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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.

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.

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

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

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

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

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

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

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

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

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

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.

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

Importance Early-onset depression has been linked to poor health outcomes. However, it is unclear the extent to which this disorder is associated with specific diseases and premature death and whether these associations remain after controlling for psychiatric comorbidity. Objective To quantify the association of youth depression with subsequent diagnoses of numerous somatic diseases and mortality. Design, Setting, and Participants A population-based cohort study was conducted using Swedish national registers containing data on all individuals born in Sweden between 1982 and 1996. A total of 1 487 964 participants were followed up from age 5 years through 2013 if no censoring occurred. Data analysis was performed from January 15, 2019, to August 10, 2020. Exposures Youth depression was defined as having received at least 1 diagnosis of depression from inpatient or outpatient care between ages 5 and 19 years. Main Outcomes and Measures This study examined 69 somatic conditions diagnosed after youth depression, as well as all-cause and cause-specific mortalities. Overall and sex-specific hazard ratios (HRs), together with 95% CIs, were estimated using Cox proportional hazards regression with attained age as underlying timescale and time-varying exposure, and adjusted for birth year and sex. All analyses were repeated controlling for psychiatric comorbidities. Absolute risk differences were calculated using standardization with Cox proportional hazards regression. Results Of 1 487 964 individuals included in the analysis, 51.2% were male. A total of 37 185 patients (2.5%; 67.4% female) had an inpatient or outpatient contact for depression between ages 5 and 19 years (mean [SD] age at first recorded diagnosis of depression, 16.7 [2.1] years for males and 16.7 [1.8] years for females). Age at the end of follow-up ranged between 17 and 31 years. Individuals with youth depression had higher relative risks for 66 of the 69 somatic diagnoses. Strong associations were observed for certain injuries, especially self-harm in females (HR, 14.4; 95% CI, 13.8-15.1), sleep disorders (HR, 8.1; 95% CI, 7.6-8.7), viral hepatitis (HR, 6.1; 95% CI, 5.4-6.8), all-cause mortality (HR, 5.9; 95% CI, 5.3-6.6), and cause-specific mortalities, especially death by intentional self-harm (HR, 14.6; 95% CI, 12.6-16.9). Most associations were attenuated but persisted after adjusting for psychiatric comorbidity. The absolute risk difference of a specific disease within 12 years from the first diagnosis of depression during youth ranged from −0.2% (95% CI, −1.0% to 0.6%) for arthropathies among males to 23.9% (95% CI, 22.7%-25.0%) for the broader category of injuries among females. Conclusions and Relevance In this Swedish population cohort study, patients with depression diagnosed during their youth appeared to have increased risks for many somatic diseases as well as for mortality, even after controlling for other psychiatric disorders. These findings suggest that several medical conditions should be considered when investigating youth depression.

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

Background Attention-deficit/hyperactivity disorder (ADHD) has been associated with several autoimmune diseases (AD), both within individuals and across relatives, implying common underlying genetic or environmental factors in line with studies indicating that immunological mechanisms are key to brain development. To further elucidate the relationship between ADHD and autoimmunity we performed a population-wide familial co-aggregation study. Methods We linked Swedish national registries, defined a birth cohort with their biological relatives and identified individuals diagnosed with ADHD and/or 13 ADs. The cohort included 5 178 225 individuals born between 1960 and 2010, of whom 118 927 (2.30%) had been diagnosed with ADHD. We then investigated the associations between ADHD and ADs within individuals and across relatives, with logistic regression and structural equation modelling. Results Within individuals, ADHD was associated with a diagnosis of any of the 13 investigated ADs (adjusted odds ratio (OR) =1.34, 95% confidence interval (CI) = 1.30-1.38) as well as several specific ADs. Familial co-aggregation was observed. For example, ADHD was associated with any of the 13 ADs in mothers (OR = 1.29, 95% CI = 1.26–1.32), fathers (OR = 1.14, 95% CI = 1.11–1.18), full siblings (OR = 1.19, 95% CI = 1.15–1.22), aunts (OR = 1.12, 95% CI = 1.10–1.15), uncles (OR = 1.07, 95% CI = 1.05–1.10) and cousins (OR = 1.04, 95% CI = 1.03–1.06). Still, the absolute risks of AD among those with ADHD were low. The genetic correlation between ADHD and a diagnosis of any of the investigated ADs was 0.13 (95% CI = 0.09–0.17) and the environmental correlation was 0.02 (95% CI = -0.03–0.06). Conclusions We found that ADHD and ADs co-aggregate among biological relatives, indicating that the relationship between ADHD and autoimmune diseases may in part be explained by shared genetic risk factors. The patterns of familial co-aggregation of ADHD and ADs do not readily support a role of maternal immune activation in the aetiology of ADHD. The findings have implications for aetiological models of ADHD. However, screening for autoimmunity among individuals with ADHD is not warranted.

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

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

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

Internalising symptoms in childhood and adolescence are as heritable as adult depression and anxiety, yet little is known of their molecular basis. This genome-wide association meta-analysis of internalising symptoms included repeated observations from 64,641 individuals, aged between 3 and 18. The N-weighted meta-analysis of overall internalising symptoms (INToverall) detected no genome-wide significant hits and showed low SNP heritability (1.66%, 95% confidence intervals 0.84-2.48%, Neffective=132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalising symptoms showing the highest heritability (5.63%, 95% confidence intervals 3.08-8.18%). Additive genetic effects on internalising symptoms appeared stable over age, with overlapping estimates of SNP heritability from early-childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the wellbeing spectrum (|rg|> 0.70), as well as with insomnia, loneliness, attention-deficit hyperactivity disorder, autism, and childhood aggression (range |rg|=0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. The pattern of genetic correlations suggests that childhood and adolescent internalising symptoms share substantial genetic vulnerabilities with adult internalising disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalising symptoms over time and the high comorbidity amongst childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

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

We examined the extent to which genetic factors shared across generations, measured covariates, and environmental factors associated with parental suicidal behavior (suicide attempt or suicide) account for the association between parental and offspring suicidal behavior. We used a Swedish cohort of 2,762,883 offspring born 1973–2001. We conducted two sets of analyses with offspring of half- and full-siblings: (1) quantitative behavior genetic models analyzing maternal suicidal behavior and (2) fixed-effects Cox proportional hazard models analyzing maternal and paternal suicidal behavior. The analyses also adjusted for numerous measured covariates (e.g., parental severe mental illness). Quantitative behavior genetic analyses found that 29.2% (95% confidence interval [CI], 5.29, 53.12%) of the intergenerational association was due to environmental factors associated with exposure to maternal suicidal behavior, with the remainder due to genetic factors. Statistical adjustment for parental behavioral health problems partially attenuated the environmental association; however, the results were no longer statistically significant. Cox hazard models similarly found that offspring were at a 2.74-fold increased risk [95% CI, 2.67, 2.83]) of suicidal behavior if their mothers attempted/died by suicide. After adjustment for familial factors and measured covariates, associations attenuated but remained elevated for offspring of discordant half-siblings (HR, 1.57 [95% CI, 1.45, 1.71]) and full-siblings (HR, 1.62 [95% CI, 1.57, 1.67]). Cox hazard models demonstrated a similar pattern between paternal and offspring suicidal behavior. This study found that the intergenerational transmission of suicidal behavior is largely due to shared genetic factors, as well as factors associated with parental behavioral health problems and environmental factors associated with parental suicidal behavior.

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

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

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

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

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

BackgroundBody dysmorphic disorder (BDD) usually begins during adolescence but little is known about the prevalence, etiology, and patterns of comorbidity in this age group. We investigated the prevalence of BDD symptoms in adolescents and young adults. We also report on the relative importance of genetic and environmental influences on BDD symptoms, and the risk for co-existing psychopathology.MethodsPrevalence of BDD symptoms was determined by a validated cut-off on the Dysmorphic Concerns Questionnaire (DCQ) in three population-based twin cohorts at ages 15 (n = 6968), 18 (n = 3738), and 20–28 (n = 4671). Heritability analysis was performed using univariate model-fitting for the DCQ. The risk for co-existing psychopathology was expressed as odds ratios (OR).ResultsThe prevalence of clinically significant BDD symptoms was estimated to be between 1 and 2% in the different cohorts, with a significantly higher prevalence in females (1.3–3.3%) than in males (0.2–0.6%). The heritability of body dysmorphic concerns was estimated to be 49% (95% CI 38–54%) at age 15, 39% (95% CI 30–46) at age 18, and 37% (95% CI 29–42) at ages 20–28, with the remaining variance being due to non-shared environment. ORs for co-existing neuropsychiatric and alcohol-related problems ranged from 2.3 to 13.2.ConclusionsClinically significant BDD symptoms are relatively common in adolescence and young adulthood, particularly in females. The low occurrence of BDD symptoms in adolescent boys may indicate sex differences in age of onset and/or etiological mechanisms. BDD symptoms are moderately heritable in young people and associated with an increased risk for co-existing neuropsychiatric and alcohol-related problems.

Background: The role of general anesthetics as a risk factor for possible neurodevelopmental disorders (NDDs) in humans is unresolved. The investigation of the role of anesthetics in the development of postgeneral anesthesia (anesthesia onward) NDDs has proven to be complicated, partly because of the inherent confounding in clinical cohort studies, and partly by the fact that anesthetics are only one part in the complex process of anesthesia‐surgery. Methods: Utilizing the Swedish databases Child and Adolescent Twins Study in Sweden (CATSS) and National Patient Register (NPR), we investigated twins discordant for anesthesia, born between 1997 and 2004 for traits of NDDs. We identified 68 twin pairs discordant for anesthesia and explored traits of Attention‐Deficit/Hyperactivity Disorder (ADHD), Learning Disability (LD), and Autism Spectrum Disorder (ASD) in them while simultaneously taking congenital abnormalities and systemic disorders (CSDs) into account. We analyzed the possible effect of anesthesia on neurodevelopmental problems, and we analyzed the within‐pair differences using conditional linear regression. Results: Twins with a recorded episode of anesthesia had higher traits of NDDs than twins without; similarly twins with CSDs had higher mean scores on all traits than twins without CSDs. The within‐pair analyses suggested that exposure to anesthesia was associated with higher scores of ADHD (regression coefficient 1.02 and 95% confidence intervals: 0.27–1.78) in monozygotic (MZ) twins discordant for anesthesia. This effect remained when adjusting for congenital abnormalities. Discussion: Our finding that traits of ADHD were slightly associated with anesthesia in a genetically sensitive design is in need of replication and warrants further investigation. Future studies should aim to elucidate mechanisms behind this possible association (e.g. anesthetics doses, age at exposure, exposure duration).

Publisher Copyright: © 2021 The Authors Background: We examined associations of adverse perinatal events with offspring violent and non-violent criminal convictions in men and women. Methods: All singleton births between 1973 and 1995 (n = 1,146,570 men, n = 1,085,217 women) were identified through Swedish population-based registers. Information about adverse perinatal events was retrieved from the Medical Birth Register. Outcomes were criminal convictions collected from the National Crime Register. We estimated absolute and relative risks of being convicted of criminal convictions using the Kaplan-Meier method and survival analyses for men and women separately. We also tested for differences in magnitudes of associations for men versus women. Results: Several adverse perinatal events were associated with an increased risk of violent and non-violent criminal convictions in both men and women. Associations between low birth weight, smallness relative to gestational age and preterm birth with non-violent criminal convictions were statistically significantly higher for men than for women. There was a dose-dependent association between adverse perinatal events with violent and non-violent criminal convictions for both men and women, indicated by the strengthened magnitude of HR estimates with exposure to an increasing number of adverse perinatal events. Conclusions: Adverse perinatal events are associated with violent and non-violent criminal convictions in men and women, with some differences in risk estimates between sexes. Findings are compatible with theoretical accounts implicating disruption of the neurodevelopment during the perinatal period.

Autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur. The presence of a genetic link between ASD and ADHD symptoms is supported by twin studies, but the genetic overlap between clinically ascertained ASD and ADHD remains largely unclear. We therefore investigated how ASD and ADHD co-aggregate in individuals and in families to test for the presence of a shared genetic liability and examined potential differences between low- and high-functioning ASD in the link with ADHD. We studied 1 899 654 individuals born in Sweden between 1987 and 2006. Logistic regression was used to estimate the association between clinically ascertained ASD and ADHD in individuals and in families. Stratified estimates were obtained for ASD with (low-functioning) and without (high-functioning) intellectual disability. Individuals with ASD were at higher risk of having ADHD compared with individuals who did not have ASD (odds ratio (OR)=22.33, 95% confidence interval (CI): 21.77-22.92). The association was stronger for high-functioning than for low-functioning ASD. Relatives of individuals with ASD were at higher risk of ADHD compared with relatives of individuals without ASD. The association was stronger in monozygotic twins (OR=17.77, 95% CI: 9.80-32.22) than in dizygotic twins (OR=4.33, 95% CI: 3.21-5.85) and full siblings (OR=4.59, 95% CI: 4.39-4.80). Individuals with ASD and their relatives are at increased risk of ADHD. The pattern of association across different types of relatives supports the existence of genetic overlap between clinically ascertained ASD and ADHD, suggesting that genomic studies might have underestimated this overlap.Molecular Psychiatry advance online publication, 28 February 2017; doi:10.1038/mp.2017.17.

BackgroundFrailty is a complex manifestation of aging and associated with increased risk of mortality and poor health outcomes. Younger individuals (under 65 years) typically have low levels of frailty and are less-studied in this respect. Also, the relationship between the Rockwood frailty index (FI) and cause-specific mortality in community settings is understudied.MethodsWe created and validated a 42-item Rockwood-based FI in The Swedish Adoption/Twin Study of Aging (n=1477; 623 men, 854 women; aged 29-95 years) and analyzed its association with all-cause and cause-specific mortality in up to 30-years of follow-up. Deaths due to cardiovascular disease (CVD), cancer, dementia and other causes were considered as competing risks.ResultsOur FI demonstrated construct validity as its associations with age, sex and mortality were similar to the existing literature. The FI was independently associated with increased risk for all-cause mortality in younger (ConclusionsThe FI showed good predictive value for all-cause mortality especially in the younger group. The FI predicted CVD mortality risk in women, whereas in men it captured vulnerability to death from various causes.

The association between obsessive-compulsive disorder (OCD) and Tourette's/chronic tic disorders (TD/CTD) with autoimmune diseases (ADs) is uncertain. In this nationwide study, we sought to clarify the patterns of comorbidity and familial clustering of a broad range of ADs in individuals with OCD, individuals with TD/CTD and their biological relatives. From a birth cohort of 7 465 455 individuals born in Sweden between 1940 and 2007, we identified 30 082 OCD and 7279 TD/CTD cases in the National Patient Register and followed them up to 31 December 2013. The risk of 40 ADs was evaluated in individuals with OCD, individuals with TD/CTD and their first- (siblings, mothers, fathers), second- (half siblings) and third-degree (cousins) relatives, compared with population controls. Individuals with OCD and TD/CTD had increased comorbidity with any AD (43% and 36%, respectively) and many individual ADs. The risk of any AD and several individual ADs was consistently higher among first-degree relatives than among second- and third-degree relatives of OCD and TD/CTD probands. The risk of ADs was very similar in mothers, fathers and siblings of OCD probands, whereas it tended to be higher in mothers and fathers of TD/CTD probands (compared with siblings). The results suggest a familial link between ADs in general (that is, not limited to Streptococcus-related conditions) and both OCD and TD/CTD. Additional mother-specific factors, such as the placental transmission of antibodies, cannot be fully ruled out, particularly in TD/CTD.

Autism spectrum disorder (ASD) has been found to be associated with alterations in resting state (RS) functional connectivity, including areas forming the default mode network (DMN) and salience network (SN). However, insufficient control for confounding genetic and environmental influences and other methodological issues limit the generalizability of previous findings. Moreover, it has been hypothesized that ASD might be marked by early hyper-connectivity followed by later hypo-connectivity. To date, only a few studies have explicitly tested age-related influences on RS connectivity alterations in ASD. Using a within-twin pair design (N=150 twins; 8-23 years), we examined altered RS connectivity between core regions of the DMN and SN in relation to autistic trait severity and age in a sample of monozygotic (MZ) and dizygotic (DZ) twins showing typical development, ASD or other neurodevelopmental conditions. Connectivity between core regions of the SN was stronger in twins with higher autistic traits compared to their co-twins. This effect was significant both in the total sample and in MZ twins alone, highlighting the effect of non-shared environmental factors on the link between SN-connectivity and autistic traits. While this link was strongest in children, we did not identify differences between age groups for the SN. In contrast, connectivity between core hubs of the DMN was negatively correlated with autistic traits in adolescents and showed a similar trend in adults but not in children. The results support hypotheses of age-dependent altered RS connectivity in ASD, making altered SN and DMN connectivity promising candidate biomarkers for ASD.

BackgroundPrior research demonstrated that attention-deficit hyperactivity disorder (ADHD) is associated with binge-eating behavior, binge-eating disorder (BED), and bulimia nervosa (BN). The aim of this study was to investigate these associations in an adult twin population, and to determine the extent to which ADHD symptoms and binge-eating behavior share genetic and environmental factors.MethodsWe used self-reports of current ADHD symptoms and lifetime binge-eating behavior and associated characteristics from a sample of over 18 000 adult twins aged 20–46 years, from the population-based Swedish Twin Registry. Mixed-effects logistic regression was used to examine the association between ADHD and lifetime binge-eating behavior, BED, and BN. Structural equation modeling was used in 13 773 female twins to determine the relative contribution of genetic and environmental factors to the association between ADHD symptoms and binge-eating behavior in female adult twins.ResultsADHD symptoms were significantly associated with lifetime binge-eating behavior, BED, and BN. The heritability estimate for current ADHD symptoms was 0.42 [95% confidence interval (CI) 0.41–0.44], and for lifetime binge-eating behavior 0.65 (95% CI 0.54–0.74). The genetic correlation was estimated as 0.35 (95% CI 0.25–0.46) and the covariance between ADHD and binge-eating behavior was primarily explained by genetic factors (91%). Non-shared environmental factors explained the remaining part of the covariance.ConclusionsThe association between adult ADHD symptoms and binge-eating behavior in females is largely explained by shared genetic risk factors.

Psychotic experiences are associated with later substance use disorder and suicidal behavior, but individual psychotic experiences have not been examined in a longitudinal data set. Also, the potential dose-response relationship between these phenomena remains unknown.Cohort study including 9242 adolescents who participated in The Child and Adolescent Twin Study in Sweden (CATSS). At ages 15 and/or 18, seven psychotic experiences (auditory and visual hallucinations, and five delusions) were assessed via questionnaires. Outcomes at follow-up were physician-assigned diagnoses of substance use disorder and suicide attempts ascertained from the Swedish Patient Register. Associations were estimated with Cox regressions and expressed as hazard ratios.All psychotic experiences were associated with later substance use disorder and/or suicide attempts, with hazard ratios ranging from 1.6 to 3.0. A dose-response relationship was observed between psychotic experiences and later substance use disorder, and suicide attempt.Auditory and visual hallucinations as well as delusions in adolescence are associated with later development of substance use disorder and suicide attempt, and there is a dose-response relationship between the load of psychotic experiences and these adverse outcomes. Clinicians should assess subclinical hallucinations as well as delusions in psychiatric evaluations of adolescents.

BACKGROUND There is a strong genetic component in prostate cancer development with an estimated heritability of 58%. In addition, recent epidemiological assessments show a familial component in prostate cancer-specific survival, which could be due to either common genetics or environment. In this study we sought to estimate the heritability of prostate cancer-specific survival by studying brothers and father–son pairs in Sweden. METHODS We used linkage records from three Swedish national registers: the Multi-Generation Register, the Cancer Register, and the Cause of Death Register. One thousand seven hundred twenty-eight brother pairs and 6,444 father–son pairs, where both family members were diagnosed with prostate cancer, were followed for prostate cancer mortality. By assuming that (i) brothers on average share 50% of their segregating alleles and 100% environment and (ii) fathers and sons share 50% of their segregating alleles and no environment, we implemented a model including influences of additive genetics (heritability), shared environment and non-shared environment for survival data. A conditional likelihood estimation procedure was developed to fit the model. Data simulation was applied to validate model assumptions. RESULTS In a model that adjusted for age at diagnosis and calendar period, the estimated heritability of prostate cancer-specific survival was 0.10 (95% CI = 0.00–0.20) that was borderline significantly different from zero (P = 0.057). The shared environment component was not significantly different from zero with a point estimate of 0.00 (95% CI = 0.00–0.13). Simulation studies and sensitivity analysis revealed that the estimated heritability component was robust, whereas the shared environmental component may be underestimated. CONCLUSIONS Heritability of prostate cancer-specific survival is considerably lower than for prostate cancer incidence. This supports a hypothesis that susceptibility of disease and progression of disease are separate mechanisms that involve different genes. Further assessment of the genetic basis of prostate cancer-specific survival is warranted. Prostate 9999: XX–XX, 2017. © 2017 Wiley Periodicals, Inc.

Adverse perinatal events may increase the risk of Tourette’s and chronic tic disorders (TD/CTD), but previous studies have been unable to control for unmeasured environmental and genetic confounding. We aimed to prospectively investigate potential perinatal risk factors for TD/CTD, taking unmeasured factors shared between full siblings into account. A population-based birth cohort, consisting of all singletons born in Sweden in 1973–2003, was followed until December 2013. A total of 3 026 861 individuals were identified, 5597 of which had a registered TD/CTD diagnosis. We then studied differentially exposed full siblings from 947 942 families; of these, 3563 families included siblings that were discordant for TD/CTD. Perinatal data were collected from the Medical Birth Register and TD/CTD diagnoses were collected from the National Patient Register, using a previously validated algorithm. In the fully adjusted models, impaired fetal growth, preterm birth, breech presentation and cesarean section were associated with a higher risk of TD/CTD, largely independent from shared family confounders and measured covariates. Maternal smoking during pregnancy was associated with risk of TD/CTD in a dose–response manner but the association was no longer statistically significant in the sibling comparison models or after the exclusion of comorbid attention-deficit/hyperactivity disorder. A dose–response relationship between the number of adverse perinatal events and increased risk for TD/CTD was also observed, with hazard ratios ranging from 1.41 (95% confidence interval (CI): 1.33–1.50) for one event to 2.42 (95% CI: 1.65–3.53) for five or more events. These results pave the way for future gene by environment interaction and epigenetic studies in TD/CTD.

Despite the high prevalence of endometriosis among women of reproductive age, risk factors or markers for developing the condition remain largely unknown. Many of the published studies are based on small selected samples. We therefore investigated the relationships of reproductive and lifestyle factors with endometriosis in a large sample of Swedish female twins.This cross-sectional study included 28,822 women. Among these, endometriosis was reported by 1,228 women and the self-reported diagnosis was confirmed by medical records. Potential risk factors or markers for risk considered were age at menarche, level of education, body mass index (BMI), parity, oral contraceptive (OC) use, infertility, coffee consumption, smoking, and alcohol intake, which were investigated using logistic regression with crude and adjusted analyses. We performed within-pair analysis to examine the sensitivity of the results.Late age at menarche and higher parity showed an inverse association and infertility showed a strong association with endometriosis. We observed positive associations with coffee consumption and smoking and an inverse association with OC use in crude analysis but not in adjusted analysis. There were no significant associations between level of education, BMI, or alcohol intake and endometriosis. Within-pair analysis showed persistent inverse association of parity and association of infertility with endometriosis.Our study suggests that late age at menarche and higher parity are inversely associated and infertility is strongly associated with endometriosis. Future studies are needed to explore the significance of these factors in the diagnosis of endometriosis and understanding of its etiology.

Previous studies report that dental caries is partially heritable, but there is uncertainty in the magnitude of genetic effects and little understanding of how genetic factors might influence caries progression or caries subtypes. This study aimed to estimate the relative importance of genetic and environmental factors in the etiology of different caries outcomes using a twin-based design. Analysis included up to 41,678 twins in the Swedish Twin Register aged 7 to 97 y, and dental data were obtained from preexisting dental records. The outcome measures were 1) summary indices of caries experience, 2) parameters representing trajectory in caries progression derived from longitudinal modeling, and 3) caries scores in groups of biologically similar tooth surfaces derived from hierarchical clustering of tooth surfaces (termed caries clusters). Additive genetic factors explained between 49.1% and 62.7% of variation in caries scores and between 50.0% and 60.5% of variation in caries trajectories. Seven caries clusters were identified, which had estimates of heritability lying between 41.9% and 54.3%. Shared environmental factors were important for only some of these clusters and explained 16% of variation in fissure caries in molar teeth but little variation in other clusters of caries presentation. The genetic factors influencing these clusters were only partially overlapping, suggesting that different biological processes are important in different groups of tooth surfaces and that innate liability to some patterns of caries presentation may partially explain why groups of tooth surfaces form clusters within the mouth. These results provide 1) improved quantification of genetic factors in the etiology of caries and 2) new data about the role of genetics in terms of longitudinal changes in caries status and specific patterns of disease presentation, and they may help lay the foundations for personalized interventions in the future.

Maintaining a symbiotic oral microbiota is essential for oral and dental health, and host genetic factors may affect the composition or function of the oral microbiota through a range of possible mechanisms, including immune pathways. The study included 836 Swedish twins divided into separate groups of adolescents (n = 418) and unrelated adults (n = 418). Oral microbiota composition and functions of non-enzymatically lysed oral bacteria samples were evaluated using 16S rRNA gene sequencing and functional bioinformatics tools in the adolescents. Adaptive immune responses were assessed by testing for serum IgG antibodies against a panel of common oral bacteria in adults. In the adolescents, host genetic factors were associated with both the detection and abundance of microbial species, but with considerable variation between species. Host genetic factors were associated with predicted microbiota functions, including several functions related to bacterial sucrose, fructose, and carbohydrate metabolism. In adults, genetic factors were associated with serum antibodies against oral bacteria. In conclusion, host genetic factors affect the composition of the oral microbiota at a species level, and host-governed adaptive immune responses, and also affect the concerted functions of the oral microbiota as a whole. This may help explain why some people are genetically predisposed to the major dental diseases of caries and periodontitis.

Objective Co-aggregation of autoimmune diseases is common, suggesting partly shared etiologies. Genetic factors are believed to be important, but objective measures of environmental vs heritable influences on co-aggregation are absent. With a novel approach to twin studies, we aimed at estimating heritability and genetic overlap in seven organ-specific autoimmune diseases. Design Prospective twin cohort study. Methods We used a cohort of 110 814 twins to examine co-aggregation and heritability of Hashimoto’s thyroiditis, atrophic gastritis, celiac disease, Graves’ disease, type 1 diabetes, vitiligo and Addison’s disease. Hazard ratios (HR) were calculated for twins developing the same or different disease as compared to their co-twin. The differences between monozygotic and dizygotic twin pairs were used to estimate the genetic influence on co-aggregation. Heritability for individual disorders was calculated using structural equational modeling adjusting for censoring and truncation of data. Results Co-aggregation was more pronounced in monozygotic twins (median HR: 3.2, range: 2.2–9.2) than in dizygotic twins (median HR: 2.4, range: 1.1–10.0). Heritability was moderate for atrophic gastritis (0.38, 95% CI: 0.23–0.53) but high for all other diseases, ranging from 0.60 (95% CI: 0.49–0.71) for Graves’ disease to 0.97 (95% CI: 0.91–1.00) for Addison’s disease. Conclusions Overall, co-aggregation was more pronounced in monozygotic than in dizygotic twins, suggesting that disease overlap is largely attributable to genetic factors. Co-aggregation was common, and twins faced up to a ten-fold risk of developing diseases not present in their co-twin. Our results validate and refine previous heritability estimates based on smaller twin cohorts.

Background It has been suggested that parents of children with autism spectrum disorder (ASD) curtail their reproduction, a phenomenon known as reproductive stoppage. To investigate the presence of reproductive stoppage, we followed the reproduction in mothers of children with or without an ASD diagnosis using Swedish population-based registries. Methods We followed all families with first child born in 1987 or later. In total 2,521,103 children, nested within 1,270,017 mothers, were included. Exposure was presence of ASD diagnosis in earlier born siblings, and outcome was considered as (1) inter-pregnancy interval and (2) number of subsequent children. Results Analyses of inter-pregnancy intervals showed that the association differed across birth orders, with a lower rate of second children when first child had ASD diagnosis, but an increased rate of third and higher birth orders in families where a previous child had an ASD diagnosis. When all birth orders were simultaneously considered, families with a child with an ASD diagnosis were less likely to have another child (hazard ratio (HR), 0.79; 95% confidence interval [95% CI], 0.78–0.80). However, when adjusted for birth order, the association was close to null (HR, 0.97; 95% CI, 0.96–0.99), and after additional adjustments (maternal age, birth period, sex, paternal age, and maternal education), the association disappeared (HR, 1.00; 95% CI, 0.99–1.02). In analyses of subsequent children, after adjustment for covariates, families with an ASD diagnosis had 4% more subsequent children (rate ratio, 1.04; 95% CI, 1.03–1.05). Limitations The study was undertaken in a country with largely tax-funded healthcare; results may not generalize to other societies. Following the current dominating umbrella concept of ASD, we did not differentiate between the ASD sub-diagnoses; it is possible that reproductive patterns can be dependent on ASD subtypes and the severity and composition of ASD phenotypes and comorbidities. Conclusions This study does not support a universal reproductive stoppage effect in ASD families, when birth order and other factors are considered. Therefore, proper attention to birth order and other factors may alleviate potential bias in familial aggregation studies of ASD.