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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.

ObjectivesThe magnitude of the genetic contribution to idiopathic inflammatory myopathies (IIMs) is unknown. In this project, we aimed to investigate the familial aggregation and heritability of IIM.MethodsThis is a family-based study using nationwide healthcare register data in Sweden. We matched each patient with IIM to individuals without IIM, identified their first-degree relatives and determined the IIM status among all first-degree relatives. We estimated the adjusted ORs (aORs) of familial aggregation of IIM using conditional logistic regression. In addition, we used tetrachoric correlation to estimate the heritability of IIM.ResultsWe included 7615 first-degree relatives of 1620 patients with IIM diagnosed between 1997 and 2016 and 37 309 first-degree relatives of 7797 individuals without IIM. Compared with individuals without IIM, patients with IIM were more likely to have ≥1 first-degree relative affected by IIM (aOR=4.32, 95% CI 2.00 to 9.34). Furthermore, the aOR of familial aggregation of IIM in full siblings was 2.53 (95% CI 1.62 to 3.96). The heritability of IIM was 22% (95% CI 12% to 31%) among any first-degree relatives and 24% (95% CI 12% to 37%) among full siblings.ConclusionsIIM has a familial component with a risk of aggregation among first-degree relatives and a heritability of about 20%. This information is of importance for future aetiological studies and in clinical counselling.

Context Neurodevelopmental disorders are more prevalent in childhood-onset type 1 diabetes than in the general population, and the symptoms may limit the individual’s ability for diabetes management. Objective This study investigated whether comorbid neurodevelopmental disorders are associated with long-term glycemic control and risk of diabetic complications. Methods This population-based cohort study used longitudinally collected data from Swedish registers. We identified 11 326 individuals born during 1973-2013, diagnosed with type 1 diabetes during 1990-2013 (median onset age: 9.6 years). Among them, 764 had a comorbid neurodevelopmental disorder, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, and intellectual disability. We used multinomial logistic regression to calculate odds ratios (ORs) of having poor glycemic control (assessed by glycated hemoglobin [HbA1c]) and Cox regression to estimate hazard ratios (HRs) of nephropathy and retinopathy. Results The median follow-up was 7.5 years (interquartile range [IQR] 3.9, 11.2). Having any neurodevelopmental disorder (ORadjusted 1.51 [95% CI 1.13, 2.03]), or ADHD (ORadjusted 2.31 [95% CI 1.54, 3.45]) was associated with poor glycemic control (mean HbA1c > 8.5%). Increased risk of diabetic complications was observed in patients with comorbid neurodevelopmental disorders (HRadjusted 1.72 [95% CI 1.21, 2.44] for nephropathy, HRadjusted 1.18 [95% CI 1.00, 1.40] for retinopathy) and patients with ADHD (HRadjusted 1.90 [95% CI 1.20, 3.00] for nephropathy, HRadjusted 1.33 [95% CI 1.07, 1.66] for retinopathy). Patients with intellectual disability have a particularly higher risk of nephropathy (HRadjusted 2.64 [95% CI 1.30, 5.37]). Conclusion Comorbid neurodevelopmental disorders, primarily ADHD and intellectual disability, were associated with poor glycemic control and a higher risk of diabetic complications in childhood-onset type 1 diabetes.

Childhood maltreatment is considered a risk factor for substance use disorders (SUD), but this is largely based on retrospective self-reports that are subject to recall bias, designs that do not control for familial confounding, or both. The specific contribution of childhood maltreatment to SUD risk thus remains unclear. Here, we evaluated this contribution in a prospective cohort with objectively recorded childhood maltreatment, using a design that allows controlling for familial confounding. We used medical records and registers to study 525 young adults (20-37 years) with prospectively and objectively documented severe maltreatment exposure, 1979 clinical controls (unexposed former child and adolescent psychiatry patients), 1388 matched healthy controls; and their siblings and cousins. We examined the association between maltreatment and SUD using Cox regression models in the population, as well as stratified within siblings in the same family. SUD risk was significantly increased with childhood maltreatment exposure (crude HR: 6.61, 95% CI: 5.81-7.53; HR adjusted for sex, birthyear, externalizing problems, parents SUD and socioeconomic factors: 3.50, 95% CI 2.95, 4.16). An approximately threefold elevated SUD risk remained when comparing exposed individuals with their unexposed siblings (adjusted HR: 3.12, 95% CI 2.21, 4.42). We provide estimates of the association between childhood maltreatment and SUD accounting for possible confounds of both recall bias and familial factors. When familial confounding is controlled for, SUD risk attributable to severe childhood maltreatment is decreased, but nevertheless considerable. These findings establish a specific contribution of childhood maltreatment to SUD, underscoring the need for SUD prevention in young people exposed to maltreatment. Funding Agencies|Swedish Research CouncilSwedish Research CouncilEuropean Commission [2013-2024, 2013-07434]; Medical Training and Research Agreement in ostergotland Region [ALF 2017: LIO-599451, ALF 2018: LIO-692621, ALF 2019: LIO-791581]; Systembolagets alkoholforskningsrad [2016-0018, 2017-0075, 2018-0030]

Background/Objectives Frailty has been linked to increased risk of COVID‐19 mortality, but evidence is mainly limited to hospitalized older individuals. This study aimed to assess and compare predictive abilities of different frailty and comorbidity measures for COVID‐19 mortality in a community sample and COVID‐19 inpatients. Design Population‐based cohort study. Setting Community. Participants We analyzed (i) the full sample of 410,199 U.K. Biobank participants in England, aged 49–86 years, and (ii) a subsample of 2812 COVID‐19 inpatients with COVID‐19 data from March 1 to November 30, 2020. Measurements Frailty was defined using the physical frailty phenotype (PFP), frailty index (FI), and Hospital Frailty Risk Score (HFRS), and comorbidity using the Charlson Comorbidity Index (CCI). PFP and FI were available at baseline, whereas HFRS and CCI were assessed both at baseline and concurrently with the start of the pandemic. Inpatient COVID‐19 cases were confirmed by PCR and/or hospital records. COVID‐19 mortality was ascertained from death registers. Results Overall, 514 individuals died of COVID‐19. In the full sample, all frailty and comorbidity measures were associated with higher COVID‐19 mortality risk after adjusting for age and sex. However, the associations were stronger for the concurrent versus baseline HFRS and CCI, with odds ratios of 20.40 (95% confidence interval = 16.24–25.63) comparing high (>15) to low (0.8. When restricting analyses to COVID‐19 inpatients, similar improvement in AUC was not observed. Conclusion HFRS and CCI constructed from medical records concurrent with the start of the pandemic can be used in COVID‐19 mortality risk stratification at the population level, but they show limited added value in COVID‐19 inpatients.

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).

Aims/hypothesis The aim of this study was to investigate the effect of childhood-onset type 1 diabetes on the risk of subsequent neurodevelopmental disorders, and the role of glycaemic control in this association. We hypothesised that individuals with poor glycaemic control may be at a higher risk of neurodevelopmental disorders compared with the general population, as well as compared with individuals with type 1 diabetes with adequate glycaemic control. Methods This Swedish population-based cohort study was conducted using data from health registers from 1973 to 2013. We identified 8430 patients with childhood-onset type 1 diabetes (diagnosed before age 18 years) with a median age of diabetes onset of 9.6 (IQR 5.9–12.9) and 84,300 reference individuals from the general population, matched for sex, birth year and birth county. Cox models were used to estimate the effect of HbA1c on the risk of subsequent neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD) and intellectual disability. Results During a median follow-up period of 5.6 years, 398 (4.7%) individuals with type 1 diabetes received a diagnosis of any neurodevelopmental disorder compared with 3066 (3.6%) in the general population, corresponding to an adjusted HR (HRadjusted) of 1.31 (95% CI 1.18, 1.46) after additionally adjusting for other psychiatric morbidity prior to inclusion, parental psychiatric morbidity and parental highest education level. The risk of any neurodevelopmental disorder increased with HbA1c levels and the highest risk was observed in patients with mean HbA1c >8.6% (>70 mmol/mol) (HRadjusted 1.90 [95% CI 1.51, 2.37]) compared with reference individuals without type 1 diabetes. In addition, when compared with patients with diabetes with HbA1c 1c >8.6% (>70 mmol/mol) had the highest risk of any neurodevelopmental disorder (HRadjusted 3.71 [95% CI 2.75, 5.02]) and of specific neurodevelopmental disorders including ADHD (HRadjusted 4.16 [95% CI 2.92, 5.94]), ASD (HRadjusted 2.84 [95% CI 1.52, 5.28]) and intellectual disability (HRadjusted 3.93 [95% CI 1.38, 11.22]). Conclusions/interpretation Childhood-onset type 1 diabetes is associated with an increased risk of neurodevelopmental disorders, with the highest risk seen in individuals with poor glycaemic control. Routine neurodevelopmental follow-up visits should be considered in type 1 diabetes, especially in patients with poor glycaemic control. Graphical abstract

Contains fulltext : 229365.pdf (Publisher’s version ) (Open Access) Associations between adult attention-deficit/hyperactivity disorder (ADHD) symptoms and dietary habits have not been well established and the underlying mechanisms remain unclear. We explored these associations using a Swedish population-based twin study with 17,999 individuals aged 20-47 years. We estimated correlations between inattention and hyperactivity/impulsivity with dietary habits and fitted twin models to determine the genetic and environmental contributions. Dietary habits were defined as (a) consumption of food groups, (b) consumption of food items rich in particular macronutrients, and (c) healthy and unhealthy dietary patterns. At the phenotypic level, inattention was positively correlated with seafood, high-fat, high-sugar, high-protein food consumptions, and unhealthy dietary pattern, with correlation coefficients ranging from 0.03 (95%CI: 0.01, 0.05) to 0.13 (95% CI: 0.11, 0.15). Inattention was negatively correlated with fruits, vegetables consumptions and healthy dietary pattern, with correlation coefficients ranging from -0.06 (95%CI: -0.08, -0.04) to -0.07 (95%CI: -0.09, -0.05). Hyperactivity/impulsivity and dietary habits showed similar but weaker patterns compared to inattention. All associations remained stable across age, sex and socioeconomic status. Nonshared environmental effects contributed substantially to the correlations of inattention (56-60%) and hyperactivity/impulsivity (63-80%) with dietary habits. The highest and lowest genetic correlations were between inattention and high-sugar food (r(A) = .16, 95% CI: 0.07, 0.25), and between hyperactivity/impulsivity and unhealthy dietary pattern (r(A) = .05, 95% CI: -0.05, 0.14), respectively. We found phenotypic and etiological overlap between ADHD and dietary habits, although these associations were weak. Our findings contribute to a better understanding of common etiological pathways between ADHD symptoms and various dietary habits.

BackgroundGenetically 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.MethodsWe 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.ResultsBoth 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.ConclusionsOur 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 ascertain the association and coaggregation of eating disorders and childhood-onset type 1 diabetes in families. RESEARCH DESIGN AND METHODS Using population samples from national registers in Sweden (n = 2,517,277) and Demark (n = 1,825,920), we investigated the within-individual association between type 1 diabetes and eating disorders and their familial coaggregation among full siblings, half siblings, full cousins, and half cousins. On the basis of clinical diagnoses, we classified eating disorders into any eating disorder (AED), anorexia nervosa (AN) and atypical AN, and other eating disorder (OED). Associations were determined with hazard ratios (HRs) with 95% CIs from Cox regressions. RESULTS Swedish and Danish individuals with a type 1 diabetes diagnosis had a greater risk of receiving an eating disorder diagnosis (HR [95% CI] Sweden: AED 2.02 [1.80–2.27], AN 1.63 [1.36–1.96], OED 2.34 [2.07–2.63]; Denmark: AED 2.19 [1.84–2.61], AN 1.78 [1.36–2.33], OED 2.65 [2.20–3.21]). We also meta-analyzed the results: AED 2.07 (1.88–2.28), AN 1.68 (1.44–1.95), OED 2.44 (2.17–2.72). There was an increased risk of receiving an eating disorder diagnosis in full siblings in the Swedish cohort (AED 1.25 [1.07–1.46], AN 1.28 [1.04–1.57], OED 1.28 [1.07–1.52]); these results were nonsignificant in the Danish cohort. CONCLUSIONS Patients with type 1 diabetes are at a higher risk of subsequent eating disorders; however, there is conflicting support for the relationship between having a sibling with type 1 diabetes and an eating disorder diagnosis. Diabetes health care teams should be vigilant about disordered eating behaviors in children and adolescents with type 1 diabetes.

Background Children with attention‐deficit/hyperactivity disorder (ADHD) have a high risk for substance use disorders (SUDs). Early identification of at‐risk youth would help allocate scarce resources for prevention programs. Methods Psychiatric and somatic diagnoses, family history of these disorders, measures of socioeconomic distress, and information about birth complications were obtained from the national registers in Sweden for 19,787 children with ADHD born between 1989 and 1993. We trained (a) a cross‐sectional random forest (RF) model using data available by age 17 to predict SUD diagnosis between ages 18 and 19; and (b) a longitudinal recurrent neural network (RNN) model with the Long Short‐Term Memory (LSTM) architecture to predict new diagnoses at each age. Results The area under the receiver operating characteristic curve (AUC) was 0.73(95%CI 0.70–0.76) for the random forest model (RF). Removing prior diagnosis from the predictors, the RF model was still able to achieve significant AUCs when predicting all SUD diagnoses (0.69, 95%CI 0.66–0.72) or new diagnoses (0.67, 95%CI: 0.64, 0.71) during age 18–19. For the model predicting new diagnoses, model calibration was good with a low Brier score of 0.086. Longitudinal LSTM model was able to predict later SUD risks at as early as 2 years age, 10 years before the earliest diagnosis. The average AUC from longitudinal models predicting new diagnoses 1, 2, 5 and 10 years in the future was 0.63. Conclusions Population registry data can be used to predict at‐risk comorbid SUDs in individuals with ADHD. Such predictions can be made many years prior to age of the onset, and their SUD risks can be monitored using longitudinal models over years during child development. Nevertheless, more work is needed to create prediction models based on electronic health records or linked population registers that are sufficiently accurate for use in the clinic.

Mammographic features influence breast cancer risk and are used in risk prediction models. Understanding how genetics influence mammographic features is important because the mechanisms through which they are associated with breast cancer are not well known. Here, using mammographic screening history and detailed questionnaire data from 56,820 women from the KARMA prospective cohort study, we investigated the association between a genetic predisposition to breast cancer and mammographic features among women with a family history of breast cancer (N = 49,674) and a polygenic risk score (PRS, N = 9,365). The heritability of mammographic features such as dense area (MD), microcalcifications, masses, and density change (MDC, cm2/year) was estimated using 1,940 sister pairs. Heritability was estimated at 58% [95% confidence interval (CI), 48%–67%) for MD, 23% (2%–45%) for microcalcifications, and 13% (1%–25%)] for masses. The estimated heritability for MDC was essentially null (2%; 95% CI, −8% to 12%). The association between a genetic predisposition to breast cancer (using PRS) and MD and microcalcifications was positive, while for masses this was borderline significant. In addition, for MDC, having a family history of breast cancer was associated with slightly greater MD reduction. In summary, we have confirmed previous findings of heritability in MD, and also established heritability of the number of microcalcifications and masses at baseline. Because these features are associated with breast cancer risk and can improve detecting women at short-term risk of breast cancer, further investigation of common loci associated with mammographic features is warranted to better understand the etiology of breast cancer. Significance: These findings provide novel data on the heritability of microcalcifications, masses, and density change, which are all associated with breast cancer risk and can indicate women at short-term risk.

Background Family history of atherosclerotic cardiovascular disease (ASCVD) is easily accessible and captures genetic cardiovascular risk, but its prognostic value in secondary prevention is unknown. Methods and Results We followed 25 615 patients registered in SWEDEHEART (Swedish Web‐System for Enhancement and Development of Evidence‐Based Care in Heart Disease Evaluated According to Recommended Therapies) from their 1‐year revisit after a first‐time myocardial infarction during 2005 to 2013, until December 31, 2018. Data on relatives, diagnoses and socioeconomics were extracted from national registers. The association between family history and recurrent ASCVD was studied with Cox proportional‐hazard regression, adjusting for risk factors and socioeconomics. A family history of ASCVD was defined as hospitalization due to myocardial infarction, angina with coronary revascularization, stroke, or cardiovascular death in ≥1 parent or full sibling, with early‐onset defined as disease‐onset before 55 years in men and 65 in women. The additional discriminatory value of family history to Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention was assessed with Harrell’s C‐index difference and reclassification was studied with continuous net reclassification improvement. Family history of early‐onset ASCVD in ≥1 first‐degree relative was present in 2.3% and was associated with recurrent ASCVD (hazard ratio [HR] 1.31; 95% CI, 1.17–1.47), fully adjusted for risk factors (HR, 1.22; 95% CI, 1.05–1.42). Early‐onset family history improved the discriminatory ability of the Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention, with Harrell’s C improving 0.003 points (95% CI, 0.001–0.005) from initial 0.587 (95% CI, 0.576–0.595) and improved reclassification (continuous net reclassification improvement 2.1%, P Conclusions Family history of early‐onset ASCVD is associated with recurrent ASCVD after myocardial infarction, independently of traditional risk factors and improves secondary risk prediction. This may identify patients to target for intensified secondary prevention.

BackgroundFrailty 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 predictive ability for adverse outcomes in geriatric patients.MethodsEHRs were extracted for 18,225 geriatric patients with unplanned admissions between 1/3/2020 and 17/6/2021 from nine 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 modelled 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.Results13,188 patients were included in analyses (mean age 83.1 years). A 10% increment in the eFI was associated with higher risks of in-hospital (odds ratio: 5.34; 95% confidence interval: 4.20-6.82), 30-day (hazard ratio [HR]: 3.28; 2.91-3.69), and 6-month mortality (HR: 2.70; 2.52-2.90) adjusted for age and sex. Of the frailty and comorbidity measures, the eFI had the best predictive accuracy for in-hospital mortality, yielding an area under receiver operating characteristic curve of 0.813. Higher eFI also predicted a longer length of stay, but had a rather poor discrimination for 30-day readmission.ConclusionsAn EHR-based eFI has good predictive accuracy for adverse outcomes, suggesting that it can be used in risk stratification in geriatric patients.

BackgroundPrevious studies on brain connectivity in clinical and dimensional autism have largely focused on selective connections and yielded inconsistent results. This study aimed to overcome these limitations. Global fiber tracking allowed a more unbiased assessment of white matter connectivity and utilizing a within-twin pair design introduced implicit control for genetic and environmental factors shared by twins and allowed conclusions regarding their impact. MethodsThe study examined the within-twin pair associations between structural brain connectivity of anatomically defined brain regions and both clinical autism spectrum diagnoses and dimensional autistic traits in 85 twin pairs (n=170; 56% monozygotic; 25 individuals with autism spectrum diagnosis). Structural connectivity was estimated using diffusion tensor imaging and linear regression models were fit, adjusted for IQ, other neurodevelopmental and psychiatric conditions and multiple testing. ResultsOverall, both clinical and dimensional autism phenotypes were associated with localized reductions in structural connectivity, despite comprehensively controlling for possible confounders, including all factors shared by twins. Twins fulfilling autism spectrum diagnostic criteria showed decreased brainstem-cuneus connectivity compared to their co-twins without the diagnosis. Further, twins with higher autistic traits showed decreased connectivity of the left hippocampus with the left fusiform and parahippocampal areas. These associations pointed into the same direction in mono- and dizygotic sub-cohorts, but were only significant in dizygotic twins.LimitationsThe recruitment approach of selecting primarily twin pairs discordant for autistic traits prevented a quantitative estimation of genetic and environmental contributions to brain correlates of clinical and dimensional autism. Further, assessing twins and excluding individuals with an IQ below 75 limited the generalizability of the findings. The statistical power allowed detecting medium-size or larger effects of dimensional autism. Finally, due the relatively small number of twin pairs discordant for a clinical autism, the results for clinical autism need to be interpreted with caution.ConclusionsReduced brainstem-cuneus connectivity might point towards alterations in low-level visual processing in clinical autism while reduced connectivity in networks crucial for visual and especially face processing seem to be more associated with dimensional aspects of autism. The results further suggest that the observed associations were potentially influenced by both genes and environment.

BACKGROUND More knowledge about risks of clinical outcomes associated with nonsuicidal self-injury (NSSI) and suicide attempts (SAs) is needed to inform risk assessment and intervention. METHODS Longitudinal cohort study based on 1,855 youths was clinically assessed for NSSI and SA, and followed up (from December, 2011 to December 2013) for the outcomes; diagnosed self-injury, alcohol/substance use disorder, and psychiatric inpatient care data derived from Swedish registers. Hazard ratios (HRs) and 95% confidence intervals (CIs) of the outcomes were estimated with Cox regressions, and additionally adjusted for the potential effect of sex and the number of clinical assessments. NSSI and SA were treated as time-varying covariates. RESULTS Youths with NSSI had elevated risks of all outcomes, compared with youths without NSSI or SA; the HR was 2.3, 95% confidence interval [1.6, 3.4] for self-injury, 1.4 [0.9, 2.1] for alcohol/substance use disorder, and 1.3 [1.0, 1.7] for psychiatric inpatient care. Youths with SA displayed higher risks for the outcomes than the NSSI group; the HR was 5.5 [2.4, 12.6] for self-injury, 2.0 [0.9, 4.4] for alcohol/substance use disorder, and 2.6 [1.5, 4.5] for psychiatric inpatient care. Youths with both NSSI and SA showed similar risks as youths with SA; HR 4.1 [2.0, 8.3] for self-injury, 2.0 [1.1, 4.1] for alcohol/substance use disorder, but a higher risk of psychiatric inpatient care; HR 5.0 [3.1, 7.9]. All results remained virtually unchanged in the adjusted analyses. CONCLUSIONS Youths with NSSI and/or SA had higher risks for subsequent adverse clinical outcomes. These excess risks were more pronounced among youths with SA and youths with both NSSI and SA, and the risk for psychiatric inpatient care was particularly high in youths with both NSSI and SA. Our findings suggest that early interventions for youths with NSSI or SA should not exclusively focus on suicide prevention, but also consider the risk of subsequent alcohol/substance use disorder.

Background Polygenic scores (PGS) for attention‐deficit/hyperactivity disorder (ADHD) negatively predicts educational attainment (EA), but it remains unclear how ADHD symptoms, PGS for EA, and shared familiar factors influence the associations between PGS for ADHD and school performance. Method We combined survey data on ADHD symptoms, PGS, and register‐based, objective measures of compulsory school performance at age 16 for 6049 twins in the Child and Adolescent Twin Study in Sweden. Linear and instrumental variable (IV) regression models were used to estimate the association between PGS for ADHD and grade point average (GPA), overall and by natural science, humanities, and practically oriented (e.g., sports, arts, music) subject categories. The models were adjusted for parent‐rated ADHD symptoms, PGS for EA, and shared familial factors (dizygotic twin comparisons) to examine how these factors influenced the associations between PGS for ADHD and school performance. Results PGS for ADHD were negatively associated with school performance; β = −0.12, 95% confidence interval = (−0.15, −0.09) for overall GPA with minor differences by subject category. Adjustment for ADHD symptoms attenuated these associations to a small degree compared to PGS for EA, and shared familial factors respectively. Stronger associations were observed using IV regressions compared to linear regression. However, in the IV regression analyses, most associations between PGS for ADHD and GPA in the practically oriented subject category were not significant. Conclusion Associations between PGS for ADHD and school performance are to a small degree influenced by ADHD symptoms, compared to PGS for EA and shared familial factors. These results highlight important considerations for research using PGS for ADHD to control for genetic factors, and for future clinical applications aiming to determine genetic liability towards ADHD.

Background Frailty has been identified as a risk factor for cognitive impairment and dementia. However, it is not known whether familial factors, such as genetics and shared environmental factors, underlie this association. We analyzed the association between frailty and the risk of dementia in a large twin cohort and examined the role of familial factors in the association. Methods The Rockwood frailty index (FI) based on 44 health deficits was used to assess frailty. The population-level association between FI and the risk of all-cause dementia was analyzed in 41,550 participants of the Screening Across the Lifespan Twin (SALT) study (full sample, aged 41–97 years at baseline), using Cox and competing risk models. A subsample of 10,487 SALT participants aged 65 and older who received a cognitive assessment (cognitive sample) was used in a sensitivity analysis to assess the effect of baseline cognitive level on the FI-dementia association. To analyze the influence of familial effects on the FI-dementia association, a within-pair analysis was performed. The within-pair model was also used to assess whether the risk conferred by frailty varies by age at FI assessment. Results A total of 3183 individuals were diagnosed with dementia during the 19-year follow-up. A 10% increase in FI was associated with an increased risk of dementia (hazard ratio [HR] 1.17 (95% confidence interval [CI] 1.07, 1.18)) in the full sample adjusted for age, sex, education, and tobacco use. A significant association was likewise found in the cognitive sample, with an HR of 1.13 (95% CI 1.09, 1.20), adjusted for age, sex, and cognitive level at baseline. The associations were not attenuated when adjusted for APOE ɛ4 carrier status or considering the competing risk of death. After adjusting for familial effects, we found no evidence for statistically significant attenuation of the effect. The risk conferred by higher FI on dementia was constant after age 50 until very old age. Conclusions A higher level of frailty predicts the risk of dementia and the association appears independent of familial factors. Targeting frailty might thus contribute to preventing or delaying dementia.

Eating disorders and schizophrenia are both moderately to highly heritable and share significant genetic risk despite distinct diagnostic criteria. Large-scale family studies on the co-aggregation of these disorders are lacking. Thus, we aimed to estimate the co-occurrence and familial co-aggregation of these disorders within the entire Swedish and Danish population. The proband cohort consisted of individuals born in Sweden (1977-2003) and Denmark (1984-2006) and still residing in their respective country at age six (NSweden = 2,535,191, NDenmark = 1,382,367). Probands were linked to their biological parents, siblings, grandparents, uncles/aunts, and cousins. Diagnoses for anorexia nervosa (AN) and other eating disorders (OED: bulimia nervosa, binge-eating disorder, and eating disorder not otherwise specified) for probands and schizophrenia diagnoses for both probands and relatives were obtained. The likelihood of having schizophrenia in those with AN or OED and their relatives was compared with individuals without eating disorder diagnoses and their relatives. Probands with AN or OED were more likely to have schizophrenia than probands without these disorders. All relatives of probands with AN or OED (except parents and uncles/aunts of probands with AN) were at increased risk of schizophrenia. In general, the magnitude of odds ratios attenuated with decreasing genetic relatedness. These results suggest familial liability contributes to the association between eating disorders and schizophrenia. Clinicians should be mindful of this comorbid and co-aggregation pattern as it may influence case conceptualization and treatment decisions.

BackgroundAnorexia nervosa and bulimia nervosa are two severe eating disorders associated with high premature mortality, suicidal risk and serious medical complications. Transition between anorexia nervosa and bulimia nervosa over the illness course and familial co-aggregation of the two eating disorders imply aetiological overlap. However, genetic and environmental liabilities to the overlap are poorly understood. Quantitative genetic research using clinical diagnosis is needed.MethodsWe acquired a clinical diagnosis of anorexia nervosa (prevalence = 0.90%) and bulimia nervosa (prevalence = 0.48%) in a large population-based sample (N = 782 938) of randomly selected full-sisters and maternal half-sisters born in Sweden between 1970 and 2005. Structural equation modelling was applied to quantify heritability of clinically diagnosed anorexia nervosa and bulimia nervosa and the contributions of genetic and environmental effects on their overlap.ResultsThe heritability of clinically diagnosed anorexia nervosa and bulimia nervosa was estimated at 43% [95% confidence interval (CI) (36–50%)] and 41% (31–52%), respectively, in the study population, with the remaining variance explained by variance in unique environmental effects. We found statistically significant genetic [0.66, 95% CI (0.49–0.82)] and unique environmental correlations [0.55 (0.43–0.66)] between the two clinically diagnosed eating disorders; and their overlap was about equally explained by genetic and unique environmental effects [co-heritability 47% (35–58%)].ConclusionsOur study supports shared mechanisms for anorexia nervosa and bulimia nervosa and extends the literature from self-reported behavioural measures to clinical diagnosis. The findings encourage future molecular genetic research on both eating disorders and emphasize clinical vigilance for symptom fluctuation between them.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is often associated with other neurodevelopmental disorders (NDs) and with risky behaviors and adverse health outcomes, including injuries. Treatment with ADHD medication has been associated with reduced risk of injuries. However, it is unknown whether the association is present in individuals with co-occurring NDs. The aim of the present study was to estimate the association between ADHD medication use and unintentional injuries in Sweden in children and adolescents with ADHD, including those with co-occurring NDs. METHODS: Using a linkage of several national registers via the unique personal identification number, we identified individuals with a diagnosis of ADHD and of other NDs, including autism spectrum disorder, intellectual disability, communication disorders, learning disorders and motor disorders. The primary outcome was unintentional injuries. Secondary outcome was traumatic brain injury (TBI). Individuals were followed from January 1st 2006 or their 5th birthday or the date of the first unintentional injury, whichever came last, to December 31st 2013 or their 18th birthday or death, whichever came first. We compared the rate of injuries during periods on-treatment with the rate of injuries during periods off-treatment within the same individual using stratified Cox regression to calculate hazard ratio (HR) with 95% confidence intervals (CIs). RESULTS: For children and adolescents with ADHD (N=9421) the rate of any unintentional injuries (HR=0.85; 95% CI=0.78–0.92) and TBIs (HR=0.27; 95% CIs=0.20–0.38) during medicated periods was lower than during non-medicated periods. Similar results were found among individuals with co-occurring NDs (N=2986), for unintentional injuries (HR= 0.88; 95% CI=0.77–1.01) and for TBIs (HR=0.27; 95% CI=0.16–0.44). CONCLUSIONS: Beneficial effects of ADHD medication may extend beyond reduction of ADHD core symptoms to prevention of unintentional injuries in children and adolescents, including individuals with co-occurring NDs.

In the latest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), obsessive-compulsive disorder (OCD) included a new “tic-related” specifier. However, strong evidence supporting tic-related OCD as a distinct subtype of OCD is lacking. This study investigated whether, at the population level, tic-related OCD has a stronger familial load than non-tic-related OCD. From a cohort of individuals born in Sweden between 1967 and 2007 (n = 4,085,367; 1257 with tic-related OCD and 20,975 with non-tic-related OCD), we identified all twins, full siblings, maternal and paternal half siblings, and cousins. Sex- and birth year-adjusted hazard ratios (aHR) were calculated to estimate the risk of OCD in relatives of individuals with OCD with and without comorbid tics, compared with relatives of unaffected individuals. We found that OCD is a familial disorder, regardless of comorbid tic disorder status. However, the risk of OCD in relatives of individuals with tic-related OCD was considerably greater than the risk of OCD in relatives of individuals with non-tic-related OCD (e.g., risk for full siblings: aHR = 10.63 [95% CI, 7.92–14.27] and aHR = 4.52 [95% CI, 4.06–5.02], respectively; p value for the difference

Twin- and family studies have shown variations in the heritability estimates of bipolar disorder (BPD). The current study uses an updated statistical methodology for heritability estimation in BPD by taking available time of follow-up into account while controlling for co-variates. We identified monozygotic and dizygotic same and different sex twins with BPD (n = 804) or unaffected from BPD (n = 91,604) from the Swedish Twin Register and the National Patient Register. We applied structural equational modeling with inversed probability weighting to estimate the heritability, taking into account censoring and truncation of data. Sex-limitation models were constructed to analyze qualitative or quantitative sex-differences in BPD. Heritability for BPD was 60.4% (95% Confidence Interval: 50.3-70.5) after age, sex, left-hand truncation and censoring of the data was taken into account. A larger proportion of females were affected from BPD (females 62.2%; males 37.8%, p 0.001), but no sex-difference in BPD heritability was found, nor any sex-specific genetic effects. We demonstrated a robust 60% heritability for BPD with no evidence of sex-specific genetic effects on disease liability.

BackgroundA recent family study of young adult males suggests a shared familial liability between attention-deficit/hyperactivity disorder (ADHD) and high body mass index (BMI), and a genome-wide meta-analysis reported a genetic correlation of 0.26 between ADHD and BMI. To date, it is unclear whether these findings generalize to the relationship between ADHD and clinically diagnosed obesity.MethodBy linking the Swedish national registers, we identified 25 38 127 individuals born between 1973 and 2000, together with their siblings and cousins. The risk of clinical obesity in individuals with ADHD was compared with the risk in those without ADHD. The relative contributions of genetic and environmental factors to the association between ADHD and clinical obesity were examined via assessment of the familial co-aggregation of the two conditions and quantitative genetic analysis.ResultsIndividuals with ADHD were at an increased risk of clinical obesity compared with those without (risk difference 3.73%, 95% confidence interval (CI) 3.55–3.90%; risk ratio 3.05, 95% CI 2.95–3.15). Familial co-aggregation of ADHD and clinical obesity was detected and the strength of the co-aggregation decreased by decreasing genetic relatedness. The correlation between the liabilities to ADHD and clinical obesity can be entirely attributed to their genetic correlation (rg 0.30, 95% CI 0.17–0.44).ConclusionThe association between ADHD and clinical obesity in adolescence and young adulthood can be entirely attributed to genetic underpinnings shared by the two conditions. Children with ADHD should be monitored for weight gain so that preventive measures can be taken for those on a suboptimal trajectory.

It is unknown whether the association between body mass index (BMI) and chronic kidney disease (CKD) is mediated by genetic confounding or obesity-associated diabetes. We investigated the association between BMI and incident CKD in 29,136 Swedish twins with no history of CKD or diabetes, first using traditional Cox regression in a cohort design, and second controlling for shared genetic factors within twin pairs. Hazard ratios (HR) per unit increase in BMI were calculated and adjusted for age, sex, comorbidities, and lifestyle factors. We contrasted CKD risk between twins with discordant BMI and adjusted for diabetes as a time-varying covariate. During an average follow-up of 12.8 years, 1,113 (3.8%) incident CKD and 2,282 (7.8%) diabetes cases were observed. BMI was associated with CKD risk in the traditional cohort analysis (HR 1.13; 95% CI, 1.11-1.14). Effect sizes were similar in analyses clustered by twin pairs to adjust for factors shared by twins (HR 1.16; 95 CI 1.09-1.22 in same-sex fraternal twins and HR 1.17; 95% CI 1.06-1.29 in identical twins). Heavier twins had higher incidence rates of both CKD and diabetes than their leaner siblings, particularly when BMI differed by >2 kg/m2. The proportion of CKD cases attributable to BMI ≥25 kg/m2 was estimated to be 32%, with approximately 19% of those cases explained by diabetes. We conclude that a higher BMI, irrespective of genetic confounding, is associated with increased CKD risk. A large proportion of CKD cases might be prevented if the population maintained a normal BMI.

Background Smoking and use of Swedish smokeless tobacco (snus) are associated with increased risk of type 2 diabetes (T2D). Our aim was to estimate the unique and shared genetic components of these traits and to what extent the association is explained by shared genetic factors. Methods We used twins of the Swedish Twin Registry who responded to a questionnaire between 1998 and 2006 (n = 40 247) and were followed until 2015 in the National Prescription and Patient Registries. We estimated hazard ratios (HRs) and odds ratios (ORs) for the association between smoking/snus use and T2D (n = 2130) and used structural equation models to estimate genetic and environmental variance components and genetic correlations. Results Current smokers [HR 1.69, 95% confidence interval (CI), 1.49–1.92] and snus users (HR 1.19, 95% CI 1.01–1.41) had an increased risk of T2D. In within-pair analyses of monozygotic twins, corresponding ORs were 1.36, 95% CI 0.75–2.46 (smoking) and 1.54, 95% CI 0.80–2.99 (snus). Heritability was 43% (95% CI 36–51) for ever smoking, 58% (95% CI 44– 70) for ever snus use and 66% (95% CI 59–72) for T2D. The genetic correlation with T2D was 18% (95% CI 1–35) for smoking and –6% (95% CI –24 to 4) for snus use, indicating that only a small fraction of the genetic influence is shared. Conclusions We could confirm that consumers of snus and cigarettes are at increased risk of T2D. Both snus use and smoking have strong genetic components, which appears to be attributable primarily to genes that are distinct from those promoting T2D.

Background\ud \ud Familial and genetic associations between autism spectrum disorder (ASD) and other neurodevelopmental and psychiatric disorders have been reported, sometimes with conflicting results. We estimated familial and genetic associations between ASD and nine disorder groups, and explored differences in these associations for ASD in the context of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations.\ud Methods\ud \ud Individuals born between 1985 and 2009 living in Sweden on their seventh birthday were linked to their biological parents in order to identify different types of relatives. We retrieved information on all the disorders considered from the National Patient Register. Logistic regression was used to estimate the familial association between ASD and other neurodevelopmental and psychiatric disorders in the different groups of relatives. Structural equation modeling was used to estimate phenotypic (rp) and genetic associations (rg), as well as the contribution of genetic influences to rp.\ud Results\ud \ud The study included 2,398,608 individuals. Among relatives of individuals diagnosed with ASD, there was an increased risk of the disorders considered, compared to relatives of individuals who were not diagnosed with ASD. Stronger associations were detected for ASD without any additional diagnosis of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations. The strongest genetic correlation was estimated between ASD and other neurodevelopmental disorders (rg = 0.73; 95% CI = 0.66–0.79). Moderate genetic correlations were estimated for anxiety disorders (rg = 0.47; 95% CI = 0.33–0.61), depression (rg = 0.52; 95% CI = 0.37–0.66), and intentional self-harm (rg = 0.54; 95% CI = 0.36–0.71).\ud Conclusions\ud \ud ASD shows familial and genetic association not only with other neurodevelopmental disorders, but also with other psychiatric disorders, such as anxiety, depression, and intentional self-harm. Family history of ASD comorbid with intellectual disability, epilepsy, congenital malformations, or chromosomal abnormalities is less related to other psychiatric disorders, potentially suggesting a different etiology for this subgroup of patients.

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.

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.

Background Familial co-aggregation studies of eating disorders (EDs) and schizophrenia reveal shared genetic and environment factors, yet their etiological and clinical relationship remains unclear. We evaluate the influence of schizophrenia family history on clinical outcomes of EDs. Methods We conducted a cohort evaluation of the association between family history of schizophrenia and ED clinical features, psychiatric comorbidities, and somatic and mental health burden in individuals born in Sweden 1977–2003 with anorexia nervosa (AN) or other EDs (OED: bulimia nervosa, binge-eating disorder, and ED not otherwise specified). Results Of 12 424 individuals with AN and 20 716 individuals with OED, 599 (4.8%) and 1118 (5.4%), respectively, had a family history of schizophrenia (in up to third-degree relatives). Among individuals with AN, schizophrenia in first-degree relatives was significantly associated with increased comorbid attention-deficit/hyperactivity disorder (ADHD) [HR(95% CI) 2.26 (1.27–3.99)], substance abuse disorder (SUD) [HR (95% CI) 1.93 (1.25–2.98)], and anxiety disorders [HR (95% CI) 1.47 (1.08–2.01)], but higher lowest illness-associated body mass index (BMI) [1.14 kg/m2, 95% CI (0.19–2.10)]. Schizophrenia in any relative (up to third-degree) in AN was significantly associated with higher somatic and mental health burden, but lower ED psychopathology scores [−0.29, 95% CI (−0.54 to −0.04)]. Schizophrenia in first-degree relatives in individuals with OED was significantly associated with increased comorbid ADHD, obsessive-compulsive disorder, SUD, anxiety disorders, somatic and mental health burden, and suicide attempts. Conclusions We observed different patterns of ED-related outcomes, psychiatric comorbidity, and illness burden in individuals with EDs with and without family histories of schizophrenia and provide new insights into the diverse manifestations of EDs.

OBJECTIVE Eating disorders commonly co-occur with gastrointestinal problems. This case-control study aimed to (a) document the prevalence of disorders of gut-brain interaction (DGBI) in eating disorders, (b) examine the specific impact of disordered eating behaviors on the risk of DGBI, and (c) explore the impact of current eating disorder psychopathology on DGBI. METHOD We included 765 cases with eating disorders and 1,240 controls. DGBI were assessed via the ROME III questionnaire. Prevalences of DGBI were calculated across eating disorder diagnoses (anorexia nervosa, bulimia nervosa, and multiple eating disorders) and in controls. The association between disordered eating behaviors and DGBI was examined using logistic regression models. Lastly, we compared the total number of DGBI in individuals with high versus low current eating disorder symptoms. RESULTS A large majority (88.2-95.5%) of individuals with eating disorders reported at least one DGBI and 34.8-48.7% reported three or more DGBI. Of the DGBI categories, functional bowel disorders were the most commonly endorsed category, and of the individual DGBI, irritable bowel syndrome was the most frequently reported (43.9-58.8%). All investigated disordered eating behaviors showed a positive association with most DGBI categories. Finally, individuals reporting high current eating disorder symptoms reported higher mean number of DGBI (3.03-3.34) than those with low current symptoms (1.60-1.84). DISCUSSION The directionality and mechanisms underlying the nature of the relationship between gastrointestinal and eating disorder symptoms is worthy of further study and clinicians should adopt an integrated approach by attending to both gastrointestinal and eating disorder symptoms in their patients.

Major depression (MD) is a heterogeneous disorder; however, the extent to which genetic factors distinguish MD patient subgroups (genetic heterogeneity) remains uncertain. This study sought evidence for genetic heterogeneity in MD. Using UK Biobank cohort, the authors defined 16 MD subtypes within eight comparison groups (vegetative symptoms, symptom severity, comorbid anxiety disorder, age at onset, recurrence, suicidality, impairment and postpartum depression; N∼3 000-47 000). To compare genetic component of these subtypes, subtype-specific genome-wide association studies were performed to estimate SNP-heritability, and genetic correlations within subtype comparison and with other related disorders or traits. The findings indicated that MD subtypes were divergent in their SNP-heritability, and genetic correlations both within subtype comparisons and with other related disorders/traits. Three subtype comparisons (vegetative symptoms, age at onset, and impairment) showed significant differences in SNP-heritability; while genetic correlations within subtype comparisons ranged from 0.55 to 0.86, suggesting genetic profiles are only partially shared among MD subtypes. Furthermore, subtypes that are more clinically challenging, e.g., early-onset, recurrent, suicidal, more severely impaired, had stronger genetic correlations with other psychiatric disorders. MD with atypical-like features showed a positive genetic correlation (+0.40) with BMI while a negative correlation (−0.09) was found in those without atypical-like features. Novel genomic loci with subtype-specific effects were identified. These results provide the most comprehensive evidence to date for genetic heterogeneity within MD, and suggest that the phenotypic complexity of MD can be effectively reduced by studying the subtypes which share partially distinct etiologies.

Context Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) are known to coaggregate in families, but the magnitude and nature of a shared etiology is unknown. Objectives To estimate the shared genetic influence on overt HT and GD and to examine if the heritability differs between men and women. Design, setting, and patients We used national health registries to identify cases of HT and GD in a cohort of 110 814 Swedish twins. By comparing intra-class and cross-twin cross-trait correlations in dizygotic and monozygotic twins, we calculated heritability and the proportions thereof shared between the diseases. Univariate estimates of heritability were calculated by sex. Results The heritability for HT and GD was 65% (95% CI, 61-70) and 63% (95% CI, 55-72), respectively. The genetic correlation was 0.35 (95% CI, 0.20-0.50) and shared genetic effects accounted for 8% of the variance for both HT and GD. Univariate heritability was significantly higher in men than in women for HT (90% vs 60%, P Conclusions From a genetic perspective, HT and GD appear to be only modestly related diseases. Hence, the term “autoimmune thyroid disease,” used to cluster these disorders, may have limited validity in a genetic context. Moreover, the mechanisms contributing to HT are partly different for the sexes, with genetic components more important in men.

BackgroundAlthough attention-deficit hyperactivity disorder (ADHD) is classified as a neurodevelopmental disorder in the latest diagnostic manuals, it shows phenotypic and genetic associations of similar magnitudes across neurodevelopmental, externalising and internalising disorders.AimsTo investigate if ADHD is aetiologically more closely related to neurodevelopmental than externalising or internalising disorder clusters, after accounting for a general psychopathology factor.MethodFull and maternal half-sibling pairs (N = 774 416), born between 1980 and 1995, were identified from the Swedish Medical Birth and Multi-Generation Registers, and ICD diagnoses were obtained from the Swedish National Patient Register. A higher-order confirmatory factor analytic model was fitted to examine associations between ADHD and a general psychopathology factor, as well as a neurodevelopmental, externalising and internalising subfactor. Quantitative genetic modelling was performed to estimate the extent to which genetic, shared and non-shared environmental effects influenced the associations with ADHD.ResultsADHD was significantly and strongly associated with all three factors (r = 0.67–0.75). However, after controlling for a general psychopathology factor, only the association between ADHD and the neurodevelopmental-specific factor remained moderately strong (r = 0.43, 95% CI = 0.42–0.45) and was almost entirely influenced by genetic effects. In contrast, the association between ADHD and the externalising-specific factor was smaller (r = 0.25, 95% CI = 0.24–0.27), and largely influenced by non-shared environmental effects. There remained no internalising-specific factor after accounting for a general factor.ConclusionsFindings suggest that ADHD comorbidity is largely explained by genetically influenced general psychopathology, but the strong link between ADHD and other neurodevelopmental disorders is also substantially driven by unique genetic influences.

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 maternal immune activation in the aetiology of ADHD. The findings have implications for aetiological models of ADHD. However, screening for autoimmunity among individuals with ADHD is not warranted.

Aim: To identify whether periodontal traits derived from electronic dental records are biologically informative and heritable.Materials and methods: The study included 11,974 adult twins (aged 30-92 years) in the Swedish Twin Registry. Periodontal records from dental examinations were retrieved from a national register and used to derive continuous measures of periodontal health. A latent class approach was used to derive categorial measures of periodontal status. The correlation patterns in these traits were contrasted in monozygotic and dizygotic twin pairs using quantitative genetic models to estimate the heritability of the traits. Results: For continuous traits, heritability estimates ranged between 41.5% and 48.3% with the highest estimates for number of missing tooth surfaces and rate of change in number of deep periodontal pockets ( 6 mm). For categorial traits the latent class approach identified 3 classes (good periodontal health, mild periodontitis signs, severe signs of periodontitis) and there was a clear difference in the hazard for subsequent tooth loss between these 3 classes. Despite this, the class allocations were only slightly more heritable than a conventional dichotomous disease definition (45.2% versus 42.6%).Conclusions: Periodontitis is a moderately heritable disease. Quantitative periodontal traits derived from electronic records are an attractive target for future genetic association studies.

While previous research has investigated neuroradiological findings in autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD), the entire range of neurodevelopmental disorders (NDDs) has not yet been well-studied using magnetic resonance imaging (MRI). Considering the overlap among NDDs and simultaneous development of the brain and face, guided by molecular signaling, we examined the relationship of actionable and incidental (non-actionable) MRI findings and NDD diagnoses together with facial morphological variants and genetic copy number variants (CNVs). A cross-sectional study was conducted with a twin cohort 8–36 years of age (57% monozygotic, 40% dizygotic), including 372 subjects (46% with NDDs; 47% female) imaged by MRI, 280 with data for facial morphological variants, and 183 for CNVs. Fifty-one percent of participants had MRI findings. Males had a statistically significantly higher percentage of MRI findings (57.7%) compared with females (43.8%, p = 0.03). Twin zygosity was not statistically significantly correlated with incidence or severity of specific MRI findings. No statistically significant association was found between MRI findings and any NDD diagnosis or facial morphological variants; however, MRI findings were statistically significantly associated with the number of CNVs (OR 1.20, 95% CI 1.00–1.44, p = 0.05, adjusted OR for sex 1.24, 95% CI 1.03–1.50, p = 0.02). When combining the presence of MRI findings, facial morphological variants, and CNVs, statistically significant relationships were found with ASD and ADHD diagnoses (p = 0.0006 and p = 0.002, respectively). The results of this study demonstrate that the ability to identify NDDs from combined radiology, morphology, and CNV assessments may be possible. Additionally, twins do not appear to be at increased risk for neuroradiological variants.

Background Despite recent advances in secondary prevention, recurrent cardiovascular events are common after a myocardial infarction (MI). It has been reported that genetic risk scores may predict the risk of recurrent cardiovascular events. Although patient-derived family history is a composite of both genetic and environmental heritability of atherosclerotic cardiovascular disease (ASCVD), it is an easily accessible information compared to genetically based risk models but the association with recurrent events is unknown. Purpose To evaluate whether a register-verified family history of ASCVD is associated with recurrent cardiovascular events (rASCVD) in patients after a first-time MI. Methods We included patients with a first-time MI during 2005 – 2014, registered in the SWEDEHEART SEPHIA registry and without prior ASCVD. Follow-up was available until Dec 31st, 2018. Data on relatives, diagnoses and prescriptions were extracted from national registers. A family history of ASCVD was defined as a register-verified hospitalisation due to MI, angina with coronary revascularization procedures, stroke or cardiovascular death in any parent. Early history was defined as such an event before the age of 55 years in fathers and 65 years in mothers. The association between family history and a composite outcome including recurrent MI, angina requiring acute revascularization, ischaemic stroke and cardiovascular death during follow-up was studied with Cox proportional hazard regression with time from SEPHIA registry completion as underlying time-scale, adjusted for age with splines, gender and year of SEPHIA registry. Regression models were then further adjusted for hypertension, diabetes, smoking and for a subset of patients, LDL-cholesterol (LDL_C) at time of first event. Results Of 25,615 patients, 2.5% and 32.1% had an early and ever-occurring family history of ASCVD, respectively. Patients with early family history were significantly younger than other patients and were more likely to be current smokers and have a higher LDL-C (Median (IQR) 3.5 (1.1) vs 3.3 (1.1) mmol/L). In total, 3,971 (15.5%) patients experienced the outcome. Early family history of ASCVD was significantly associated with rASCVD (Hazard ratio (HR) 1.52, 95% confidence interval (CI) 1.23–1.87), and the effect was sustained when adjusted for cardiovascular risk factors (HR 1.48, 95% CI 1.20–1.83) and LDL-C (HR 1.35, 95% CI 1.04–1.74). Ever-occurring family history was weakly associated with ASCVD (HR 1.09, 95% CI 1.02 – 1.17) and the association remained unchanged with adjustments for risk factors. Conclusions Early family history of cardiovascular disease is a potent risk factor for recurrent cardiovascular events in a secondary prevention setting, independent of traditional risk factors including LDL-C. This is a novel finding and these patients may potentially benefit from intensified secondary preventive measures after a first-time MI. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): This work was funded by grants from The Swedish Heart and Lung Association

Studies have shown that men with Peyronie's disease often suffer from psychological problems, but the psychiatric burden of this disorder remains largely unknown. We assessed risks of a range of psychiatric outcomes in a population based Swedish cohort comprising 3.5 million men.We conducted a longitudinal cohort study based on Swedish national registers. A total of 8,105 men diagnosed with Peyronie's disease and 3.5 million comparison subjects from the general Swedish population were selected, and followed up with for diagnosed psychiatric outcomes including substance use disorder, alcohol misuse, anxiety disorder, depression, and self-injurious behaviors. Risks of psychiatric outcomes were estimated with Cox regressions and additionally adjusted for birth year.Men with Peyronie's disease had increased risks of being diagnosed with substance use disorder (HR 1.4, 95% CI 1.1-1.9), no excess risk of alcohol misuse (HR 0.9, CI 0.8-1.1), but elevated risks of anxiety disorder (HR 1.9, CI 1.6-2.2), depression (HR 1.7, CI 1.5-2.0), self-injurious behaviors (HR 2.0, 95% CI 1.7-2.3) as well as any psychiatric outcomes (HR 1.4, 95% CI 1.2-1.5). The risk estimates were slightly decreased when adjusted for birth year. A limitation of the study was that we had no information about Peyronie's disease diagnoses assigned before year 1997.Men with Peyronie's disease are at increased risk of being diagnosed with adverse psychiatric outcomes. Health care providers should ensure that men with Peyronie's disease have a documented mental health status assessment.

Internalising symptoms in childhood and adolescence are as heritable as adult depression and anxiety, yet little is known of their molecular basis. This genome-wide association meta-analysis of internalising symptoms included repeated observations from 64,641 individuals, aged between 3 and 18. The N-weighted meta-analysis of overall internalising symptoms (INToverall) detected no genome-wide significant hits and showed low SNP heritability (1.66%, 95% confidence intervals 0.84-2.48%, Neffective=132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalising symptoms showing the highest heritability (5.63%, 95% confidence intervals 3.08-8.18%). Additive genetic effects on internalising symptoms appeared stable over age, with overlapping estimates of SNP heritability from early-childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the wellbeing 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. The pattern of genetic correlations suggests that childhood and adolescent internalising symptoms share substantial genetic vulnerabilities with adult internalising disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalising symptoms over time and the high comorbidity amongst childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

Importance: Adult mood disorders are often preceded by behavioral and emotional problems in childhood. It is yet unclear what explains the associations between childhood psychopathology and adult traits.Objective: To investigate whether genetic risk for adult mood disorders and associated traits is associated with childhood disorders.Design, setting, and participants: This meta-analysis examined data from 7 ongoing longitudinal birth and childhood cohorts from the UK, the Netherlands, Sweden, Norway, and Finland. Starting points of data collection ranged from July 1985 to April 2002. Participants were repeatedly assessed for childhood psychopathology from ages 6 to 17 years. Data analysis occurred from September 2017 to May 2019.Exposures: Individual polygenic scores (PGS) were constructed in children based on genome-wide association studies of adult major depression, bipolar disorder, subjective well-being, neuroticism, insomnia, educational attainment, and body mass index (BMI).Main outcomes and measures: Regression meta-analyses were used to test associations between PGS and attention-deficit/hyperactivity disorder (ADHD) symptoms and internalizing and social problems measured repeatedly across childhood and adolescence and whether these associations depended on childhood phenotype, age, and rater.Results: The sample included 42 998 participants aged 6 to 17 years. Male participants varied from 43.0% (1040 of 2417 participants) to 53.1% (2434 of 4583 participants) by age and across all cohorts. The PGS of adult major depression, neuroticism, BMI, and insomnia were positively associated with childhood psychopathology (β estimate range, 0.023-0.042 [95% CI, 0.017-0.049]), while associations with PGS of subjective well-being and educational attainment were negative (β, -0.026 to -0.046 [95% CI, -0.020 to -0.057]). There was no moderation of age, type of childhood phenotype, or rater with the associations. The exceptions were stronger associations between educational attainment PGS and ADHD compared with internalizing problems (Δβ, 0.0561 [Δ95% CI, 0.0318-0.0804]; ΔSE, 0.0124) and social problems (Δβ, 0.0528 [Δ95% CI, 0.0282-0.0775]; ΔSE, 0.0126), and between BMI PGS and ADHD and social problems (Δβ, -0.0001 [Δ95% CI, -0.0102 to 0.0100]; ΔSE, 0.0052), compared with internalizing problems (Δβ, -0.0310 [Δ95% CI, -0.0456 to -0.0164]; ΔSE, 0.0074). Furthermore, the association between educational attainment PGS and ADHD increased with age (Δβ, -0.0032 [Δ 95% CI, -0.0048 to -0.0017]; ΔSE, 0.0008).Conclusions and relevance: Results from this study suggest the existence of a set of genetic factors influencing a range of traits across the life span with stable associations present throughout childhood. Knowledge of underlying mechanisms may affect treatment and long-term outcomes of individuals with psychopathology.

Background: Exhaled nitric oxide and blood eosinophils are clinical asthma type 2 markers in use. Immunoglobulin E (IgE) is often involved in the inflammation associated with atopic asthma. The effect of both blood eosinophils and allergen-specific IgE on exhaled nitric oxide levels is not completely understood. Twin-design studies can improve understanding of the underlying contribution of genetically and/or environmentally driven inflammation markers in asthma. Our aim was to disentangle the covariance between asthma and exhaled nitric oxide into genetic and environmental contributions that can account for inflammation markers in a paediatric population. Methods: This population-based, cross-sectional twin study enrolled 612 monozygotic (MZ) and same-sex dizygotic (DZ) schoolchildren. Multivariate structural equation modelling was utilized to separate the covariance between asthma and exhaled nitric oxide into genetic and/or environmental effects, taking allergen-specific IgE level and blood eosinophil count into account while controlling for confounding factors. Results: The cross-twin/cross-trait correlations had a higher magnitude in the MZ twins than in the DZ twins indicating that genes affect the association. The likelihood ratio test for model fitting resulted in the AE model as the most parsimonious. A majority, 73%, of the phenotypic correlation between asthma and exhaled nitric oxide, r=0.19 (0.05–0.33), was attributable to genetic effects which mainly was due to the allergen-specific IgE level. Conclusions: This study indicate that the association between asthma - exhaled nitric oxide in children is to a large extent explained by genetics via allergen-specific IgE-level but not blood eosinophils. This might partly explain the clinical heterogeneity in this group. A next step could be to include allergen-specific IgE level in multivariate omic-studies.

BackgroundWhile ADHD is currently classified as a neurodevelopmental disorder in the latest diagnostic manuals, the disorder shows phenotypic and genetic associations of similar magnitudes across neurodevelopmental, externalizing and internalizing disorders. This study aimed to investigate if ADHD is etiologically more closely related to neurodevelopmental than externalizing or internalizing disorder clusters after accounting for a general psychopathology factor.MethodsFull- and maternal half-sibling pairs (N=774,416), born between 1980 and 1995, were identified from the Swedish Medical Birth and Multi-Generation Registers, and ICD-diagnoses were obtained using the Swedish National Patient Register. A higher-order confirmatory factor analytic model was performed to examine associations between ADHD and a general psychopathology factor as well as a neurodevelopmental, externalizing, and internalizing subfactor. Quantitative genetic modelling was performed to estimate the extent to which genetic, shared and non-shared environmental effects influenced the associations with ADHD.ResultsADHD was significantly and strongly associated with all three neurodevelopmental, externalizing and internalizing factors (r=0.67-0.75). However, after controlling for a general psychopathology factor, only the association between ADHD and the neurodevelopmental-specific factor remained moderately strong (r=0.43, 95%Confidence Interval [CI]=0.42-0.45) and was almost entirely influenced by genetic effects. In contrast, the association between ADHD and the externalizing-specific factor was smaller (r=0.25, 95%CI=0.24-0.27), and largely influenced by non-shared environmental effects. There remained no internalizing-specific factor after accounting for a general factor.ConclusionsADHD comorbidity is largely explained by genetically influenced general psychopathology, but the strong link between ADHD and other neurodevelopmental disorders is also substantially driven by unique genetic influences.

Aims To assess whether parental substance use disorder (SUD) is associated with lower cognitive ability in offspring, and whether the association is independent of shared genetic factors. Design A population family-based cohort study utilizing national Swedish registries. Linear regression with increased adjustment of covariates was performed in the full population. In addition, the mechanism of the association was investigated with children-of-sibling analyses using fixed-effects regression with three types of sibling parents with increasing genetic relatedness (half-siblings, full siblings and monozygotic twins). Setting and participants A total of 3 004 401 people born in Sweden between 1951 and 1998. Measurements The exposure variable was parental SUD, operationalized as having a parent with life-time SUD diagnosis or substance-related criminal conviction in the National Patient Register or Crime Register, respectively. Outcomes were cognitive test score at military conscription and final school grades when graduating from compulsory school. Covariates included in the analyses were sex, birth year, parental education, parental migration status and parental psychiatric comorbid diagnoses. Findings In the full population, parental SUD was associated with decreased cognitive test stanine scores at conscription [4.56, 95% confidence interval (CI) = 4.55-4.57] and lower Z-standardized school grades (-0.43, 95% CI = -0.43 to -0.42) compared to people with no parental SUD (cognitive test: 5.17, 95% CI = 5.17-5.18; grades: 0.09, 95% CI = 0.08-0.09). There was evidence of a dose-response relationship, in that having two parents with SUD (cognitive test: 4.17, 95% CI = 4.15-4.20; grades: -0.83, 95% CI = -0.84 to -0.82) was associated with even lower cognitive ability than having one parent with SUD (cognitive test: 4.60, 95% CI = 4.59-4.60; grades: -0.38, 95% CI = -0.39 to -0.380). In the children-of-siblings analyses when accounting for genetic relatedness, these negative associations were attenuated, suggestive of shared underlying genetic factors. Conclusions There appear to be shared genetic factors between parental substance use disorder (SUD) and offspring cognitive function, suggesting that cognitive deficits may constitute a genetically transmitted risk factor in SUD.

International audience; Females might possess protective mechanisms regarding autism spectrum disorder (ASD) and require a higher detrimental load, including structural brain alterations, before developing clinically relevant levels of autistic traits. This study examines sex differences in structural brain morphology in autism and autistic traits using a within-twin pair approach. Twin design inherently controls for shared confounders and enables the study of gene-independent neuroanatomical variation. N = 148 twins (62 females) from 49 monozygotic and 25 dizygotic same-sex pairs were included. Participants were distributed along the whole continuum of autism including twin pairs discordant and concordant for clinical ASD. Regional brain volume, surface area, and cortical thickness were computed. Within-twin pair increases in autistic traits were related to decreases in cortical volume and surface area of temporal and frontal regions specifically in female twin pairs, in particular regions involved in social communication, while only two regions were associated with autistic traits in males. The same pattern was detected in the monozygotic twin pairs only. Thus, non-shared environmental factors seem to impact female more than male cerebral architecture associated with autistic traits. Our results are in line with the hypothesis of a female protective effect in autism and highlights the need to study ASD in females separately from males.

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.

Large-scale family studies on the co-occurrence of attention-deficit/hyperactivity disorder (ADHD) and borderline personality disorder (BPD) are lacking. Thus, we aimed to estimate the co-occurrence and familial co-aggregation of clinically ascertained ADHD and BPD diagnoses using the entire Swedish population. In a register-based cohort design we included individuals born in Sweden 1979–2001, and identified their diagnoses during 1997–2013; in total, 2,113,902 individuals were included in the analyses. We obtained clinical diagnoses of ADHD and BPD from inpatient and outpatient care. Individuals with an ADHD diagnosis had an adjusted (for birth year, sex, and birth order) odds ratio (aOR) of 19.4 (95% confidence interval [95% CI] = 18.6–20.4) of also having a BPD diagnosis, compared to individuals not diagnosed with ADHD. Having a sibling with ADHD also increased the risk for BPD (monozygotic twins, aOR = 11.2, 95% CI = 3.0–42.2; full siblings, aOR = 2.8, 95% CI = 2.6–3.1; maternal half-siblings, aOR = 1.4, 95% CI = 1.2–1.7; paternal half-siblings, aOR = 1.5, 95% CI = 1.3–1.7). Cousins also had an increased risk. The strength of the association between ADHD and BPD was similar in females and males, and full siblings showed similar increased risks regardless of sex. Among both males and females, ADHD and BPD co-occur within individuals and co-aggregate in relatives; the pattern suggests shared genetic factors and no robust evidence for etiologic sex differences was found. Clinicians should be aware of increased risks for BPD in individuals with ADHD and their relatives, and vice versa.

Summary Background Several studies have assessed the possible association between attention deficit hyperactivity disorder (ADHD) and asthma. However, existing evidence is inconclusive as to whether this association remains after controlling for possible important confounders. To fill this knowledge gap, we did a systematic review and meta-analysis, followed by a population-based study. Methods For the systematic review and meta-analysis, we searched PubMed, PsycINFO, Embase, Embase Classic, Ovid MEDLINE, and Web of Knowledge databases up to Oct 31, 2017, for observational studies allowing estimation of the association between asthma and ADHD. No restrictions to date, language, or article type were applied. Unpublished data were collected from authors of the identified studies. We extracted unadjusted and adjusted odds ratios (ORs) from the identified studies and calculated ORs when they were not reported. We assessed study quality using the Newcastle-Ottawa Scale and study heterogeneity using I 2 statistics. A random-effects model was used to calculate pooled ORs. The systematic review is registered with PROSPERO (CRD42017073368). To address the fact that the ORs obtained in the meta-analysis were adjusted for confounders that inevitably varied across studies, we did a population-based study of individuals in multiple national registers in Sweden. We calculated an unadjusted OR and an OR that was simultaneously adjusted for all confounders identified in a directed acyclic graph based on the studies of asthma and ADHD identified in our systematic review. Findings We identified 2649 potentially eligible citations, from which we obtained 49 datasets including a total of 210 363 participants with ADHD and 3 115 168 without. The pooled unadjusted OR was 1·66 (95% CI 1·22–2·26; I 2 =99·47) and the pooled adjusted OR was 1·53 (1·41–1·65; I 2 =50·76), indicating a significant association between asthma and ADHD. Possible lack of representativeness of the study population was detected with the Newcastle-Ottawa Scale in 42 of 49 datasets. In the population-based study, we included 1 575 377 individuals born between Jan 1, 1992, and Dec 31, 2006, of whom 259 253 (16·5%) had asthma and 57 957 (3·7%) had ADHD. Asthma was significantly associated with ADHD (OR 1·60, 95% CI 1·57–1·63) in the crude model adjusting for sex and year of birth, and this association remained significant after simultaneous adjustment for all covariates (1·45, 1·41–1·48). Interpretation The combined results of the meta-analysis and the population-based study support a significant association between asthma and ADHD, which remained even after simultaneously controlling for several possible confounders in the population-based study. Awareness of this association might help to reduce delay in the diagnosis of both ADHD and asthma. Funding Swedish Research Council and Shire International GmbH.