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Additional file 1: Fig S1. Bifactor confirmatory factor analysis model of pain scales. Fig S2. Associations between pain conditions and suicidal behaviors using univariate and multivariate logistic regression model, excluding participants with suicide diagnoses before the STAGE survey. Fig S3. Associations between pain conditions and suicidal behaviors using univariate and multivariate logistic regression model, excluding the undetermined intent diagnoses. Fig S4. Associations between pain conditions and suicidal behaviors using univariate and multivariate Cox regression model. Fig S5. Associations between pain conditions and suicidal behaviors using univariate and multivariate logistic regression model, including self-reported somatic disorders as covariates. Table S1. Frequency distribution of the nine pain conditions among MZ and DZ twins. Table S2. Frequency distribution of the nine pain conditions among suicidal behaviors. Table S3. Standardized factor loadings from the confirmatory bifactor model based on 9 pain scales. Supplemental Method. Details of chronic pain items and scales.

Background β-blockers are widely used for treating cardiac conditions and are suggested for the treatment of anxiety and aggression, although research is conflicting and limited by methodological problems. In addition, β-blockers have been associated with precipitating other psychiatric disorders and suicidal behaviour, but findings are mixed. We aimed to examine associations between β-blockers and psychiatric and behavioural outcomes in a large population-based cohort in Sweden. Methods and findings We conducted a population-based longitudinal cohort study using Swedish nationwide high-quality healthcare, mortality, and crime registers. We included 1,400,766 individuals aged 15 years or older who had collected β-blocker prescriptions and followed them for 8 years between 2006 and 2013. We linked register data on dispensed β-blocker prescriptions with main outcomes, hospitalisations for psychiatric disorders (not including self-injurious behaviour or suicide attempts), suicidal behaviour (including deaths from suicide), and charges of violent crime. We applied within-individual Cox proportional hazards regression to compare periods on treatment with periods off treatment within each individual in order to reduce possible confounding by indication, as this model inherently adjusts for all stable confounders (e.g., genetics and health history). We also adjusted for age as a time-varying covariate. In further analyses, we adjusted by stated indications, prevalent users, cardiac severity, psychiatric and crime history, individual β-blockers, β-blocker selectivity and solubility, and use of other medications. In the cohort, 86.8% (n = 1,215,247) were 50 years and over, and 52.2% (n = 731,322) were women. During the study period, 6.9% (n = 96,801) of the β-blocker users were hospitalised for a psychiatric disorder, 0.7% (n = 9,960) presented with suicidal behaviour, and 0.7% (n = 9,405) were charged with a violent crime. There was heterogeneity in the direction of results; within-individual analyses showed that periods of β-blocker treatment were associated with reduced hazards of psychiatric hospitalisations (hazard ratio [HR]: 0.92, 95% confidence interval [CI]: 0.91 to 0.93, p < 0.001), charges of violent crime (HR: 0.87, 95% CI: 0.81 to 0.93, p < 0.001), and increased hazards of suicidal behaviour (HR: 1.08, 95% CI: 1.02 to 1.15, p = 0.012). After stratifying by diagnosis, reduced associations with psychiatric hospitalisations during β-blocker treatment were mainly driven by lower hospitalisation rates due to depressive (HR: 0.92, 95% CI: 0.89 to 0.96, p < 0.001) and psychotic disorders (HR: 0.89, 95% CI: 0.85 to 0.93, p < 0.001). Reduced associations with violent charges remained in most sensitivity analyses, while associations with psychiatric hospitalisations and suicidal behaviour were inconsistent. Limitations include that the within-individual model does not account for confounders that could change during treatment, unless measured and adjusted for in the model. Conclusions In this population-wide study, we found no consistent links between β-blockers and psychiatric outcomes. However, β-blockers were associated with reductions in violence, which remained in sensitivity analyses. The use of β-blockers to manage aggression and violence could be investigated further.

The Roadmap for Mental Health and Wellbeing Research in Europe (ROAMER) identified child and adolescent mental illness as a priority area for research. CAPICE (Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe) is a European Union (EU) funded training network aimed at investigating the causes of individual differences in common childhood and adolescent psychopathology, especially depression, anxiety, and attention deficit hyperactivity disorder. CAPICE brings together eight birth and childhood cohorts as well as other cohorts from the EArly Genetics and Life course Epidemiology (EAGLE) consortium, including twin cohorts, with unique longitudinal data on environmental exposures and mental health problems, and genetic data on participants. Here we describe the objectives, summarize the methodological approaches and initial results, and present the dissemination strategy of the CAPICE network. Besides identifying genetic and epigenetic variants associated with these phenotypes, analyses have been performed to shed light on the role of genetic factors and the interplay with the environment in influencing the persistence of symptoms across the lifespan. Data harmonization and building an advanced data catalogue are also part of the work plan. Findings will be disseminated to non-academic parties, in close collaboration with the Global Alliance of Mental Illness Advocacy Networks-Europe (GAMIAN-Europe).

International audience; BACKGROUND: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.METHODS: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).RESULTS: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.CONCLUSIONS: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.

Ralf Kuja-Halkola,1 Benjamin Lebwohl,1,2 Jonas Halfvarson,3 Louise Emilsson,4–6 Patrik K Magnusson,1 Jonas F Ludvigsson1,2,7,8 1Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 2Department of Medicine, Celiac Disease Center, Columbia University Medical Center, Columbia University, New York, NY, USA; 3Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 4Department of Health Management and Health Economy, Institute of Health and Society, University of Oslo, Oslo, Norway; 5Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; 6Centre for Clinical Research, Vårdcentralen Värmlands Nysäter, County Council of Värmland, Värmland, 7Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; 8Division of Epidemiology and Public Health, School of Medicine, City Hospital, University of Nottingham, Nottingham, UK Objective: Earlier research suggests that birth weight may be associated with celiac disease (CD), but the direction of association has been unclear potentially due to confounding effect from genetic and intrafamilial factors. Through within-twin analyses, we aimed to minimize confounding effects such as twins that share genetic and early environmental exposures.Materials and methods: Using the Swedish Twin Registry, we examined the birth weight of 146,830 twins according to the CD status. CD was defined as having villous atrophy according to a small intestinal biopsy reports.Results: The prevalence of diagnosed CD was 0.5% (n=669), and we included 407 discordant pairs of CD–non-CD twins. Comparing the 669 CD patients with non-CD twins, the association between birth weight and future CD was not statistically significant (odds ratio [OR] per 1000g increase in birth weight: 1.16; 95% confidence interval [CI]=0.97–1.38). In males, the association was positive and statistically significant (OR=1.50; 95% CI=1.11–2.02). However, the association was not significant in within-pair analyses for both dizygotic and monozygotic twins and for both sexes.Conclusion: This population-based study found that in male twins, higher birth weight was associated with higher risk of CD. However, when comparing discordant twin pairs in within-twin pair analyses, there was no statistically significant association between birth weight, intrauterine growth, and future risk of CD. Keywords: autoimmune, gestational age, gluten, registries, risk factors, twins

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Importance: Substance misuse and anxiety-related and depressive disorders (ADs) are among the most common psychiatric conditions and often co-occur. Despite adversities associated with the comorbidity, its causes remain unclear. Objective: We used Swedish nationwide register data aiming to (1) estimate associations of substance misuse and ADs in the population, (2) investigate gender differences in comorbidity, and (3) test the associations while accounting for genetic and shared environmental factors in stratified analyses within twin pairs and siblings. Design, Setting, and Participants: Individuals born in Sweden between January 1968 and December 1997 (n=2,996,403) were followed-up with register-based data for 1997-2013. Main Outcomes and Measures Substance misuse was defined using ICD-10 diagnoses of substance use disorders (F10-F16, F18-F19) and drug-related criminal convictions. ADs included anxiety (F40-F43) and depressive disorders (F32-F34, F38-F39). Confounding by sex, birth year, personality disorders (F60.0-F60.9), socioeconomic covariates, and parental history of psychopathology was adjusted for. Results: Risk of ADs was substantially increased in individuals with substance misuse (Risk Ratios (RR): 2.5-4.5). Of the AD diagnosis clusters derived from exploratory factor analysis, generalized anxiety/depression had the strongest association with substance misuse (RR=4.46, 95% CI 4.42- 4.50). Similarly, those with substance misuse had a 4.6-fold (95% CI: 4.52-4.60) risk of generalized anxiety/depression and a 4.7-fold (95% CI: 4.65-4.84) risk of panic disorder/social phobia as compared to those without substance misuse. The associations were stronger in women than in men, and were attenuated in within-family analyses. However, elevated risks were found even among MZ twins suggesting the comorbidity was not fully explained by familial factors. Conclusions and Relevance: Risk of ADs is elevated in individuals with substance misuse, and vice versa, and these associations are partially confounded by familial liabilities. However, the results are also compatible with a partially causal relationship between substance misuse and ADs.

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.

Objective: Understanding the role of premorbid body mass index (BMI) in the emergence of eating disorders may be key to identifying effective prevention strategies. We explore relations between BMI and eating disorders traits in young twins. Method: The effect of BMI at age 9/12 and 15 on eating disorder traits measured using the Eating Disorders Inventory-2 (EDI) at ages 15 and 18 was examined using bivariate modelling in a longitudinal population sample of Swedish twins. Results: The correlation between BMI and EDI within individuals was stable across all ages and remained significant after adjusting for later BMI. Bivariate analysis indicated significant positive genetic correlations between BMI ages 9/12 and 15 and subsequent EDI scores. The relationship remained significant for BMI age 9/12 and EDI age 15 in the adjusted model, indicating a longitudinal association. Conclusion: Our results have implications for conceptualizing the interrelation of BMI and eating disorders across childhood and adolescence.

Objective: We examined epidemiological associations between anorexia nervosa (AN) and bulimia nervosa (BN) and risks of committing theft and other crimes in a nationwide female population. Method: Females born in Sweden during 1979–1998 (N = 957,106) were followed from age 15 for up to 20 years using information on clinically diagnosed AN and BN (exposures), convictions of theft and other crimes (outcomes), psychiatric comorbidities, and familial relatedness from Swedish national registers. We estimated hazard ratios (HRs) of criminality in exposed versus unexposed females using Cox proportional hazards regressions and explored how comorbidities and unmeasured familial factors explained the associations. Results: The cumulative incidence of convictions of theft (primarily petty theft) and other crimes was higher in exposed females (AN: 11.60% theft, 7.39% other convictions; BN: 17.97% theft, 13.17% other convictions) than in unexposed females (∼5% theft, ∼6% other convictions). The significantly increased risk of being convicted of theft in exposed females (AN: HR = 2.51, 95% confidence interval = [2.29, 2.74], BN: 4.31 [3.68, 5.05]) was partially explained by comorbidities; unmeasured familial factors partially explained the association with convictions of theft in BN but not in AN. Females with BN had a doubled risk of convictions of other crimes, which was partially explained by comorbidities. Discussion: Individuals with eating disorders had increased risk for convictions of theft and potentially other crimes. Results underscore the importance of regular forensic screening and encourage research on mechanisms underlying the relation between crime and eating disorder psychopathology and efforts to determine how best to address such relation in treatment.

OBJECTIVE: The risk of certain psychiatric disorders is elevated among immigrants. To date, no population studies on immigrant health have addressed eating disorders. We examined whether risk of eating disorders in first- and second-generation immigrants differs from native-born Danes and Swedes. METHOD: All individuals born 1984-2002 (Danish cohort) and 1989-1999 (Swedish cohort) and residing in the respective country on their 10th birthday were included. They were followed up for the development of eating disorders based on out-patient and in-patient data. RESULTS: The risks of all eating disorder types were lower among first-generation immigrants compared to the native populations: Incidence-rate ratio (95% confidence interval) was 0.39 (0.29, 0.51) for anorexia nervosa, 0.60 (0.42, 0.83) for bulimia nervosa, and 0.62 (0.47, 0.79) for other eating disorders in Denmark and 0.27 (0.21, 0.34) for anorexia nervosa, 0.30 (0.18, 0.51) for bulimia nervosa, and 0.39 (0.32, 0.47) for other eating disorders in Sweden. Likewise, second-generation immigrants by both parents were at lower risk, whereas those with only one foreign-born parent were not. CONCLUSION: The decreased risk of eating disorders among immigrants is opposite to what has been observed for other psychiatric disorders, particularly schizophrenia. Possible explanations include buffering sociocultural factors and underdetection in health care.

Background: 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. Methods: 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). Results: 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. Conclusions: 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.