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Objective: The pathways from internalizing psychopathology to substance misuse remain largely unclear. We estimated associations between childhood internalizing problems and subsequent substance misuse in 2 family-based samples. We also investigated sex differences and the role of externalizing comorbidity.Method: We studied associations of childhood internalizing psychopathology with register-based substance misuse after age 13 years. Sample 1 included all individuals born in Sweden from 1984 to 2000 (N = 1,768,516). Depressive and anxiety disorders were included as register-based International Classification of Diseases Ninth Revision (ICD-9) or Tenth Revision (ICD-10) diagnoses before age 13. Sample 2 was a subsample within the population sample, the Child and Adolescent Twin Study in Sweden (CATSS) twin cohort (n = 12,408; born 1992-1998), with mood and anxiety problems assessed at age 9/12 by parents. In both samples, substance misuse was defined as an ICD-9/10 alcohol/drug use disorder or an alcohol/drug-related criminal conviction until December 2013. To account for familial effects, stratified analyses were conducted within siblings and twin pairs.Results: In the population sample, both depressive (hazard ratio [HR] = 2.75, 95% CI = 2.36-3.20) and anxiety disorders (HR = 1.52, 95% CI = 1.35-1.73) were associated with substance misuse. Childhood mood problems (HR = 2.28, 95% CI = 1.69-3.08) were associated with substance misuse in the CATSS sample. The associations were partially explained by familial factors, and comorbid externalizing disorders explained the associations in men but not in women.Conclusion: Childhood mood problems were associated with substance misuse, but familial factors shared by siblings partially explained the associations. The relationship of anxiety with substance misuse was complex and depended on measurement and the type of anxiety disorder. Internalizing problems may be especially important for substance misuse risk in women. [ABSTRACT FROM AUTHOR]

Parents with substance misuse provide their children with a potentially risky rearing environment. According to the evolutionary life history theory, such environments steer individuals towards faster reproductive strategy. However, parents providing their children with hazardous environments may also pass on genes associated with early parenthood. In register data on individuals born in Sweden 1973–1993 (N = 2,176,128), the hazard ratio of entering parenthood by age 25 was 1.70 (95% CI 1.69–1.72) and 1.85 (1.82–1.89) among offspring of fathers and mothers with substance misuse, respectively, compared to others. In analyses using an offspring-of-siblings design in three types of parental sibling pairs (half siblings, full siblings and dizygotic twins, and monozygotic twins) increasingly controlling for genetic confounding, associations between parental substance misuse and offspring's early reproduction gradually attenuated. Our results suggest that the association between parental substance misuse and earlier parenthood in offspring is at least partly genetically confounded. Life history theory should be further tested with genetically informative research designs. [ABSTRACT FROM AUTHOR]

Although attention-deficit/hyperactivity disorder (ADHD) and eating disorders (EDs) frequently co-occur, little is known about the shared etiology. In this study, we comprehensively investigated the genetic association between ADHD and various EDs, including anorexia nervosa (AN) and other EDs such as bulimia nervosa. We applied different genetically informative designs to register-based information of a Swedish nationwide population (N = 3,550,118). We first examined the familial coaggregation of clinically diagnosed ADHD and EDs across multiple types of relatives. We then applied quantitative genetic modeling in full-sisters and maternal half-sisters to estimate the genetic correlations between ADHD and EDs. We further tested the associations between ADHD polygenic risk scores and ED symptoms, and between AN polygenic risk scores and ADHD symptoms, in a genotyped population-based sample (N = 13,472). Increased risk of all types of EDs was found in individuals with ADHD (any ED: odds ratio [OR] = 3.97, 95% confidence interval [CI] = 3.81, 4.14; AN: OR = 2.68, 95% CI = 2.15, 2.86; other EDs: OR = 4.66, 95% CI = 4.47, 4.87; bulimia nervosa: OR = 5.01, 95% CI = 4.63, 5.41) and their relatives compared with individuals without ADHD and their relatives. The magnitude of the associations decreased as the degree of relatedness decreased, suggesting shared familial liability between ADHD and EDs. Quantitative genetic models revealed stronger genetic correlation of ADHD with other EDs (.37, 95% CI =.31,.42) than with AN (.14, 95% CI =.05,.22). ADHD polygenic risk scores correlated positively with ED symptom measures overall and with the subscales Drive for Thinness and Body Dissatisfaction despite small effect sizes. We observed stronger genetic association with ADHD for non-AN EDs than for AN, highlighting specific genetic correlation beyond a general genetic factor across psychiatric disorders. [ABSTRACT FROM AUTHOR]

Abstract Background Uncertainty remains whether bipolar I disorder (BDI) and bipolar II disorder (BDII) differ etiologically. We used a population-based family sample to examine the etiological boundaries between BDI and BDII by assessing their familial aggregation/coaggregation and by assessing the coaggregation between them and schizophrenia, depression, attention-deficit/hyperactivity disorder, eating disorders, autism spectrum disorder, substance use disorders, anxiety disorders, and personality disorders. Methods By linking Swedish national registers, we established a population-based cohort (N = 15,685,511) and identified relatives with different biological relationships. Odds ratios (ORs) were used to measure the relative risk of BDI and BDII in relatives of individuals diagnosed with BDI (n = 4309) and BDII (n = 4178). The heritability for BDI and BDII and the genetic correlation across psychiatric disorders were estimated by variance decomposition analysis. Results Compared with the general population, the OR of BDI was 17.0 (95% confidence interval [CI] 13.1–22.0) in first-degree relatives of BDI patients, higher than that of BDII patients (OR 9.8, 95% CI 7.7–12.5). The ORs of BDII were 13.6 (95% CI 10.2–18.2) in first-degree relatives of BDII patients and 9.8 (95% CI 7.7–12.4) in relatives of BDI patients. The heritabilities for BDI and BDII were estimated at 57% (95% CI 32%–79%) and 46% (95% CI 21%–67%), respectively, with a genetic correlation estimated as 0.78 (95% CI 0.36–1.00). The familial coaggregation of other psychiatric disorders, in particular schizophrenia, showed different patterns for BDI and BDII. Conclusions Our results suggest a distinction between BDI and BDII in etiology, partly due to genetic differences. [ABSTRACT FROM AUTHOR]

Background Women with polycystic ovary syndrome (PCOS) are at elevated risk for suffering from depression. Neuroticism is a personality trait that has been associated with an increased risk for developing major depressive disorder (MDD). The aim of the present study was to quantify and decompose the correlation between neuroticism, PCOS, and MDD into shared and unique genetic and environmental etiologies, by using quantitative genetic methods. Methods In a cohort of 12,628 Swedish female twins born from 1959 to 1985, neuroticism, PCOS identified by symptoms of hyperandrogenemia (i.e., hirsutism) and oligo- and/or anovulation, and lifetime MDD status were determined through questionnaire responses. Structural equation modeling was used to study the genetic and environmental sources of the variation within, and covariation between neuroticism, PCOS, and MDD. Results Female twins with PCOS (n = 752) had significantly higher levels of neuroticism than women without PCOS, and a 2-fold increase in odds for a lifetime prevalence of MDD. The phenotypic correlation between PCOS and MDD was 0.19, with 63% of the correlation attributable to common genetic factors between the two traits. When taking into account neuroticism, 41% was attributable to common genetic factors and 9% attributable to common environmental factors shared between all three traits, with the remainder attributable to components unique to PCOS and MDD. Conclusion There are common genetic factors between neuroticism, PCOS, and MDD; however, neuroticism shares approximately half of the genetic and environmental components behind the phenotypic correlation between PCOS and MDD, providing some etiological evidence behind the comorbidity between PCOS and depression. [ABSTRACT FROM AUTHOR]

A recent study has suggested that labor epidural analgesia may be associated with increased rates of offspring autism spectrum disorder. Subsequent replication attempts have lacked sufficient power to confidently exclude the possibility of a small effect, and the causal nature of this association remains unknown. This study aimed to investigate the extent to which exposure to labor epidural analgesia is associated with offspring autism spectrum disorder and attention-deficit/hyperactivity disorder following adjustments for unmeasured familial confounding. We identified 4,498,462 singletons and their parents using the Medical Birth Registers in Finland (cohorts born from 1987–2005), Norway (1999–2015), and Sweden (1987–2011) linked with population and patient registries. These cohorts were followed from birth until they either had the outcomes of interest, emigrated, died, or reached the end of the follow-up (at mean ages 13.6–16.8 years), whichever occurred first. Cox regression models were used to estimate country-specific associations between labor epidural analgesia recorded at birth and outcomes (eg, at least 1 secondary care diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder or at least 1 dispensed prescription of medication used for the treatment of attention-deficit/hyperactivity disorder). The models were adjusted for sex, birth year, birth order, and unmeasured familial confounders via sibling comparisons. Pooled estimates across all the 3 countries were estimated using inverse variance weighted fixed-effects meta-analysis models. A total of 4,498,462 individuals (48.7% female) were included, 1,091,846 (24.3%) of which were exposed to labor epidural analgesia. Of these, 1.2% were diagnosed with autism spectrum disorder and 4.0% with attention-deficit/hyperactivity disorder. On the population level, pooled estimates showed that labor epidural analgesia was associated with increased risk of offspring autism spectrum disorder (adjusted hazard ratio, 1.12; 95% confidence interval, 1.10–1.14, absolute risks, 1.20% vs 1.07%) and attention-deficit/hyperactivity disorder (adjusted hazard ratio, 1.20; 95% confidence interval, 1.19–1.21; absolute risks, 3.95% vs 3.32%). However, when comparing full siblings who were differentially exposed to labor epidural analgesia, the associations were fully attenuated for both conditions with narrow confidence intervals (adjusted hazard ratio [autism spectrum disorder], 0.98; 95% confidence interval, 0.93–1.03; adjusted hazard ratio attention-deficit/hyperactivity disorder, 0.99; 95% confidence interval, 0.96–1.02). In this large cross-national study, we found no support for the hypothesis that exposure to labor epidural analgesia causes either offspring autism spectrum disorder or attention-deficit/hyperactivity disorder. [ABSTRACT FROM AUTHOR]

Objective: Attention-deficit/hyperactivity disorder (ADHD) has been linked to immaturity relative to peers in childhood, yet it is unclear how such immaturity is associated with ADHD across development. This longitudinal twin study examined the genetic and environmental contributions to the association between parents' perception of their child's immaturity relative to peers (RI) in childhood and ADHD symptoms across development.Method: 1,302 twin pairs from the Swedish Twin Study of Child and Adolescent Development were followed prospectively from childhood to early adulthood. Parent ratings of RI were collected at 8 to 9 years and parent and self-ratings of ADHD symptoms were collected at 8 to 9, 13 to 14, 16 to 17, and 19 to 20 years using the Child Behavior Checklist Attention Problems scale. In addition, ADHD symptoms corresponding to DSM criteria were used for sensitivity analysis. Analyses were conducted using longitudinal structural equation modeling with multiple raters.Results: RI-related etiologic factors, predominantly influenced by genes, explained 10-14% of the variance in ADHD symptoms from 8 to 9 up to 16 to 17 years. The influence of these RI-related factors on ADHD symptoms attenuated to 4% by 19 to 20 years of age. The remaining variance in ADHD symptoms was primarily explained by genetic factors independent of RI, which remained relatively stable across development, explaining 19% to 30% of the variance in ADHD symptoms from 13 to 14 up to 19 to 20 years.Conclusion: The results show that RI is significantly associated with ADHD symptoms, particularly during childhood and adolescence, and that the association is primarily explained by a shared genetic liability. Nevertheless, the magnitude of associations across development was modest, highlighting that RI is merely one aspect contributing to the complex etiology of ADHD symptoms. [ABSTRACT FROM AUTHOR]

We examine how parental criminality is associated with offspring education at different educational stages from primary to tertiary education and conduct separate analyses for non-violent and violent crimes and incarceration, and for paternal and maternal criminality. We use Swedish total population register data of 513,886 children and their parents and estimate both population-level linear probability models and cousin fixed-effects models. Parental criminality was negatively associated with all stages of offspring education. In population-level models accounting for parental education, the strongest associations were observed for parental violent crimes and incarceration with offspring secondary education completion (beta: −0.16 to −0.18). Cousin fixed-effects models suggested that family-level unobserved heterogeneity played a role in the associations as they were reduced when analyzing cousins differently exposed to parental criminality. Parental criminality is negatively associated with offspring educational attainment, and the associations are in part due to shared familial factors. The association is different at different educational stages and for parental violent vs. non-violent crime. • Parental criminality was negatively associated with all stages of offspring education. • Different crime types of parents were differently associated • The associations are in part due to shared familial factors. [ABSTRACT FROM AUTHOR]

Objectives: Gastrointestinal problems are common in all eating disorders; however, the extent to which these problems predate the onset of eating disorders is not clear. We explored longitudinal associations between childhood gastrointestinal problems and adolescent disordered eating, and assessed whether observed associations are potentially causal or due to familial confounding factors.Methods: Data from a population-based Swedish twin sample were used to investigate associations between parent- and self-reported protracted constipation and diarrhea in childhood and adolescence, and later disordered eating, measured by the Eating Disorders Inventory-2 (EDI). Linear regression models were used to investigate the associations. Possible familial confounding was explored by using a within-twin pair analysis.Results: We found that those who reported a history of constipation at age 15 scored 5.55 and 5.04 points higher, respectively, on the EDI total score at age 15 and 18, compared with those without constipation. Those reporting a history of diarrhea at age 15 scored 5.15 points higher, and the group reporting both problems scored 9.52 points higher on the EDI total score at age 15 than those reporting no problems. We observed that the association between constipation and disordered eating was attenuated in the within-twin pair analysis, but remained positive.Conclusions: Gastrointestinal problems in childhood and adolescence are significantly associated with disordered eating. Associations were partly due to familial confounding, but might also be consistent with a causal interpretation. Clinicians should be aware of the increased risk of disordered eating when following children and adolescents who present with gastrointestinal problems. [ABSTRACT FROM AUTHOR]

Objective Individuals with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for poor school performance, and pharmacological treatment of ADHD may have beneficial effects on school performance. Conclusions from previous research have been limited by small sample sizes, outcome measures, and treatment follow-up. The current study analyzed school performance in students with ADHD compared to students without ADHD, and the association between pharmacological treatment of ADHD and school performance. Method A linkage of Swedish national registers covering 657,720 students graduating from year 9 of compulsory school provided measures of school performance, electronically recorded dispensations of ADHD medication, and potentially confounding background factors such as parental socioeconomic status. Primary measures of school performance included student eligibility to upper secondary school and grade point sum. Results ADHD was associated with substantially lower school performance independent of socioeconomic background factors. Treatment with ADHD medication for 3 months was positively associated with all primary outcomes, including a decreased risk of no eligibility to upper secondary school, odds ratio = 0.80, 95% confidence interval (CI) = 0.76−0.84, and a higher grade point sum (range, 0.0−320.0) of 9.35 points, 95% CI = 7.88−10.82; standardized coefficient = 0.20. Conclusion ADHD has a substantial negative impact on school performance, whereas pharmacological treatment for ADHD is associated with higher levels in several measures of school performance. Our findings emphasize the importance of detection and treatment of ADHD at an early stage to reduce the negative impact on school performance. [ABSTRACT FROM AUTHOR]

Background Obsessive-compulsive disorder (OCD) is associated with increased mortality, but the causes of this increase are poorly understood. This study examined whether OCD is associated with an increased risk of metabolic and cardiovascular complications. Methods Individuals diagnosed with OCD ( n = 25,415) were identified from a cohort of 12,497,002 individuals living in Sweden between 1973 and 2013. Cox proportional hazard regression analyses were used to investigate the risk of metabolic and cardiovascular complications in OCD patients compared with the general population and unaffected full siblings of OCD individuals. Exploratory analyses were used to examine the effect of treatment with serotonin reuptake inhibitors, with or without antipsychotics, on the outcomes of interest. Results Individuals with OCD had a higher risk of any metabolic or cardiovascular complications compared with the general population (adjusted hazard ratio = 1.45; 95% confidence interval = 1.42–1.49) and their unaffected full siblings (adjusted hazard ratio = 1.47; 95% confidence interval = 1.40–1.54). In the fully adjusted sibling comparison models, patients had higher risks of obesity, type 2 diabetes mellitus, and circulatory system diseases. The risks were already evident from the beginning of the follow-up period and remained largely unchanged when excluding different groups of psychiatric comorbidities. Compared with patients who were not taking serotonin reuptake inhibitors, patients taking higher doses of serotonin reuptake inhibitors and who had a longer duration of treatment had significantly lower risks of metabolic and cardiovascular complications, regardless of whether they were also taking antipsychotics. Conclusions OCD is associated with an increased risk of metabolic and cardiovascular complications. Our results underscore the importance of carefully monitoring metabolic and cardiovascular health in patients with OCD early in the course of the disorder. [ABSTRACT FROM AUTHOR]

Background Epilepsy and attention-deficit/hyperactivity disorder (ADHD) are strongly associated; however, the underlying factors contributing to their co-occurrence remain unclear. A shared genetic liability has been proposed as one possible mechanism. Therefore, our goal in this study was to investigate the familial coaggregation of epilepsy and ADHD and to estimate the contribution of genetic and environmental risk factors to their co-occurrence. Methods We identified 1,899,654 individuals born between 1987 and 2006 via national Swedish registers and linked each individual to his or her biological relatives. We used logistic regression to estimate the association between epilepsy and ADHD within individual and across relatives. Quantitative genetic modeling was used to decompose the cross-disorder covariance into genetic and environmental factors. Results Individuals with epilepsy had a statistically significant increased risk of ADHD (odds ratio [OR] = 3.47, 95% confidence interval [CI] = 3.33–3.62). This risk increase extended to children whose mothers had epilepsy (OR = 1.85, 95% CI = 1.75–1.96), children whose fathers had epilepsy (OR = 1.64, 95% CI = 1.54–1.74), full siblings (OR = 1.56, 95% CI = 1.46–1.67), maternal half siblings (OR = 1.28, 95% CI = 1.14–1.43), paternal half siblings (OR = 1.10, 95% CI = 0.96–1.25), and cousins (OR = 1.15, 95% CI = 1.10–1.20). The genetic correlation was 0.21 (95% CI = 0.02–0.40) and explained 40% of the phenotypic correlation between epilepsy and ADHD, with the remaining variance largely explained by nonshared environmental factors (49%, nonshared environmental correlation = 0.36, 95% CI = 0.23–0.49). The contribution of shared environmental factors to the cross-disorder overlap was not statistically significant (11%, shared environmental correlation = 0.32, 95% CI = −0.16–0.79). Conclusions This study demonstrates a strong and etiologically complex association between epilepsy and ADHD, with shared familial factors and risk factors unique to the individual contributing to co-occurrence of the disorders. Our findings suggest that epilepsy and ADHD may share less genetic risk as compared with other neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Objective: Although many studies document an association between attention-deficit/hyperactivity disorder (ADHD) and intellectual disability (ID), little is known about the etiology of this comorbidity and how it should be addressed in clinical settings. We sought to clarify this issue.Method: All individuals born in Sweden between 1987 and 2006 (n = 2,049,587) were identified using the Medical Birth Register (MBR). From this we selected 7 cohorts of relatives: 1,899,654 parent-offspring pairs, 4,180 monozygotic twin pairs, 12,655 dizygotic twin pairs, 914,848 full sibling pairs, 136,962 maternal half-sibling pairs, 134,502 paternal half-sibling pairs, and 2,790,164 full cousin pairs. We used within-individual and within-family analyses to assess the association between ADHD and ID.Results: Individuals with ID were at increased risk for ADHD compared to those without ID, and relatives of participants with ID were at increased risk of ADHD compared with relatives of those without ID. The magnitude of this association was positively associated with the fraction of the genome shared by the relative pair and was lower for severe compared with mild and moderate ID. Model-fitting analyses demonstrated that 91% of the correlation between the liabilities of ADHD and ID was attributable to genetic factors.Conclusion: These data provide evidence that nearly all of the comorbidity between ADHD and ID can be attributed to genetic factors, which has implications for diagnostic practice. [ABSTRACT FROM AUTHOR]

Objective: To estimate the relative contribution of genetic influences and prevalence on endometriosis.Design: Analysis of self-reported data from a nationwide population-based twin registry.Setting: Not applicable.Patient(s): A total of 28,370 women, female monozygotic (MZ) or dizygotic (DZ) twins, who participated in either of two surveys (1998-2002 or 2005-2006).Intervention(s): None.Main Outcome Measure(s): Self-reported endometriosis, validated by medical records.Result(s): A history of endometriosis was reported by 1,228 female twins. The probandwise concordance was 0.21 for MZ and 0.10 for DZ twins. Higher within-pair (tetrachoric) correlation was observed among MZ (0.47) compared with DZ (0.20) twins. The best-fitting model revealed a contribution of 47% by additive genetic factors and the remaining 53% attributed to unique environmental effects.Conclusion(s): Our findings suggest both genetic and unique (nonshared) environmental influences on the complex etiology of endometriosis and support the hypothesis that genes have a strong influence on phenotypic manifestations of endometriosis. [ABSTRACT FROM AUTHOR]

Objective Emerging evidence suggests that physical activity (PA) enhances cognition and may be a protective factor for attention-deficit/hyperactivity disorder (ADHD). Yet the impact of PA on ADHD symptoms has been investigated only in a few undersized, nonrandomized, and retrospective studies. We examined the effect of PA during late adolescence on ADHD symptoms in early adulthood while controlling for unmeasured genetic and shared environmental confounding. Method The effect of PA at age 16 to 17 years (baseline) on ADHD symptoms at age 19 to 20 years (follow-up) was examined using a within-monozygotic (MZ) twins fixed-effects model in 232 MZ twin pairs born in Sweden between May 1985 and December 1986. Parents rated their children's DSM ADHD symptoms at baseline and follow-up. Participants' weekly energy expenditure (in metabolic equivalent task minutes per week) was based on self-reports at baseline of PA frequency, intensity, and duration. Results Greater weekly energy expenditure in adolescence was significantly associated with reduced ADHD symptom levels in early adulthood, even when controlling for unmeasured confounding (all genetic and environmental factors shared within MZ twin pairs) as well as ADHD symptoms and body mass index (BMI) at baseline, β = -0.21, p = .013 (95% CI = -0.38 to -0.05). Similar results were observed for the 2 ADHD subcomponents: hyperactivity/impulsivity, β = -0.21, p = .022 (95% CI = -0.39 to -0.03), and inattention, β = -0.19, p = .049 (95% CI = -0.36 to -0.0005). Conclusion In line with a causal hypothesis, PA was inversely associated with ADHD symptoms, even after adjusting for unmeasured confounding. These findings suggest that PA in adolescence might decrease ADHD symptoms in early adulthood. However, given the size of the effect, the clinical value of this intervention needs to be explored further. [ABSTRACT FROM AUTHOR]

We examined associations of adverse perinatal events with offspring violent and non-violent criminal convictions in men and women. All singleton births between 1973 and 1995 (n = 1,146,570 men, n = 1,085,217 women) were identified through Swedish population-based registers. Information about adverse perinatal events was retrieved from the Medical Birth Register. Outcomes were criminal convictions collected from the National Crime Register. We estimated absolute and relative risks of being convicted of criminal convictions using the Kaplan-Meier method and survival analyses for men and women separately. We also tested for differences in magnitudes of associations for men versus women. Several adverse perinatal events were associated with an increased risk of violent and non-violent criminal convictions in both men and women. Associations between low birth weight, smallness relative to gestational age and preterm birth with non-violent criminal convictions were statistically significantly higher for men than for women. There was a dose-dependent association between adverse perinatal events with violent and non-violent criminal convictions for both men and women, indicated by the strengthened magnitude of HR estimates with exposure to an increasing number of adverse perinatal events. Adverse perinatal events are associated with violent and non-violent criminal convictions in men and women, with some differences in risk estimates between sexes. Findings are compatible with theoretical accounts implicating disruption of the neurodevelopment during the perinatal period. • Adverse perinatal events were associated with an increased risk of violent and non-violent criminal offending • Associations between some adverse perinatal events with criminal convictions were significantly higher for men than for women • There was a dose-dependent association between adverse perinatal events with criminal convictions for both men and women [ABSTRACT FROM AUTHOR]