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BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) has been associated with several autoimmune diseases (AD), both within individuals and across relatives, implying common underlying genetic or environmental factors in line with studies indicating that immunological mechanisms are key to brain development. To further elucidate the relationship between ADHD and autoimmunity we performed a population-wide familial co-aggregation study. METHODS: We linked Swedish national registries, defined a birth cohort with their biological relatives and identified individuals diagnosed with ADHD and/or 13 ADs. The cohort included 5 178 225 individuals born between 1960 and 2010, of whom 118 927 (2.30%) had been diagnosed with ADHD. We then investigated the associations between ADHD and ADs within individuals and across relatives, with logistic regression and structural equation modelling. RESULTS: Within individuals, ADHD was associated with a diagnosis of any of the 13 investigated ADs (adjusted odds ratio (OR) =1.34, 95% confidence interval (CI) = 1.30-1.38) as well as several specific ADs. Familial co-aggregation was observed. For example, ADHD was associated with any of the 13 ADs in mothers (OR = 1.29, 95% CI = 1.26-1.32), fathers (OR = 1.14, 95% CI = 1.11-1.18), full siblings (OR = 1.19, 95% CI = 1.15-1.22), aunts (OR = 1.12, 95% CI = 1.10-1.15), uncles (OR = 1.07, 95% CI = 1.05-1.10) and cousins (OR = 1.04, 95% CI = 1.03-1.06). Still, the absolute risks of AD among those with ADHD were low. The genetic correlation between ADHD and a diagnosis of any of the investigated ADs was 0.13 (95% CI = 0.09-0.17) and the environmental correlation was 0.02 (95% CI = -0.03-0.06). CONCLUSIONS: We found that ADHD and ADs co-aggregate among biological relatives, indicating that the relationship between ADHD and autoimmune diseases may in part be explained by shared genetic risk factors. The patterns of familial co-aggregation of ADHD and ADs do not readily support a role of matern, Funding agency:Stiftelsen Kristian Gerhard JebsenUniversity of BergenWestern Norway Regional Health AuthoritiesSwedish Initiative for Research onMicrodata in the Social And Medical Sciences (SIMSAM) framework 340-2013-5867Strategic Research Programme in Neuroscience (StratNeuro) of Karolinska Institutet

Keeping appropriate interpersonal distance is an evolutionary conserved behavior that can be adapted based on learning. Detailed knowledge on how interpersonal space is represented in the brain and whether such representation is genetically influenced is lacking. We measured brain function using functional magnetic resonance imaging in 294 twins (71 monozygotic, 76 dizygotic pairs) performing a distance task where neural responses to human figures were compared to cylindrical blocks. Proximal viewing distance of human figures was compared to cylinders facilitated responses in the occipital face area (OFA) and the superficial part of the amygdala, which is consistent with these areas playing a role in monitoring interpersonal distance. Using the classic twin method, we observed a genetic influence on interpersonal distance related activation in the OFA, but not in the amygdala. Results suggest that genetic factors may influence interpersonal distance monitoring via the OFA whereas the amygdala may play a role in experience-dependent adjustments of interpersonal distance., Funding agency:Bank of Sweden Tercentenary Foundation

Background Frailty assessment in the Swedish health system relies on the Clinical Frailty Scale (CFS), but it requires training, in-person evaluation, and is often missing in medical records. We aimed to develop an electronic frailty index (eFI) from routinely collected electronic health records (EHRs) and assess its association with adverse outcomes in hospitalized older adults. Methods EHRs were extracted for 18 225 patients with unplanned admissions between 1 March 2020 and 17 June 2021 from 9 geriatric clinics in Stockholm, Sweden. A 48-item eFI was constructed using diagnostic codes, functioning and other health indicators, and laboratory data. The CFS, Hospital Frailty Risk Score, and Charlson Comorbidity Index were used for comparative assessment of the eFI. We modeled in-hospital mortality and 30-day readmission using logistic regression; 30-day and 6-month mortality using Cox regression; and length of stay using linear regression. Results Thirteen thousand one hundred and eighty-eight patients were included in analyses (mean age 83.1 years). A 0.03 increment in the eFI was associated with higher risks of in-hospital (odds ratio: 1.65; 95% confidence interval: 1.54-1.78), 30-day (hazard ratio [HR]: 1.43; 1.38-1.48), and 6-month mortality (HR: 1.34; 1.31-1.37) adjusted for age and sex. Of the frailty and comorbidity measures, the eFI had the highest area under receiver operating characteristic curve for in-hospital mortality of 0.813. Higher eFI was associated with longer length of stay, but had a rather poor discrimination for 30-day readmission. Conclusions An EHR-based eFI has robust associations with adverse outcomes, suggesting that it can be used in risk stratification in hospitalized older adults.

Background & aims: Research quantifying dietary intake in individuals with bulimia nervosa and binge-eating disorder (i.e., binge-type eating disorders) is surprisingly scant. We assessed the dietary intake of women and men with binge-type eating disorders in a large case-control study and compared them with healthy controls. We also evaluated the extent to which their dietary intake adhered to the Nordic Nutrition Recommendations. Among cases, we assessed the relationship of binge eating frequency with energy and macronutrient intake. Methods: We derived the total daily energy, macro-, and micronutrient intake of 430 cases with binge-type eating disorders (women: n = 391, men: n = 39) and 1227 frequency-matched controls (women: n = 1,213, men: n = 14) who completed the MiniMeal-Q, a validated food frequency questionnaire. We calculated mean intake for men and women and, in women, compared mean intake of energy and nutrients between cases and controls using linear regression. We calculated the proportion of women and men who met the recommended intake levels from the NNR, and compared these proportions in female cases and controls using logistic regression. We used linear regression to examine energy and macronutrient intake of women with varying frequencies of current binge-eating. Results: Female, but not male cases, had a higher mean intake of total energy/day compared with controls and higher intake than recommended. The majority in all groups (male and female cases and controls) exceeded saturated fat recommendations, and did not meet recommendations for omega-3 fatty acid intake. Among all groups, adherence was low for vitamin D, selenium, and salt. Iron and folate intake was low among the majority of women, especially controls. Female cases with >= 4 binge-eating episodes in the past 28 days had higher intake of energy and percent carbohydrates, and lower intake of percent fat, compared to cases with no binge-eating episodes in the past month. Conclusi

OBJECTIVE: To assess the association and familial coaggregation between early-onset type 2 diabetes (diagnosed before age 45 years) and mood, anxiety, and stress-related disorders and estimate the contribution of genetic and environmental factors to their co-occurrence. RESEARCH DESIGN AND METHODS: This population-based cohort study included individuals born in Sweden during 1968-1998, from whom pairs of full siblings, half-siblings, and cousins were identified. Information on diagnoses of early-onset type 2 diabetes and mood (including unipolar depression and bipolar disorder), anxiety, and stress-related disorders was obtained from the National Patient Register. Logistic and Cox regression models were used to assess the phenotypic association and familial coaggregation between type 2 diabetes and psychiatric disorders. Quantitative genetic modeling was conducted in full and maternal half-sibling pairs to estimate the relative contributions of genetic and environmental factors to the association. RESULTS: Among a total of 3,061,192 individuals, 7,896 (0.3%) were diagnosed with early-onset type 2 diabetes. These individuals had higher risks of any diagnosis (odds ratio [OR] 3.62 [95% CI 3.44, 3.80]) and specific diagnosis of unipolar depression (3.97 [3.75, 4.22]), bipolar disorder (4.17 [3.68, 4.73]), anxiety (3.76 [3.54, 3.99]), and stress-related disorders (3.35 [3.11, 3.61]). Relatives of individuals with early-onset type 2 diabetes also had higher overall risks of the examined psychiatric disorders (ORs 1.03-1.57). These associations are largely explained by genetic factors (51-78%), with the rest explained by nonshared environmental factors. CONCLUSIONS: Our findings highlight the burden of mood, anxiety, and stress-related disorders in early-onset type 2 diabetes and demonstrate that shared familial liability may contribute to their co-occurrence, suggesting that in future research investigators should aim to identify shared risk factors and ultimately refine, Funding agency:Karolinska Institutet, Strategic Research Program in Neuroscience (StratNeuro)

Importance: Psychiatric disorders are common among autistic children and adults. Little is known about sex differences in psychiatric disorders and hospitalization in early adulthood. Objective: To examine sex differences in psychiatric diagnoses and hospitalizations in autistic compared with nonautistic young adults. Design, Setting, and Participants: This population-based cohort study assessed all individuals born in Sweden between 1985 and 1997. A total of 1 335 753 individuals, including 20 841 autistic individuals (7129 [34.2%] female individuals), were followed up from age 16 through 24 years between 2001 and 2013. Analysis took place between June 2021 and August 2022. Exposures: Autism was defined as having received at least 1 clinical diagnosis of autism based on the International Classification of Diseases. Main Outcomes and Measures: The cumulative incidence of 11 psychiatric diagnoses up until age 25 years was estimated, and birth year-standardized risk difference was used to compare autistic female and male individuals directly. Sex-specific birth year-adjusted hazard ratios (HRs) with 95% CIs were calculated using Cox regression. Analyses were repeated for inpatient diagnoses to assess psychiatric hospitalization. Results: Of 1 335 753 individuals included in this study, 650 314 (48.7%) were assigned female at birth. Autism was clinically diagnosed in 20 841 individuals (1.6%; 7129 [34.2%] female) with a mean (SD) age of 16.1 (5.1) years (17.0 [4.8] years in female individuals and 15.7 [5.2] years in male individuals) for the first recorded autism diagnosis. For most disorders, autistic female individuals were at higher risk for psychiatric diagnoses and hospitalizations. By age 25 years, 77 of 100 autistic female individuals and 62 of 100 autistic male individuals received at least 1 psychiatric diagnosis. Statistically significant standardized risk differences were observed between autistic female and male individuals for any psychiatric disorder (-0., Funding agency:MQ Mental Health Research MQF20/19

Background: Sleep disorders in youth have been associated with increased risks of injury, including suicidal behavior. This study investigated whether melatonin, which is themost common medication for sleep disturbances in youth in Sweden, is associated with a decreased risk of injury. Methods: This population-based cohort study included 25,575 youths who initiated melatonin treatment between ages 6 and 18. Poisson regression was used to estimate rate of injuries in the year prior to and following melatonin-treatment initiation. A within-individual design was used to estimate relative risks by comparing injury risk in the last unmedicated month with injury risks in the 12 months after medication initiation. Analyses were stratified by sex, in-jury type, psychiatric comorbidities, and age at melatonin-treatment initiation. Results: While body injuries, falls, and transport accident rates were comparable in the year before and after melatonin-treatment initiation, the risk of self-injurious behavior was highest in the months immediately prior medication and decreased thereafter. This was particularly prominent among adolescents with depression and/or anxiety, with females displaying greater absolute risks than males. Compared to the last unmedicated month, the 12 months post medication initiation had decreased relative risks for self-harm, with an IRR [95% CI] in the month following melatonin-treatment initiation of 0.46 [0.27-0.76] among adolescent females with psychiatric disorders, after excluding antidepressant users. Discussion: Decreased risk of intentional injury was observed following melatonin-treatment initiation among females with depression and anxiety, suggesting that sleep interventions could be considered in an effort to reduce risk of self-injurious behavior in this population.

Understanding the relationship between chronic pain conditions and suicidal behavior is imperative for suicide prevention efforts. Although chronic pain conditions are associated with suicidal behaviors, these associations might be attributed to unmeasured confounding, or mediated via pain comorbidity. We linked a population-based Swedish twin study (N = 17 148 twins) with 10 years of longitudinal, nationwide records of suicidal behavior from health and mortality registers through 2016. To investigate whether pain comorbidity versus specific pain conditions were more important for later suicidal behavior, we modeled a general factor of pain and two independent specific pain factors (measuring pain-related somatic symptoms and neck-shoulder pain, respectively) based on 9 self-reported chronic pain conditions. To examine whether the pain-suicidal behavior associations were attributable to familial confounding, we applied a co-twin control model. Individuals scoring one standard deviation above the mean on the general pain factor had 51% higher risk of experiencing suicidal behavior (Odds Ratio (OR), 1.51; 95% Confidence Interval (CI), 1.34–1.72). The specific factor of somatic pain was also associated with increased risk for suicidal behavior (OR, 1.80; 95% CI, 1.45–2.22]). However, after adjustment for familial confounding, the associations were greatly attenuated and not statistically significant within monozygotic twin pairs (general pain factor OR, 0.89; 95% CI, 0.59–1.33; somatic pain factor OR, 1.02; 95% CI, 0.49–2.11) Clinicians might benefit from measuring not only specific types of pain, but also pain comorbidity; however, treating pain might not necessarily reduce future suicidal behavior, as the associations appeared attributable to familial confounding., Funding agencies:American Foundation for Suicide Prevention SRG-0-133-19China Scholarship Council CSC201806360008

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., Funding agency:University of Helsinki

OBJECTIVE: To estimate the association and familial coaggregation of childhood-onset type 1 diabetes with depression, anxiety, and stress-related disorders. RESEARCH DESIGN AND METHODS: This was a population-based cohort study with use of data from Swedish nationwide registers. A total of ∼3.5 million individuals born in Sweden 1973-2007 were linked to their biological parents, full siblings and half-siblings, and cousins. Cox models were used to estimate the association and familial coaggregation of type 1 diabetes with depression, anxiety, and stress-related disorders. RESULTS: Individuals diagnosed with childhood-onset type 1 diabetes (n = 20,005) were found to be at greater risks of all outcomes: any psychiatric diagnosis (adjusted hazard ratio [aHR] 1.66 [95% CI 1.59-1.72]) or specific diagnoses of depression (1.85 [1.76-1.94]), anxiety (1.41[1.33-1.50]), and stress-related disorders (1.75 [1.62-1.89]), as well as use of antidepressants or anxiolytics (1.30 [1.26-1.34]), compared with individuals without type 1 diabetes. Overall, relatives of individuals with type 1 diabetes were at elevated risks of developing these outcomes, with the highest risks seen in parents (aHRs 1.18-1.25), followed by full siblings (aHRs 1.05-1.20), and the magnitudes of risk estimates appear proportional to familial relatedness. CONCLUSIONS: These results support existing evidence that children and adolescents with type 1 diabetes are at greater risks of developing depression, anxiety, and stress-related disorders and indicate that shared familial factors might contribute to these elevated risks. Our findings highlight the need for psychological consulting for children and their families in diabetes care. Quantitative and molecular genetic studies are warranted to further understand the etiology of these psychiatric disorders in type 1 diabetes., Funding agencies:Strategic Research Program in Neuroscience (StratNeuro)H.M. Queen Silvia's Jubileumsfond for research on children with comorbid somatic and psychiatric disorders

Suicidal and aggressive behaviours cause significant personal and societal burden. As risk factors associated with these behaviours frequently overlap, combined approaches in predicting the behaviours may be useful in identifying those at risk for either. The current study aimed to create a model that predicted if individuals will exhibit suicidal behaviour, aggressive behaviour, both, or neither in late adolescence. A sample of 5,974 twins from the Child and Adolescent Twin Study in Sweden (CATSS) was broken down into a training (80%), tune (10%) and test (10%) set. The Netherlands Twin Register (NTR; N = 2702) was used for external validation. Our longitudinal data featured genetic, environmental, and psychosocial predictors derived from parental and self-report data. A stacked ensemble model was created which contained a gradient boosted machine, random forest, elastic net, and neural network. Model performance was transferable between CATSS and NTR (macro area under the receiver operating characteristic curve (AUC) [95% CI] AUCCATSS(test set) = 0.709 (0.671-0.747); AUCNTR = 0.685 (0.656-0.715), suggesting model generalisability across Northern Europe. The notable exception is suicidal behaviours in the NTR, which was no better than chance. The 25 highest scoring variable importance scores for the gradient boosted machines and random forest models included self-reported psychiatric symptoms in mid-adolescence, sex, and polygenic scores for psychiatric traits. The model's performance is comparable to current prediction models that use clinical interviews and is not yet suitable for clinical use. Moreover, genetic variables may have a role to play in predictive models of adolescent psychopathology.

BACKGROUND: The knowledge of how the separate Attention-Deficit/Hyperactivity Disorder (ADHD) subdimensions (impulsivity, hyperactivity, and inattention) are associated with nonsuicidal self-injury (NSSI) and suicidal behavior (SB) is limited. The objective of this study was to investigate the associations of childhood ADHD subdimensions with NSSI and SB in children at risk of neurodevelopmental disorders (NDDs; including ADHD). METHODS: The sample (N = 391) included twin pairs where at least one twin screened positive for at least one NDD or common comorbidity at age 9 or 12. Data on ADHD subdimensions was collected through a telephone interview with a caregiver/legal guardian at age 9 or 12, and data on NSSI and SB was collected through an in-person clinical assessment at age 15. The associations between the ADHD subdimensions and NSSI or SB were tested in three different models: (1) univariable, (2) together with the other ADHD subdimensions, and (3) in a confounder-adjusted model including other NDD symptoms in addition to ADHD subdimensions, for NSSI and SB separately. RESULTS: A total of 32 (8.2%) adolescents reported life-time engagement of NSSI, and 18 (4.6%) SB. Childhood impulsivity was associated with SB and childhood inattention with NSSI, in all models. Hyperactivity was not meaningfully associated with any of the outcomes. CONCLUSION: Impulsivity and inattention, but not hyperactivity, may be of particular importance in understanding SB and NSSI. Brief screening for impulsivity and inattention in childhood could facilitate detection of children vulnerable to NSSI and SB and indicate valuable information for preventive and intervention strategies., Funding agencies:National Board of Forensic MedicineSoderstrom-Konigska FoundationKarolinska Institutet Center of Neurodevelopmental Disorders (KIND)ALF medicine projects in Sweden 2019-0433 SystembolagetCorrection: Associations of impulsivity, hyperactivity, and inattention with nonsuicidal self-injury and suicidal behavior: longitudinal cohort study following children at risk for neurodevelopmental disorders into mid-adolescence. Ojala, O., Kuja-Halkola, R., Bjureberg, J. et al. BMC Psychiatry 23, 864 (2023). https://doi.org/10.1186/s12888-023-05338-y

AIM: To examine the association of childhood-onset type 1 diabetes (T1D) and attention-deficit/hyperactivity disorder (ADHD) with educational outcomes from compulsory school to university. METHODS: Using multiple Swedish nationwide registers, we followed up on 1,474,941 individuals born in Sweden from 1981-1995 to December 31, 2013. Associations of T1D and ADHD with achieving educational milestones (from compulsory school to university) and school performances were estimated using logistic and linear regression models and sibling comparison models. RESULTS: Compared to their peers, children with both T1D and ADHD were less likely to achieve any of the educational attainments, including completing compulsory school (adjusted OR [aOR] [95% CI]: 0.43[0.26,0.72]), be eligible to and finishing upper secondary school (0.26[0.19,0.36], 0.24[0.17,0.35], respectively), and starting university (0.38[0.17,0.90]). The odds of achieving these educational milestones were substantially lower in children with ADHD alone (aORs: 0.14-0.44), but were slightly worse or no differences in children with T1D alone (aORs: 0.86-1.08). All associations above remained similar in the sibling comparison models. CONCLUSION: Children and adolescents with both T1D and ADHD had long-term educational underachievement, with ADHD being the major contributor. Our findings suggest the importance of assessing ADHD in children with T1D and targeted support for minimizing the education gap between the affected children and their peers., Funding agencies:Strategic Research Program in Neuroscience (StratNeuro)Swedish Initiative for Research on Microdata in the Social and Medical Sciences (SIMSAM) frameworkDrottning Silvias Jubileumsfond

Objective: Childhood attention-deficit /hyperactivity disorder (ADHD) is known to be associated with adult Borderline Personality Disorder (BPD). We investigated if any of the subdimensions of childhood ADHD, that is, impulsivity, inattention, or hyperactivity was more prominent in this association. Methods: In a nation-wide cohort (N = 13,330), we utilized parent reported symptoms of childhood ADHD and clinically ascertained adult BPD diagnoses. The summed total scores of ADHD symptoms and its three subdimensions were used and standardized for effect size comparison. Associations were analyzed using Cox regression with sex and birth-year adjustments. Secondary outcomes were BPD-associated traits (i.e., self-harm and substance use) analyzed using logistic- and linear regression respectively. Results: ADHD symptom severity was positively associated with BPD with a hazard ratio (HR) of 1.47 (95% confidence interval [CI]: 1.22-1.79) per standard deviation increase in total ADHD symptoms. Impulsivity was the most prominent subdimension with the only statistically significant association when analyzed in a model mutually adjusted for all ADHD subdimensions-HR for inattention: 1.15 (95% CI: 0.85-1.55), hyperactivity: 0.94 (95% CI: 0.69-1.26), impulsivity: 1.46 (95% CI: 1.12-1.91). In secondary analyses, weak positive associations were seen between total ADHD symptom score and self-harm and substance use. In analyses by subdimensions of ADHD, associations were weak and most prominent for inattention in the model with self-harm. Conclusion: Childhood ADHD symptoms were associated with subsequent development of BPD diagnosis and appeared to be driven primarily by impulsivity. Our findings are important for understanding the association between childhood symptoms of ADHD and subsequent BPD.

Objectives: 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. Methods: 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. Results: 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. Conclusions: 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., Funding agencies:University of HelsinkiStrategic Research Council (SRC), FLUX consortium 345130 345131

Anxiety and depression are common in youth and are frequently accompanied by attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, it is unclear how common ADHD, ASD, and other neurodevelopmental disorders (NDDs, i.e., ADHD, ASD, developmental coordination disorder, learning disorder, and tic disorders) are in children versus adolescents with anxiety and depression. We aimed to delineate whether different anxiety/depression age-of-onset groups show distinguishable NDD patterns. The study was based on 4492 twins born in Sweden between 1998 and 2003 from the nation-wide population-based Child and Adolescent Twin Study in Sweden. Prevalence and odds ratios were calculated using screening measures of anxiety and depression at ages 9 and 15, and NDDs at age 9. Individuals with childhood-onset anxiety/depression had a substantially higher NDD prevalence compared to individuals with adolescent-onset anxiety/depression. Highest prevalence was found for individuals with anxiety/depression both in childhood and adolescence. In this group, individuals also had substantially higher odds of having at least one NDD (14.7, 95% CI 6.3 - 34.0) compared to individuals without anxiety/depression. This emphasizes the need to further investigate the etiology of childhood and adolescent anxiety/depression, as they most likely represent different constructs depending on age-of-onset, lending support for possibly different treatment approaches.

Background Genetically informed studies have provided mixed findings as to what extent parental substance misuse is associated with offspring substance misuse and antisocial behavior due to shared environmental and genetic factors. Methods We linked data from nationwide registries for a cohort of 2 476 198 offspring born in Sweden 1958-1995 and their parents. Substance misuse was defined as International Classification of Diseases diagnoses of alcohol/drug use disorders or alcohol/drug-related criminal convictions. Quantitative genetic offspring-of-siblings analyses in offspring of monozygotic and dizygotic twin, full-sibling, and half-sibling parents were conducted. Results Both maternal and paternal substance misuse were robustly associated with offspring substance misuse [maternal adjusted hazard ratio (aHR) = 1.83 (95% confidence interval (CI) 1.80-1.87); paternal aHR = 1.96 (1.94-1.98)] and criminal convictions [maternal aHR = 1.56 (1.54-1.58); paternal aHR = 1.66 (1.64-1.67)]. Additive genetic effects explained 42% (95% CI 25-56%) and 46% (36-55%) of the variance in maternal and paternal substance misuse, respectively, and between 36 and 44% of the variance in substance misuse and criminality in offspring. The associations between parental substance misuse and offspring outcomes were mostly due to additive genetic effects, which explained 54-85% of the parent-offspring covariance. However, both nuclear and extended family environmental factors also contributed to the associations, especially with offspring substance misuse. Conclusions Our findings from a large offspring-of-siblings study indicate that shared genetic influences mostly explain the associations between parental substance misuse and both offspring substance misuse and criminality, but we also found evidence for the contribution of environmental factors shared by members of nuclear and extended families.

Objective: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. Method: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. Results: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, neffective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (|rg| > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range |rg| = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. Conclusion: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way t

OBJECTIVE: Depression is common in individuals with endocrine-metabolic disorders and vice versa, and a better understanding of the underlying factors contributing to the comorbidity of these disorders is needed. This study investigated the familial coaggregation of depression and endocrine-metabolic disorders and estimated the contribution of genetic and environmental factors to their co-occurrence. METHODS: This population-based cohort study included 2.2 million individuals born in Sweden between 1973 and 1996, with follow-up through 2013. Participants were linked to their biological parents, allowing identification of full siblings, maternal half siblings, and paternal half siblings. Diagnoses of depression and endocrine-metabolic conditions were investigated, with the latter grouped into autoimmune disorders (autoimmune hypothyroidism, Graves' disease, and type 1 diabetes) and non-autoimmune disorders (type 2 diabetes, obesity, and polycystic ovary syndrome). Logistic regression and Cox regression were used to estimate the associations between endocrine-metabolic disorders and depression within the same individual and across siblings. Quantitative genetic modeling was performed to investigate the relative contribution of genetic and environmental influences. RESULTS: Individuals with endocrine-metabolic disorders had a significantly higher risk of depression, with odds ratios ranging from 1.43 (95% CI=1.30, 1.57) for Graves' disease to 3.48 (95% CI=3.25, 3.72) for type 2 diabetes. Increased risks extended to full and half siblings. These correlations were mainly explained by shared genetic influences for non-autoimmune conditions, and by nonshared environmental factors for autoimmune disorders, especially for type 1 diabetes. CONCLUSIONS: These findings provide phenotypic and etiological insights into the co-occurrence of depression and various endocrine-metabolic conditions, which could guide future research aiming at identifying pathophysiological mechanisms a

Early-life infections have been linked with subsequent depression and self-harm. Examination of specific groups of infections and the role of familial factors may elucidate this observed relationship. We addressed these considerations in our investigations of the association of severe childhood infections with the risks of depression and self-harm in adolescence and early-adulthood. This population-based cohort study included all individuals born in Sweden between 1982 and 1996, with follow-up through 2013 (N = 1,506,070). Severe childhood infections were identified using inpatient and outpatient diagnoses from birth through age 12. Any infection as well as specific groups of infections were investigated. We examined diagnoses of depression and self-harm within inpatient and outpatient care and death by self-harm between ages 13 and 31. Cox proportional hazards regression models were used to estimate absolute risks, hazard ratios (HRs), and 95% CIs. When adjusting for sex and birth year, individuals exposed to any childhood infection demonstrated increased absolute risk differences for both outcomes (2.42% [95% CI, 0.41%-4.43%] of being diagnosed with depression up until age 31, and 0.73% [-2.05%-3.51%] of self-harm up until age 31) and increased relative risks (HR, 1.22 [1.20-1.24] for depression and HR, 1.29 [1.25-1.32] for self-harm). When controlling for unmeasured factors shared between family members by comparing discordant siblings, no strong association persisted. Our findings show that childhood infections may not be involved in the etiology of later depression and self-harm, and highlight the importance of identifying these genetic and environmental familial risk factors, which may serve as targets for interventions.

In one of the largest, most comprehensive studies on borderline personality disorder (BPD) to date, this article places into context associations between this diagnosis and (1) 16 different psychiatric disorders, (2) eight somatic illnesses, and (3) six trauma and adverse behaviors, e.g., violent crime victimization and self-harm. Second, it examines the sex differences in individuals with BPD and their siblings. A total of 1,969,839 Swedish individuals were identified from national registers. Cumulative incidence with 95% confidence intervals (CI) was evaluated after 5 years of follow-up from BPD diagnosis and compared with a matched cohort. Associations were estimated as hazard ratios (HR) with 95% CIs from Cox regression. 12,175 individuals were diagnosed with BPD (85.3% female). Individuals diagnosed with BPD had higher cumulative incidences and HRs for nearly all analyzed indicators, especially psychiatric disorders. Anxiety disorders were most common (cumulative incidence 95% CI 33.13% [31.48-34.73]). Other notable findings from Cox regressions include psychotic disorders (HR 95% CI 24.48 [23.14-25.90]), epilepsy (3.38 [3.08-3.70]), violent crime victimization (7.65 [7.25-8.06]), and self-harm (17.72 [17.27-18.19]). HRs in males and females with BPD had overlapping CIs for nearly all indicators. This indicates that a BPD diagnosis is a marker of vulnerability for negative events and poor physical and mental health similarly for both males and females. Having a sibling with BPD was associated with an increased risk for psychiatric disorders, trauma, and adverse behaviors but not somatic disorders. Clinical implications include the need for increased support for patients with BPD navigating the health care system., Funding agencies:Brain & Behaviour Research FoundationUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) R01 MH123724

Background: Neurodevelopmental disorders (NDs) are associated with experiences of victimization, but mechanisms remain unclear. We explored sex differences and the role of familial factors and externalizing problems in the association between several NDs and violent victimization in adolescence and young adulthood. Methods: Individuals born in Sweden 1985-1997, residing in Sweden at their 15th birthday, were followed until date of violent victimization causing a hospital visit or death, death due to other causes, emigration, or December 31, 2013, whichever came first. The exposures were diagnoses of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), intellectual disability (ID) and other NDs. We used three different Cox regression models: a crude model, a model adjusted for familial confounding using sibling-comparisons, and a model additionally adjusted for externalizing problems. Results: Among 1 344 944 individuals followed, on average, for 5 years, 74 487 were diagnosed with NDs and 37 765 had a hospital visit or died due to violence. ADHD was associated with an increased risk of violent victimization in males [hazard ratio (HR) 2.56; 95% confidence interval (CI) 2.43-2.70) and females (HR 5.39; 95% CI 4.97-5.85). ASD and ID were associated with an increased risk of violent victimization in females only. After adjusting for familial factors and externalizing problems, only ADHD was associated with violent victimization among males (HR 1.27; 95% CI 1.06-1.51) and females (HR 1.69; 95% CI 1.21-2.36). Conclusions: Females with NDs and males with ADHD are at greater risk of being victim of severe violence during adolescence and young adulthood. Relevant mechanisms include shared familial liability and externalizing problems. ADHD may be independently associated with violent victimization., Funding agency:Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) 340-2013-5867

Low resting heart rate (HR) is a well-replicated correlate of antisocial behavior. Previous findings have suggested that low resting HR is associated with criminal offending, psychopathy, conduct problems and aggression. More recent work has also indicated that low systolic blood pressure is associated with an increased risk of criminal offending. However, little is known about the predictive value of low autonomic arousal for reoffending. Thus, the present study examined associations of resting HR and systolic blood pressure with reoffending. We used Swedish population-based registers to conduct a cohort study of all male conscripts born between 1958 and 1990 who had been convicted of a crime (N=407,533). Resting HR and systolic blood pressure was measured at the conscription assessment. Criminal convictions were obtained from the National Crime Register. We used survival analyses to test for associations between resting HR and systolic blood pressure with reoffending while covarying for socioeconomic status, height, weight, physical energy capacity and birth year. A lower resting HR was associated with an increased risk of reoffending for violent and nonviolent crime compared to a higher resting HR. Lower systolic blood pressure was also associated with an increased risk of reoffending for violent and nonviolent crime compared to a higher systolic blood pressure. Low autonomic arousal should be further investigated as a predictor for reoffending as it may help to improve identification of individuals at risk for repeated criminal justice involvement.

BACKGROUND: The prevalence of diagnosed Autism Spectrum Disorder (ASD) has increased substantially across the world. Much - or even most - prevalence increase seems to reflect changes in diagnostic practice and ascertainment. A key part of ASD assessment is to document that the relevant symptoms are associated with clinical impairment. The aim of the present study is to capitalize on a nationwide longitudinal study spanning 15 consecutive birth year cohorts in order to investigate whether there has been a secular change in how parents perceive the impairment and suffering conferred by autism symptomatology in their children. METHODS: Data came from the Child and Adolescent Twin Study in Sweden (27,240 individuals), where parents had reported on their child's ASD symptoms and impairment. Impairment due to ASD symptoms was regressed on an ASD symptom score across time. This was done for five 3-year birth cohorts (1995-1997, 1998-2000, 2001-2003, 2004-2006, and 2007-2009). RESULTS: Reported impairment increased with consecutively later birth cohorts. This was evident across all levels of autism symptomatology. At clinically relevant levels of symptomatology, parents of those born 2007-2009 reported a 23% higher degree of impairment as compared with parents of those born in 1995-1997. The relative difference, however, was even greater at levels that previously would have been considered below the diagnostic threshold. DISCUSSION: The results presented here contribute to the notion of a growing diffuseness in the conceptualization of the ASD diagnosis by adding the element of secular changes in the parental perception of the consequences of ASD symptom expression.

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 depe, Funding agency:University of Helsinki Doctoral Programme in Population Health

Background: Internalizing disorders, such as anxiety and depressive disorders, are common mental disorders in young people, but a detailed understanding of the symptom continuity from childhood to adolescence that additionally includes a variety of neurodevelopmental disorder (NDD) symptoms is lacking. We therefore aimed to assess the extent to which parent-reported anxiety, depression, and NDD symptoms in childhood predict parent-reported internalizing symptoms in adolescence. Methods: We used the nation-wide population-based Child and Adolescent Twin Study in Sweden, comprising 4492 twins born in Sweden between 1998 and 2003 that were assessed at age 9, and then again at age 15. Linear regression in a structural equation modelling framework was used to analyze the data. Results: Overall, our results indicate that 15.9% of the variance in internalizing symptoms at age 15 can be predicted by anxiety, depression, and NDD symptoms at age 9. Anxiety and NDD symptoms in childhood predicted the largest amount of internalizing symptoms in adolescence. Conclusions: Adolescent internalizing symptoms are modestly affected by childhood symptoms of anxiety, depression, and NDDs, suggesting that they may represent different constructs across age. Future studies should further empirically investigate differences in etiology and trajectories of childhood versus adolescent internalizing symptoms.

Anxiety and depression are common in youth and are frequently accompanied by attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, it is unclear how common ADHD, ASD, and other neurodevelopmental disorders (NDDs, i.e., ADHD, ASD, developmental coordination disorder, learning disorder, and tic disorders) are in children versus adolescents with anxiety and depression. We aimed to delineate whether different anxiety/depression age-of-onset groups show distinguishable NDD patterns. The study was based on 4492 twins born in Sweden between 1998 and 2003 from the nation-wide population-based Child and Adolescent Twin Study in Sweden. Prevalence and odds ratios were calculated using screening measures of anxiety and depression at ages 9 and 15, and NDDs at age 9. Individuals with childhood-onset anxiety/depression had a substantially higher NDD prevalence compared to individuals with adolescent-onset anxiety/depression. Highest prevalence was found for individuals with anxiety/depression both in childhood and adolescence. In this group, individuals also had substantially higher odds of having at least one NDD (14.7, 95% CI 6.3 – 34.0) compared to individuals without anxiety/depression. This emphasizes the need to further investigate the etiology of childhood and adolescent anxiety/depression, as they most likely represent different constructs depending on age-of-onset, lending support for possibly different treatment approaches.

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).

Background: Intellectual disability (ID) aggregates in families, but factors affecting individual risk and heritability estimates remain unknown. Methods: A population-based family cohort study of 4,165,785 individuals born 1973–2013 in Sweden, including 37,787 ID individuals and their relatives. The relative risks (RR) of ID with 95% confidence intervals (95% CI) were obtained from stratified Cox proportional-hazards models. Relatives of ID individuals were compared to relatives of unaffected individuals. Structural equation modeling was used to estimate heritability. Results: Relatives of ID individuals were at increased risk of ID compared to individuals with unaffected relatives. The RR of ID among relatives increased proportionally to the degree of genetic relatedness with ID probands; 256.70(95% CI 161.30–408.53) for monozygotic twins, 16.47(13.32–20.38) for parents, 14.88(12.19–18.16) for children, 7.04(4.67–10.61) for dizygotic twins, 8.38(7.97–8.83) for full siblings, 4.56(4.02–5.16) for maternal, 2.90(2.49–3.37) for paternal half-siblings, 3.03(2.61–3.50) for nephews/nieces, 2.84(2.45–3.29) for uncles/aunts, and 2.04(1.91–2.20) for cousins. Lower RRs were observed for siblings of probands with chromosomal abnormalities (RR 5.53, 4.74–6.46) and more severe ID (mild RR 9.15, 8.55–9.78, moderate RR 8.13, 7.28–9.08, severe RR 6.80, 5.74–8.07, and profound RR 5.88, 4.52–7.65). Male sex of relative and maternal line of relationship with proband was related to higher risk (RR 1.33, 1.25–1.41 for brothers vs. sisters and RR 1.49, 1.34–1.68 for maternal vs. paternal half-siblings). ID was substantially heritable with 0.95(95% CI 0.93–0.98) of the variance in liability attributed to genetic influences. Conclusions: The risk estimates will benefit researchers, clinicians, families in understanding the risk of ID in the family and the whole population. The higher risk of ID related to male sex and maternal linage will be of value for planning and interpreting etiologi, Funding agency:Swedish Research Council, European Commission Grant number: 2016-01989, 2017-00788, D088650, 2017-00641Swedish Research Council through the Swedish Initiative for Research on Microdata in the Social and Medical Sciences (SIMSAM) Grant number: 340-2013-5867Horizon 2020 Program of the European Union (COSYN, RIA grant) Grant number: 610307United States Department of Health & Human Services, National Institutes of Health (NIH) - USA, NIH National Institute of Mental Health (NIMH) Grant number:: U01 MH109528, R01 MH077139Shire

INTRODUCTION: We examined the extent to which attention-deficit/hyperactivity disorder (ADHD), a neurodevelopmental disorder, is linked with Alzheimer's disease (AD) and any dementia, neurodegenerative diseases, across generations. METHODS: A nationwide cohort born between 1980 and 2001 (index persons) were linked to their biological relatives (parents, grandparents, uncles/aunts) using Swedish national registers. We used Cox models to examine the cross-generation associations. RESULTS: Among relatives of 2,132,929 index persons, 3042 parents, 171,732 grandparents, and 1369 uncles/aunts had a diagnosis of AD. Parents of individuals with ADHD had an increased risk of AD (hazard ratio 1.55, 95% confidence interval 1.26-1.89). The associations attenuated but remained elevated in grandparents and uncles/aunts. The association for early-onset AD was stronger than late-onset AD. Similar results were observed for any dementia. DISCUSSION: ADHD is associated with AD and any dementia across generations. The associations attenuated with decreasing genetic relatedness, suggesting shared familial risk between ADHD and AD.

BACKGROUND: Genetically informed studies have provided mixed findings as to what extent parental substance misuse is associated with offspring substance misuse and antisocial behavior due to shared environmental and genetic factors. METHODS: We linked data from nationwide registries for a cohort of 2 476 198 offspring born in Sweden 1958-1995 and their parents. Substance misuse was defined as International Classification of Diseases diagnoses of alcohol/drug use disorders or alcohol/drug-related criminal convictions. Quantitative genetic offspring-of-siblings analyses in offspring of monozygotic and dizygotic twin, full-sibling, and half-sibling parents were conducted. RESULTS: Both maternal and paternal substance misuse were robustly associated with offspring substance misuse [maternal adjusted hazard ratio (aHR) = 1.83 (95% confidence interval (CI) 1.80-1.87); paternal aHR = 1.96 (1.94-1.98)] and criminal convictions [maternal aHR = 1.56 (1.54-1.58); paternal aHR = 1.66 (1.64-1.67)]. Additive genetic effects explained 42% (95% CI 25-56%) and 46% (36-55%) of the variance in maternal and paternal substance misuse, respectively, and between 36 and 44% of the variance in substance misuse and criminality in offspring. The associations between parental substance misuse and offspring outcomes were mostly due to additive genetic effects, which explained 54-85% of the parent-offspring covariance. However, both nuclear and extended family environmental factors also contributed to the associations, especially with offspring substance misuse. CONCLUSIONS: Our findings from a large offspring-of-siblings study indicate that shared genetic influences mostly explain the associations between parental substance misuse and both offspring substance misuse and criminality, but we also found evidence for the contribution of environmental factors shared by members of nuclear and extended families.

Background: We examined associations of adverse perinatal events with offspring violent and non-violent criminal convictions in men and women. Methods: 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. Results: 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. Conclusions: 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.