for the cohort was 10.0 years [SD 6.5] and 8.7 years, respectively. 91% of the patients had schizophrenia spectrum disorder (F2*), and 63.5% had a substance use disorder. A total of 83 patients (16.6%) committed any crime after being released from care, and the mean time to recidivism was 3.8 years. The recidivism rate was 2015 per 100,000 person years. A total of 48 patients (9.6%) committed a violent crime. The mean time to violent recidivism was 4.2 years. The violent recidivism rate was 1,083 per 100,000 person years. A longer duration of treatment was associated with a decreased risk of general recidivism (HR 0.95, 95% CI 0.90 to 1.00, p = 0.05). Factors associated with higher recidivism were male sex, having a comorbid substance use disorder and younger age at discharge. Conclusion: The recidivism rate in Finland was markedly lower than has been previously reported for other Western countries, and the mean duration of treatment was also longer. A longer treatment time may reduce the risk of criminal recidivism in forensic psychiatric patients. The results suggest, as previous studies have found, that more effort is indicated on the treatment of substance abuse.

Hormonal contraception use and insomnia: A nested case-control study.

Evidence is limited concerning possible associations between the use of hormonal contraception and insomnia. We applied the nested case-control design on a nationwide sample of women, aged 15-49 years, derived from national health care registries to characterize the association between the use of hormonal contraception and the occurrence of insomnia. There were altogether 294,356 users and 294,356 non-users of hormonal contraception. 11,105 new cases of insomnia emerged among the 1,148,969 person-years of the follow-up period of two years. All the significant associations of hormonal contraception with insomnia emerged among the participants aged 34 years or younger, and if only the tertiary care data was concerned, among the those aged 15-19 years. The users of the fixed combination of drospirenone and ethinylestradiol as well as that of cyproterone and ethinylestradiol had significantly decreased odds for insomnia, whereas the users levonorgestrel-releasing intrauterine devise as well as those of vaginal ring with etonogestrel and ethinylestradiol had significantly increased odds for insomnia as compared with non-users. Our findings suggest that different products prescribed for hormonal contraception may be differentially associated with the occurrence of insomnia.

Genetic and Environmental Factors Underlying Parallel Changes in Body Mass Index and Alcohol Consumption: A 36-Year Longitudinal Study of Adult Twins.

INTRODUCTION: While the genetic and environmental underpinnings of body weight and alcohol use are fairly well-known, determinants of simultaneous changes in these traits are still poorly known. We sought to quantify the environmental and genetic components underlying parallel changes in weight and alcohol consumption and to investigate potential covariation between them. METHODS: The analysis comprised 4,461 adult participants (58% women) from the Finnish Twin Cohort with four measures of alcohol consumption and body mass index (BMI) over a 36-year follow-up. Trajectories of each trait were described by growth factors, defined as intercepts (i.e., baseline) and slopes (i.e., change over follow-up), using latent growth curve modeling. Growth values were used for male (190 monozygotic pairs, 293 dizygotic pairs) and female (316 monozygotic pairs, 487 dizygotic pairs) same-sex complete twin pairs in multivariate twin modeling. The variances and covariances of growth factors were then decomposed into genetic and environmental components. RESULTS: The baseline heritabilities were similar in men (BMI: h2 = 79% [95% confidence interval: 74, 83]; alcohol consumption: h2 = 49% [32, 67]) and women (h2 = 77% [73, 81]; h2 = 45% [29, 61]). Heritabilities of BMI change were similar in men (h2 = 52% [42, 61]) and women (h2 = 57% [50, 63]), but the heritability of change in alcohol consumption was significantly higher (p = 0.03) in men (h2 = 45% [34, 54]) than in women (h2 = 31% [22, 38]). Significant additive genetic correlations between BMI at baseline and change in alcohol consumption were observed in both men (rA = -0.17 [-0.29, -0.04]) and women (rA = -0.18 [-0.31, -0.06]). Non-shared environmental factors affecting changes in alcohol consumption and BMI were correlated in men (rE = 0.18 [0.06, 0.30]). Among women, non-shared environmental factors affecting baseline alcohol consumption and the change in BMI were inversely correlated (rE = -0.11 [-0.20, -0.01]). CONCLUSIONS: Based on genetic correlations, genetic variation underlying BMI may affect changes in alcohol consumption. Independent of genetic effects, change in BMI correlates with change in alcohol consumption in men, suggesting direct effects between them.

Association of intellectual disability with violent and sexual crime and victimization: a population-based cohort study.

BACKGROUND: Intellectual disability (ID) is associated with violent and sexual offending and victimization, but the importance of neuropsychiatric comorbidity and severity of disability remains unclear. METHODS: In a register-based cohort study of people born in Sweden 1980-1991 (n = 1 232 564), we investigated associations of mild and moderate/severe ID with any, violent and sexual crimes, and with assault victimization, stratified by comorbid autism and attention deficit hyperactivity disorder (ADHD). We defined ID by attendance at a special school or registered diagnosis and obtained data on criminal convictions and injuries or deaths due to assaults from nationwide registers until end of 2013. RESULTS: Compared to people without ID, autism or ADHD, men and women with mild or moderate/severe ID and comorbid ADHD had elevated risks of violent crimes [range of hazard ratios (HRs) 4.4-10.4] and assault victimization (HRs 2.0-7.7). Women with mild ID without comorbidities or with comorbid autism also had elevated risks of violent crimes and victimization (HRs 1.8-4.6) compared to women without ID, autism or ADHD. The relative risks of sexual offending and victimization were elevated in men and women with ID without comorbidities (HRs 2.6-12.7). The highest risks for sexual offending in men (HRs 9.4-11.0) and for sexual assault victimization in women (HRs 11.0-17.1) related to ID and comorbid ADHD. CONCLUSIONS: The elevated risk of violent offending and assault victimization in people with ID is largely explained by comorbid ADHD, whereas ID is independently associated with sexual crimes and victimization, even though absolute risks are low.

Literacy skills seem to fuel literacy enjoyment, rather than vice versa.

Children who like to read and write tend to be better at it. This association is typically interpreted as enjoyment impacting engagement in literacy activities, which boosts literacy skills. We fitted direction-of-causation models to partial data of 3690 Finnish twins aged 12. Literacy skills were rated by the twins' teachers and literacy enjoyment by the twins themselves. A bivariate twin model showed substantial genetic influences on literacy skills (70%) and literacy enjoyment (35%). In both skills and enjoyment, shared-environmental influences explained about 20% in each. The best-fitting direction-of-causation model showed that skills impacted enjoyment, while the influence in the other direction was zero. The genetic influences on skills influenced enjoyment, likely via the skills→enjoyment path. This indicates an active gene-environment correlation: children with an aptitude for good literacy skills are more likely to enjoy reading and seek out literacy activities. To a lesser extent, it was also the shared-environmental influences on children's skills that propagated to influence children's literacy enjoyment. Environmental influences that foster children's literacy skills (e.g., families and schools), also foster children's love for reading and writing. These findings underline the importance of nurturing children's literacy skills. HIGHLIGHTS: It's known that how much children enjoy reading and writing and how good they are at it correlates ∼0.30, but causality remains unknown. We tested the direction of causation in 3690 twins aged 12. Literacy skills impacted literacy enjoyment, but not the other way around. Genetics influence children's literacy skills and how much they like and choose to read and write, indicating genetic niche picking.

Clinical, environmental, and genetic risk factors for substance use disorders: characterizing combined effects across multiple cohorts.

Substance use disorders (SUDs) incur serious social and personal costs. The risk for SUDs is complex, with risk factors ranging from social conditions to individual genetic variation. We examined whether models that include a clinical/environmental risk index (CERI) and polygenic scores (PGS) are able to identify individuals at increased risk of SUD in young adulthood across four longitudinal cohorts for a combined sample of N = 15,134. Our analyses included participants of European (NEUR = 12,659) and African (NAFR = 2475) ancestries. SUD outcomes included: (1) alcohol dependence, (2) nicotine dependence; (3) drug dependence, and (4) any substance dependence. In the models containing the PGS and CERI, the CERI was associated with all three outcomes (ORs = 01.37-1.67). PGS for problematic alcohol use, externalizing, and smoking quantity were associated with alcohol dependence, drug dependence, and nicotine dependence, respectively (OR = 1.11-1.33). PGS for problematic alcohol use and externalizing were also associated with any substance dependence (ORs = 1.09-1.18). The full model explained 6-13% of the variance in SUDs. Those in the top 10% of CERI and PGS had relative risk ratios of 3.86-8.04 for each SUD relative to the bottom 90%. Overall, the combined measures of clinical, environmental, and genetic risk demonstrated modest ability to distinguish between affected and unaffected individuals in young adulthood. PGS were significant but added little in addition to the clinical/environmental risk index. Results from our analysis demonstrate there is still considerable work to be done before tools such as these are ready for clinical applications.

Exploring the relationships between adolescent alcohol misuse and later life health outcomes.

BACKGROUND: We sought to clarify the impact of adolescent alcohol misuse on adult physical health and subjective well-being. To do so, we investigated both the direct associations between adolescent alcohol misuse and early midlife physical health and life satisfaction and the indirect effects on these outcomes attributable to subsequent alcohol problems. METHOD: The sample included 2733 twin pairs (32% monozygotic; 52% female) from the FinnTwin16 study. Adolescent alcohol misuse was a composite of frequency of drunkenness, frequency of alcohol use, and alcohol problems at ages 16, 17, and 18.5. The early midlife outcomes included somatic symptoms, self-rated health, and life satisfaction at age 34. The mediators examined as part of the indirect effect analyses included alcohol problems from the Rutgers Alcohol Problem Index at ages 24 and 34. Serial mediation and co-twin comparison models were applied and included covariates from adolescence and early midlife. RESULTS: There were weak direct associations between adolescent alcohol misuse and early midlife physical health and life satisfaction. However, there was stronger evidence for indirect effects, whereby young adult and early midlife alcohol problems serially mediated the relationship between adolescent alcohol misuse and early midlife somatic symptoms (ß = 0.03, 95% CI [0.03, 0.04]), self-rated health (ß = -0.02, 95% CI [-0.03, -0.01]), and life satisfaction (ß = -0.03, CI [-0.04, -0.02]). These serial mediation effects were robust in co-twin comparison analyses. CONCLUSIONS: These results provide evidence that alcohol problems are a primary driver linking adolescent alcohol misuse and poor health outcomes across the lifespan.

Parental alcohol and drug abuse and offspring mortality by age 10: a population-based register study.

BACKGROUND: Parental substance abuse (SA) of alcohol and drugs is associated with offspring mortality, including sudden infant death syndrome (SIDS), in infancy, but research on cause-specific mortality and mortality in later childhood is scarce. METHODS: Using population-based register data on all births in Sweden in 1973-2013 (N = 4.2 million) and Cox regressions, we examined the associations of mother's and father's SA registered between 2 years before and 12 years after the child birth with offspring all-cause and cause-specific mortality in infancy and childhood. RESULTS: Parental SA was associated with increased offspring all-cause and natural-cause mortality in infancy, but not in the neonatal period, and with external-cause mortality in ages 1-9. Risk of SIDS was 130-280% higher in infants with parental SA compared to infants with no parental SA. Adjusting for parental socioeconomic and immigrant status and severe psychiatric disorders, paternal SA was associated with 66% higher mortality due to communicable diseases and infections in infancy, and both maternal and paternal SA were associated with 40-174% higher mortality due to accidents in infancy and in ages 1-9. The associations between parental SA and offspring mortality were similar for male and female offspring. CONCLUSIONS: Child mortality is rare in contemporary Sweden, and parental SA has variable associations with elevated offspring mortality throughout the first 10 years of life, excluding the neonatal period, which is indicative of insufficient recognition of children at risk. Preventive measures should be long-term and targeted to both parental and offspring behaviour.

Alcohol consumption at age 18-25 and number of children at a 33-year follow-up: Individual and within-pair analyses of Finnish twins.

BACKGROUND: Do drinking patterns in late adolescence/early adulthood predict lifetime childlessness and number of children? Research on this question has been only tangentially relevant and the results inconsistent. The designs used to date have been compromised by genetic and environmental confounds that are poorly controlled; covariate effects of smoking and education that are often ignored; males being understudied; population-based sampling rare, and long-term prospective studies with genetically informative designs yet to be reported. METHOD: In a 33-year follow-up, we linked the drinking patterns of >3500 Finnish twin pairs, assessed at ages 18-25, to registry data on their eventual number of children. Analyses distinguished associations of early drinking patterns with lifetime childlessness from those predictive of family size. Within-twin pair analyses used fixed-effects regression models to account for shared familial confounds and genetic liabilities. Childlessness was analyzed with Cox proportional hazards models and family size with Poisson regression. Analyses within-pairs and of twins as individuals were run before and after adjustment for smoking and education, and for oral contraceptive (OC) use in individual-level analyses of female twins. RESULTS: Baseline abstinence and heavier drinking both significantly predicted lifetime childlessness in individual-level analyses. Few abstinent women used OCs, but they were nonetheless more often eventually childless; adjusting for smoking and education did not affect this finding. Excluding childless twins, Poisson models of family size showed heavier drinking at 18-25 to be predictive of fewer children in both men and women. Those associations were replicated in within-pair analyses of dizygotic twins, each level of heavier drinking being associated with smaller families. Among monozygotic twins, associations of drinking with completed family size yielded effects of similar magnitude, reaching significance at the highest levels of consumption, ruling out familial confounds. CONCLUSIONS: Compared to moderate levels of drinking, both abstinence and heavier drinking in late adolescence/early adulthood predicted a greater likelihood of lifetime childlessness and eventual number of children. Familial confounds do not fully explain these associations.

Association of Obsessive-Compulsive Disorder and Obsessive-Compulsive Symptoms With Substance Misuse in 2 Longitudinal Cohorts in Sweden.

Importance: Neurobiological models have postulated shared neural mechanisms between obsessive-compulsive disorder (OCD) and substance use disorders, but results from clinical and epidemiological studies are conflicting or even suggest that OCD may be protective against substance misuse. Objective: To investigate whether OCD and obsessive-compulsive symptoms are associated with substance misuse and the extent to which shared genetic and/or environmental factors account for this association. Design, Setting, and Participants: In this cohort study, individuals in the general population of Sweden born between January 1, 1932, and December 31, 1997 (population cohort), were followed up through Swedish nationwide registers from January 1, 1997, to December 31, 2013. The second cohort included twin participants in the Child and Adolescent Twin Study in Sweden (CATSS) followed up from ages 18 to 24 years. Data were analyzed from March 1, 2021, to March 31, 2022. Exposures: Lifetime International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnosis of OCD in the National Patient Register (population cohort 1), and self-reported obsessive-compulsive symptoms at 18 years of age (CATSS cohort). Main Outcomes and Measures: Substance misuse was defined as registered substance use-related disorder, criminal conviction, or death (population cohort), and self-reported alcohol and drug dependence symptoms at 18 and 24 years of age (CATSS cohort). Results: The general population cohort included 6 304 188 individuals (48.9% women and 51.1% men; median baseline age, 30.5 [IQR, 15.0-46.4] years), of whom 27 342 had an OCD diagnosis. Obsessive-compulsive disorder was associated with an elevated risk of substance misuse (hazard ratio, 3.68 [95% CI, 3.52-3.85]). In the 9230 individuals in the CATSS cohort (5551 women [60.1%] and 3679 men [39.9%]), obsessive-compulsive symptoms at 18 years of age were associated with increased symptoms of alcohol dependence (concurrent [n = 9219], ß = 0.18 [95% CI, 0.16-0.20]; longitudinal [n = 3381], ß = 0.10 [95% CI, 0.06-0.14]) and drug dependence (concurrent [n = 749], ß = 0.19 [95% CI, 0.11-0.27]; longitudinal [n = 452], ß = 0.15 [95% CI, 0.04-0.25]). Comorbid anxiety and depression did not entirely explain the associations in either cohort. Using data from full siblings and maternal half-siblings (population cohort) and monozygotic and dizygotic twins (CATSS cohort) provided estimates of the relative contribution of genetic and environmental influences to the covariance between OCD and obsessive-compulsive symptoms and substance misuse or dependence. The associations were explained by genetic (56%-68%) and nonshared environmental (32%-44%) factors. Conclusions and Relevance: The findings of this Swedish population-based cohort study challenge the notion that OCD is protective against developing substance misuse. The association of OCD and obsessive-compulsive symptoms with substance misuse was largely explained by shared genetics but was also compatible with partial environmental mediation.

Metabolomics profile of 5649 users and nonusers of hormonal intrauterine devices in Finland.

BACKGROUND: Use of hormonal intrauterine devices has grown during the last decades. Although hormonal intrauterine devices act mostly via local effects on the uterus, measurable concentrations of levonorgestrel are absorbed into the systemic circulation. The possible metabolic changes and large-scale biomarker profiles associated with hormonal intrauterine devices have not yet been studied in detail. OBJECTIVE: To examine through the metabolomics approach the metabolic profile of patients using hormonal intrauterine devices and how this metabolic profile is affected by duration and discontinuation of use. STUDY DESIGN: The study consisted of cross-sectional analyses of 5 population-based surveys (FINRISK and FinHealth studies), spanning from 1997 to 2017. All fertile-aged participants (18-49 years) in the surveys with available information on hormonal contraceptive use and metabolomics data (n=5649) were included in the study. Altogether, 211 metabolic measures of users of hormonal intrauterine devices (n=1006) were compared with those of nonusers of hormonal contraception (n=4643) via multivariable linear regression models. To allow comparison across multiple measures, association magnitudes were reported in standard deviation units of difference in biomarker concentration compared with the reference group. RESULTS: After adjustment for covariates, levels of 141 metabolites differed in current users of hormonal intrauterine devices compared with nonusers of hormonal contraception (median difference in biomarker concentration, 0.09 standard deviation): lower levels of particle concentration of larger lipoprotein subclasses, triglycerides, cholesterol and derivatives, apolipoproteins A and B, fatty acids, glycoprotein acetyls, and aromatic amino acids. The metabolic pattern of hormonal intrauterine device use did not change according to duration of use. When comparing previous users and never-users of hormonal intrauterine devices, no significant metabolic differences were observed. CONCLUSION: The use of hormonal intrauterine devices was associated with several moderate metabolic changes previously associated with reduced arterial cardiometabolic risk. The metabolic effects were independent of duration of use of the hormonal intrauterine devices. Moreover, the metabolic profiles were similar after discontinuation of hormonal intrauterine device use and in never-users.

Systemic hormonal contraception and risk of venous thromboembolism.

INTRODUCTION: The increased risk of venous thromboembolism associated with the use of hormonal contraception is well recognized, but evidence regarding hormonal contraception containing natural estradiol is limited. This study aimed to assess the associations between the patterns of use of different systemic hormonal contraceptives and the risk of venous thromboembolism during 2017-2019. MATERIAL AND METHODS: All fertile-aged women (15-49 years) living in Finland in 2017 and using hormonal contraception in 2017 and their 1:1 age- and residence-matched controls not using hormonal contraception in 2017 (altogether 587 559 women) were selected from the Prescription Centre. All incident venous thromboembolism cases during 2018-2019 and their 4:1 age-matched controls were further analyzed in a prospective nested case-control design to assess the associations between the use (starting, stopping, continuous vs no use) of different hormonal contraception types and venous thromboembolism. RESULTS: Altogether, 1334 venous thromboembolism cases occurred during the follow-up period (incidence rate 1.14 per 1000 person-years, 95% confidence interval [CI] 1.08-1.20), with an incidence rate ratio of hormonal contraception vs no hormonal contraception use of 1.42 (95% CI 1.27-1.58). Compared with non-use, starting the use of gestodene and ethinylestradiol (adjusted odds ratio [aOR] 2.85; 95% CI 1.62-5.03), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 0.98-2.44), desogestrel and ethinylestradiol (aOR 1.97; 95% CI 0.99-3.92), and transdermal patch releasing norelgestromin and ethinylestradiol (aOR 5.10; 95% CI 1.12-23.16), as well as continuing the use of gestodene and ethinylestradiol (aOR 2.60; 95% CI 1.61-4.21), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 1.02-2.37), cyproterone-acetate and estrogen/ethinylestradiol (aOR 1.66; 95% CI 1.06-2.61), and vaginal ring releasing etonogestrel and ethinylestradiol (aOR 3.27; 95% CI 1.95-5.48) were associated with venous thromboembolism risk. Regarding the type of estrogen, the highest risk was associated with current use (vs non use in the previous 180 days) of ethinylestradiol-containing preparations (aOR 2.20; 95% CI 1.82-2.65), followed by estradiol-containing preparations (aOR 1.39; 95% CI 1.04-1.87) with no risk for progestin-only hormonal contraception. Current use of estradiol-containing preparations was not associated with venous thromboembolism risk after exclusion of cyproterone-acetate and estrogen/ethinylestradiol (aOR 1.05; 95% CI 0.66-1.66). CONCLUSIONS: An increased risk of venous thromboembolism is associated with ethinylestradiol-containing combined preparations. The use of estradiol-containing combined preparations confers only a slightly increased risk, possibly driven by cyproterone-containing combined oral contraceptives, whereas the use of progestin-only contraception is not associated with venous thromboembolism.