Search

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.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.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.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 minimising the education gap between the affected children and their peers.

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.

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.

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% to 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.

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.

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.

Psychiatric disorders are common among autistic children and adults. Little is known about sex differences in psychiatric disorders and hospitalization in early adulthood.To examine sex differences in psychiatric diagnoses and hospitalizations in autistic compared with nonautistic young adults.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.Autism was defined as having received at least 1 clinical diagnosis of autism based on the International Classification of Diseases.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.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 (-0.18; 95% CI, -0.26 to -0.10) and specifically for anxiety, depressive, and sleep disorders. Risk differences were larger among autistic than nonautistic individuals. Compared with nonautistic same-sex individuals, autistic female individuals (HR range [95% CI], 3.17 [2.50-4.04.]-20.78 [18.48-23.37]) and male individuals (HR range [95% CI], 2.98 [2.75-3.23]-18.52 [17.07-20.08]) were both at increased risk for all psychiatric diagnoses. Any psychiatric hospitalization was statistically significantly more common in autistic female individuals (32 of 100) compared with autistic male individuals (19 of 100). However, both autistic female and male individuals had a higher relative risk for psychiatric hospitalization compared with nonautistic female and male individuals for all disorders (female individuals: HR range [95% CI], 5.55 [4.63-6.66]-26.30 [21.50-32.16]; male individuals: HR range [95% CI], 3.79 [3.22-4.45]-29.36 [24.04-35.87]).These findings highlight the need for profound mental health services among autistic young adults. Autistic female individuals, who experience more psychiatric difficulties at different levels of care, require increased clinical surveillance and support.

Objective To assess the association and familial co-aggregation between early-onset type 2 diabetes (diagnosed before age 45) 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 1968-1998, from whom pairs of full-siblings, half-siblings, and cousins were identified. Diagnoses of early-onset type 2 diabetes and mood (including unipolar depression and bipolar disorder), anxiety, and stress-related disorders were obtained from the National Patient Register. Logistic and Cox regression models were used to assess the phenotypic association and familial co-aggregation 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 showed higher risks of any diagnosis (Odds Ratio [OR][95%CI]: 3.62[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 non-shared environmental factors. Conclusion 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 future research should aim to identify shared risk factors and ultimately refine preventive and intervention strategies.

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.

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 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.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.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.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.

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.

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

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 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.

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.

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.

BackgroundSocial anxiety disorder (SAD) has been linked to academic underachievement, but previous studies had methodological limitations. We investigated the association between SAD and objective indicators of educational performance, controlling for a number of covariates and unmeasured confounders shared between siblings.MethodsThis population-based birth cohort study included 2 238 837 individuals born in Sweden between 1973 and 1997, followed-up until 2013. Within the cohort, 15 755 individuals had a recorded ICD-10 diagnosis of SAD in the Swedish National Patient Register. Logistic regression models tested the association between SAD and educational performance. We also identified 6488 families with full siblings discordant for SAD.ResultsCompared to unexposed individuals, individuals diagnosed with SAD were less likely to pass all subjects in the last year of compulsory education [adjusted odds ratios (aOR) ranging from 0.19 to 0.44] and less likely to be eligible for a vocational or academic programme in upper secondary education [aOR = 0.31 (95% confidence interval [CI] 0.30–0.33) and aOR = 0.52 (95% CI 0.50–0.55), respectively], finish upper secondary education [aOR = 0.19 (95% CI 0.19–0.20)], start a university degree [aOR = 0.47 (95% CI 0.45–0.49)], obtain a university degree [aOR = 0.35 (95% CI 0.33–0.37)], and finish postgraduate education [aOR = 0.58 (95% CI 0.43–0.80)]. Results were attenuated but remained statistically significant in adjusted sibling comparison models. When psychiatric comorbidities were taken into account, the results were largely unchanged.ConclusionsTreatment-seeking individuals with SAD have substantially impaired academic performance throughout the formative years. Early detection and intervention are warranted to minimise the long-term socioeconomic impact of the disorder.

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 to future GWAS success. Dr. Border has received support from the National Institutes of Health (NIH; MH100141 and MH016880 ). Dr. Peterson has received support from NIH (K01MH113848) and the Brain & Behavior Research Foundation Young Investigator Grant (28632). Drs. Sallis and Munafò have served as members of the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/7). Dr. Shabalin has received support from a NARSAD Young Investigator Award. Dr. Vilor-Tejedor has received support from a post-doctoral grant, Juan de la Cierva Programme (FJC2018-038085-I), Ministerio de Ciencia, Innovación y Universidades – Spanish State Research Agency. Her research has received additional support of “la Caixa” Foundation (LCF/PR/GN17/10300004) and the Health Department of the Catalan Government (Health Research and Innovation Strategic Plan (PERIS) 2016-2020 grant# SLT002/16/00201). She has acknowledged the support of the Spanish Ministry of Science, Innovation and Universities to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya. Dr. Alemany has received support from a Juan de la Cierva – Incorporación Postdoctoral Contract from Ministerio de Economía, Industria y Competitividad (IJCI-2017-34068). Dr. Corley has received support from NIH (DA011015, AG046938, and DA035804). Dr. Evans has received support from NIH (MH100141, DA044283, and AG046938). Dr. Havdahl has received support from the South-Eastern Norway Regional Health Authority (2018059) at Nic Waals Institute, Lovisenberg Diaconal Hospital. Dr. Rimfeld has received support from a Sir Henry Wellcome Postdoctoral Fellowship. Dr. Andreassen has served as a consultant to HealthLytix and has received funding from the Research Council of Norway (223273 and 273291) and KG Jebsen Stiftelsen. Dr. Boomsma has received support from the Royal Netherlands Academy of Science Professor Award (PAH/5535). Dr. Brown has received support from NIH (DA035804). Dr. Copeland has received support from NIH (MH117559 and HD093651). Dr. Dick has received support from a mid-career award NIH K02 AA018755, NIH R01 AA015416 (Finnish Twin Study), P50 AA022537 (Alcohol Research Center), R25 AA027402 (VCU GREAT), and U10 AA008401 (COGA) from the National Institute on Alcohol Abuse and Alcoholism. Drs. Hewitt, Krauter, Smolen, and Stallings have received support from NIH (DA011015 and DA035804). Dr. Hopfer has received support from NIH (DA042755, DA035804, and DA032555). Dr. Kaprio has received support from the Academy of Finland (grants 308248 and 312073). Dr. Larsson has served as a speaker for Evolan Pharma and Shire/Takeda and has received research grants from Shire/Takeda, all outside the submitted work. Dr. Lichtenstein has received support from the Swedish Research Council for Health, Working Life and Welfare (project 2012-1678) and the Swedish Research Council (2016-1989). Dr. Lundström has received support from the Swedish Research Council ( 2017-02552 ). Dr. Magnus has received support from the Research Council of Norway through its Centers of Excellence scheme, project no 262700. Dr. Njølstad has received support from the European Research Council (AdG #293574). Stiftelsen Kristian Gerhard Jebsen has received support from the Research Council of Norway (FRIPRO 240413), the Western Norway Regional Health Authority (Strategic Fund “Personalized Medicine for Children and Adults”) and the Novo Nordisk Foundation (54741). Dr. Plomin has received support from a MRC Professorship award (G19/2). Dr. Reichborn-Kjennerud has received support from the Research Council of Norway grant 274611 . Drs. Reynolds and Wadsworth have received support from NIH (AG046938). Dr. Rose has received support from a NIH Research Scientist Award (AA-000145). Dr. Wall has received support from NIH (DA03580 and DA021905). Dr. Whitehouse has received support from an Investigator Grant from the National Health and Medical Research Council. Dr. Ystrøm has received support from the Research Council of Norway (262177 and 288083). Dr. Nivard has received support from ZonMW (849200011), the Netherlands Organisation for Health Research and Development (531003014 937), a Jacobs Foundation Research Fellowship, and a VENI grant awarded by NWO (VI.Veni.191G.030). Dr. Bartels has received support from an ERC Consolidator Grant (WELL-BEING 771057). Ms. Hagenbeek and Mr. Ip have received support from the Aggression in Children: Unraveling gene-environment interplay to inform Treatment and Intervention strategies project (ACTION). ACTION received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no 602768

Objective Type 1 diabetes and Hashimoto’s thyroiditis frequently cluster in individuals and in families, indicating shared origins. The objective of this study was to investigate familial co-aggregation of these diseases and to quantify shared genetic and environmental factors. Design This study is a twin cohort study. Methods National health registers were used to identify cases among 110 814 Swedish twins. Co-aggregation was calculated as risk ratios for type 1 diabetes among co-twins of individuals with Hashimoto’s thyroiditis, and vice-versa. Variance explained by genetics (i.e. heritability), and the proportions thereof shared between the diseases, was estimated by contrasting associations in monozygotic and dizygotic twins using structural equation models. Results Individuals with one disease were at a high risk for the other disease (adjusted risk ratio: 11.4 (95% CI: 8.5–15.3)). Co-aggregation was more common in monozygotic than in dizygotic pairs, with adjusted risk ratios of 7.0 (95% CI: 3.2–15.1) and 1.7 (95% CI: 0.7–4.1), respectively. Genetic effects shared across diseases accounted for 11% of the variance for type 1 diabetes and 9% of the variance for Hashimoto’s thyroiditis, while environmental factors unique to individual twins, but shared across diseases, accounted for 10% of the variance for type 1 diabetes and 18% of the variance for Hashimoto’s thyroiditis. Conclusions Both genes and environment unique to individual twins contribute to considerable etiologic overlap between type 1 diabetes and Hashimoto’s thyroiditis. These findings add to the current knowledge on the mechanisms behind autoimmune disease clustering and could guide future research aimed at identifying pathophysiological mechanisms and intervention targets.

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.

Intellectual disability (ID) aggregates in families, but factors affecting individual risk and heritability estimates remain unknown.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.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.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 etiological studies in ID.

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 1,227 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. CONCLUSIONS: Higher than recommended total daily energy intake among women with binge-type eating disorders may lead to weight gain and downstream health complications, if persistent. In most women, iron and folate intake was insufficient, which may have negative consequences for reproductive health. We found suboptimal adherence for key nutrients that are important to limit (saturated fat and salt) or meet (omega-3 fatty acids) for cardiovascular and overall health in all groups. Nutrition counseling should form an important pillar of treatment to assist with normalization of eating patterns and may also benefit individuals without eating disorders to optimize nutrient intake for long term health promotion.

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 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.

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.

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 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.

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.

Obsessive−compulsive disorder (OCD) is associated with high risk of suicide. It is yet unknown whether OCD and suicidal behaviors coaggregate in families and, if so, what are the mechanisms underlying this coaggregation. In a population-based birth cohort and family study, we linked individuals born in Sweden in 1967–2003 (n = 3,594,181) to their parents, siblings, and cousins, and collected register-based diagnoses of OCD, suicide attempts, and deaths by suicide and followed them until December 31, 2013. We also applied quantitative genetic modeling to estimate the contribution of genetic and environmental factors to the familial coaggregation of OCD and suicidal behavior. An elevated risk of suicide attempts was observed across all relatives of individuals with OCD, increasing proportionally to the degree of genetic relatedness, with odds ratios (OR) ranging from 1.56 (95% confidence interval (CI) 1.49–1.63) in parents to 1.11 (95% CI 1.07–1.16) in cousins. The risk of death by suicide also increased alongside narrowing genetic distance, but was only significant in parents (OR 1.55; 95% CI 1.40–1.72) and full siblings (OR 1.80; 95% CI 1.43–2.26) of individuals with OCD. Familial coaggregation of OCD and suicide attempts was explained by additive genetic factors (60.7%) and non-shared environment (40.4%), with negligible contribution of shared environment. Similarly, familial coaggregation with death by suicide was attributed to additive genetics (65.8%) and nonshared environment (34.2%). Collectively, these observations indicate that OCD and suicidal behaviors coaggregate in families largely due to genetic factors. The contribution of unique environment is also considerable, providing opportunities to target high-risk groups for prevention and treatment.

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.

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 304188 individuals (48.9% women and 51.1% men; median baseline age, 30.5 [IQR, 15.0-46.4] years), of whom 27 342 had an OCD diagnosis. Obsessive-compulsive disorder was associated with an elevated risk of substance misuse (hazard ratio, 3.68 [95% CI, 3.52-3.85]). In the 9230 individuals in the CATSS cohort (5551 women [60.1%] and 3679 men [39.9%]), obsessive-compulsive symptoms at 18 years of age were associated with increased symptoms of alcohol dependence (concurrent [n = 9219], beta = 0.18 [95% CI, 0.16-0.20]; longitudinal [n = 3381], beta = 0.10 [95% CI, 0.06-0.14]) and drug dependence (concurrent [n = 749], beta = 0.19 [95% CI, 0.11-0.27]; longitudinal [n = 452]. beta = 0.15 [95% CI, 0.04-0.25]). Comorbid anxiety and depression did not entirely explain the associations in either cohort. Using data from full siblings and maternal half-siblings (population cohort) and monozygotic and dizygotic twins (CATSS cohort) provided estimates of the relative contribution of genetic and environmental influences to the covariance between OCD and obsessive-compulsive symptoms and substance misuse or dependence. The associations were explained by genetic (56%-68%) and nonshared environmental (32%-44%) factors.CONCLUSIONS AND RELEVANCE The findings of this Swedish population-based cohort study challenge the notion that OCD is protective against developing substance misuse. The association of OCD and obsessive-compulsive symptoms with substance misuse was largely explained by shared genetics but was also compatible with partial environmental mediation.

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.

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.

Osteoarthritis and obesity are diseases with high prevalence, and they share common etiologies. We investigated the sex-specific genetic susceptibility to hip and knee osteoarthritis necessitating total joint replacement (TJR), and how body mass index (BMI) moderated the heritability of these osteoarthritis phenotypes.We linked 29,893 twin pairs with information on BMI in the Swedish Twin Registry with the Swedish National Patient Register to identify twins who underwent primary TJR of the hip or knee combined with a concomitant diagnosis of primary osteoarthritis of these joints. Structural equation modeling was used to calculate the heritability of hip and knee osteoarthritis treated with TJR, with estimates adjusted for the first available BMI, birth year, and sex. We also investigated how heritability varied with BMI treated as a continuous variable.Similar heritability estimates for hip replacement (0.65 [95% confidence interval (CI), 0.59 to 0.70]) and knee replacement (0.57 [95% CI, 0.50 to 0.64]) were found. Heritability decreased with higher BMI in both sexes for hip replacement and in men for knee replacement. In contrast, heritability for knee replacement increased with higher BMI in women; the estimate was 0.37 (90% likelihood interval [LI], 0.25 to 0.49) for a BMI of 20 kg/m2 and 0.87 (90% LI, 0.68 to 0.94) for a BMI of 35 kg/m2.In our population, heritability explained, on average, about half of the susceptibility to undergo primary TJR of the hip or knee with the indication of primary osteoarthritis, but it varied with BMI and sex. We demonstrated substantial heritability for knee replacement in obese women.Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

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.

Frailty is influenced by numerous genetic and environmental factors. However, sex differences in how these factors affect frailty, and the gene-environment interplay among frailty and two of its well-established risk factors, unhealthy body mass index (BMI) and low education, are less clear. In a large sample of 42,994 Swedish twins, we used structural equation models to estimate the genetic (heritability) and environmental sources of variance in frailty, defined as the frailty index (FI), separately in men and women. Genetic and individual-specific environmental factors contributed approximately equally to the FI variance. The heritability of FI was slightly, but significantly, higher in women (52%) than in men (45%), yet we found only weak-to-no indication of different sources of genetic variance influencing frailty across sexes. We observed a small-to-moderate genetic overlap between FI and BMI, and that the correlation between FI and education was largely explained by environmental factors common to twins in a pair. Additionally, genetic factors accounted for more of FI variation at both low and high BMI levels, with similar patterns in both sexes. In conclusion, the twin-based heritability of frailty is higher in women than in men, and different mechanisms may underlie the associations of frailty with BMI and education.

Key Points Question Is cesarean delivery associated with neurodevelopmental and psychiatric disorders in children? Findings In this Swedish population-based birth cohort study of more 1.1 million children, births via planned or intrapartum cesarean delivery were associated with a moderately increased risk of neurodevelopmental disorders in children, but these associations were attenuated after adjusting for familial factors. Meaning The association between cesarean delivery and neurodevelopmental disorders may be explained by unmeasured familial confounding; observational studies on the association between prenatal risk factors and child outcomes may be spurious owing to unmeasured confounders., This cohort study uses data from multiple Swedish birth registries to assess whether cesarean birth is associated with neurodevelopmental or psychiatric disorders in children delivered in this manner., Importance Recent studies suggest that cesarean delivery (CD) is associated with increased risk of neurodevelopmental disorders in children, although they were unable to control for indications for CD or familial confounding beyond full siblings. Objective To examine the association between CD and neurodevelopmental and psychiatric disorders in children. Design, Setting, and Participants This Swedish register-based cohort study included 1 179 341 term-birth singletons born between January 1, 1990, and December 31, 2003, and followed up through December 31, 2013. All individuals were linked to their full siblings, maternal and paternal half siblings, and maternal full cousins. Statistical analyses were performed from September 26, 2019, to January 16, 2021. Exposures Birth by CD recorded at birth, stratified into planned and intrapartum CD. Main Outcomes and Measures Registered diagnoses of neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), intellectual disability, tic disorders, communication disorders, learning disorders, and any neurodevelopmental disorder; and psychiatric disorders, including anxiety disorders, obsessive-compulsive disorder, depressive disorders, eating disorders, bipolar disorders, psychotic disorders, and any psychiatric disorder. Results Of 1 179 341 individuals, 1 048 838 (533 140 boys [50.8%]) were delivered vaginally, 59 514 (30 138 boys [50.6%]) were delived via planned CD, and 70 989 (39 191 boys [55.2%]) were delivered via intrapartum CD. Mean (SD) age at follow-up was 17.7 (4.1) years for vaginal delivery, 16.6 (4.2) years for planned CD, and 16.8 (4.1) years for intrapartum CD. Compared with vaginal delivery, and after controlling for measured covariates (parental and neonatal characteristics, maternal comorbidities, and pregnancy complications), CD was associated with higher risk in children of any neurodevelopmental disorder (planned CD, hazard ratio [HR], 1.17; 95% CI, 1.13-1.22; intrapartum CD, HR, 1.10; 95% CI, 1.05-1.14), ADHD (planned CD, HR, 1.17; 95% CI, 1.12-1.23; intrapartum CD, HR, 1.10; 95% CI, 1.05-1.15), and intellectual disability (planned CD, HR, 1.26; 95% CI, 1.14-1.39; intrapartum CD, HR, 1.17; 95% CI, 1.06-1.28). Only planned CD was associated with a higher risk of ASD (HR, 1.20; 95% CI, 1.10-1.31), communication disorders (HR, 1.14; 95% CI, 1.02-1.28), and learning disorders (HR, 1.15; 95% CI, 1.01-1.30). Cesarean delivery was not associated with the remaining disorders. The associations between CD and any neurodevelopmental disorder, ADHD, ASD, and intellectual disability attenuated in full cousins and paternal half siblings, and further attenuated (became nonsignificant) in maternal half siblings and full siblings (risk of any neurodevelopmental disorder in full siblings, planned CD, HR, 0.93; 95% CI, 0.81-1.06; intrapartum CD, HR, 1.07; 95% CI, 0.96-1.21). Conclusions and Relevance The findings of this study suggest that the association between CD and increased risk of neurodevelopmental disorders in the children was most likely explained by unmeasured familial confounding.

Summary Background Emerging evidence suggests increased risk of several physical health conditions in people with ADHD. Only a few physical conditions have been thoroughly studied in relation to ADHD, and there is little knowledge on associations in older adults in particular. We aimed to investigate the phenotypic and aetiological associations between ADHD and a wide range of physical health conditions across adulthood. Methods We did a register study in Sweden and identified full-sibling and maternal half-sibling pairs born between Jan 1, 1932, and Dec 31, 1995, through the Population and Multi-Generation Registers. We excluded individuals who died or emigrated before Jan 1, 2005, and included full-siblings who were not twins and did not have half-siblings. ICD diagnoses were obtained from the National Patient Register. We extracted ICD diagnoses for physical conditions, when participants were aged 18 years or older, from inpatient (recorded 1973–2013) and outpatient (recorded 2001–13) services. Diagnoses were regarded as lifetime presence or absence. Logistic regression models were used to estimate the associations between ADHD (exposure) and 35 physical conditions (outcomes) in individuals and across sibling pairs. Quantitative genetic modelling was used to estimate the extent to which genetic and environmental factors accounted for the associations with ADHD. Findings 4 789 799 individuals were identified (2 449 146 [51%] men and 2 340 653 [49%] women), who formed 4 288 451 unique sibling pairs (3 819 207 full-sibling pairs and 469 244 maternal half-sibling pairs) and 1 841 303 family clusters (siblings, parents, cousins, spouses). The mean age at end of follow-up was 47 years (range 18–81; mean birth year 1966); ethnicity data were not available. Adults with ADHD had increased risk for most physical conditions (34 [97%] of 35) compared with adults without ADHD; the strongest associations were with nervous system disorders (eg, sleep disorders, epilepsy, dementia; odds ratios [ORs] 1·50–4·62) and respiratory diseases (eg, asthma, chronic obstructive pulmonary disease; ORs 2·42–3·24). Sex-stratified analyses showed similar patterns of results in men and women. Stronger cross-disorder associations were found between full-siblings than between half-siblings for nervous system, respiratory, musculoskeletal, and metabolic diseases (p