Background: Meta-analyses suggest an association between autism spectrum disorder (ASD) and obesity, but the factors underlying this association remain unclear. This study investigated the association between ASD and obesity stratified on intellectual disability (ID). In addition, in order to gain insight into possible shared etiological factors, the potential role of shared familial liability was examined.

Method: We studied a cohort of 3,141,696 individuals by linking several Swedish nationwide registers. We identified 35,461 individuals with ASD and 61,784 individuals with obesity. Logistic regression models were used to estimate the association between ASD and obesity separately by ID and sex and by adjusting for parental education, psychiatric comorbidity, and psychotropic medication. Potential shared familial etiologic factors were examined by comparing the risk of obesity in full siblings, maternal and paternal half-siblings, and full- and half-cousins of individuals with ASD to the risk of obesity in relatives of individuals without ASD.

Results: Individuals with ASD + ID (OR = 3.76 [95% CI, 3.38-4.19]) and ASD-ID (OR = 3.40 [95% CI, 3.23-3.58]) had an increased risk for obesity compared with individuals without ASD. The associations remained statistically significant when adjusting for parental education, psychiatric comorbidity, and medication. Sex-stratified analyses indicated a higher relative risk for males compared with females, with statistically significant interaction effects for ASD-ID, but not for ASD+ID in the fully adjusted model. First-degree relatives of individuals with ASD+ID and ASD-ID had an increased risk of obesity compared with first-degree relatives of individuals without ASD. The obesity risk was similar in second-degree relatives of individuals with ASD+ID but was lower for and ASD-ID. Full cousins of individuals with ASD+ID had a higher risk compared with half-cousins of individuals with ASD+ID). A similar difference in the obesity risk between full cousins and half-cousins was observed for ASD-ID.

Conclusions: Individuals with ASD and their relatives are at increased risk for obesity. The risk might be somewhat higher for males than females. This warrants further studies examining potential common pleiotropic genetic factors and shared family-wide environmental factors for ASD and obesity. Such research might aid in identifying specific risks and underlying mechanisms in common between ASD and obesity.

BACKGROUND: Studies using self-reports indicate that individuals with ADHD are at increased risk for functional impairments in social and occupational settings, but evidence around real-life instability remains limited. It is furthermore unclear if these functional impairments in ADHD differ across sex and across the adult lifespan.

METHOD: A longitudinal observational cohort design of 3,448,440 individuals was used to study the associations between ADHD and residential moves, relational instability and job shifting using data from Swedish national registers. Data were stratified on sex and age (18-29 years, 30-39 years, and 40-52 years at start of follow up).

RESULTS: 31,081 individuals (17,088 males; 13,993 females) in the total cohort had an ADHD-diagnosis. Individuals with ADHD had an increased incidence rate ratio (IRR) of residential moves (IRR 2.35 [95% CI, 2.32-2.37]), relational instability (IRR = 1.07 [95% CI, 1.06-1.08]) and job shifting (IRR = 1.03 [95% CI, 1.02-1.04]). These associations tended to increase with increasing age. The strongest associations were found in the oldest group (40-52 years at start of follow). Women with ADHD in all three age groups had a higher rate of relational instability compared to men with ADHD.

CONCLUSION: Both men and women with a diagnosis of ADHD present with an increased risk of real-life instability in different domains and this behavioral pattern was not limited to young adulthood but also existed well into older adulthood. It is therefore important to have a lifespan perspective on ADHD for individuals, relatives, and the health care sector.

OBJECTIVE: The association between attention-deficit/hyperactivity disorder (ADHD) and shorter height is unclear. This study examined the risk of shorter height in individuals with ADHD, and the influence of prenatal factors, ADHD medication, psychiatric comorbidity, socioeconomic factors and familial liability.

METHOD: We draw on Swedish National Registers for two different study designs. First, height data for 14,268 individuals with ADHD and 71,339 controls were stratified into two groups: 1: Before and 2: After stimulant treatment were introduced in Sweden. Second, we used a family-based design including 833,172 relatives without ADHD with different levels of relatedness to the individuals with ADHD and matched controls.

RESULTS: ADHD was associated with shorter height both before (below average height: OR=1.31, 95 % CI=1.22-1.41) and after (below average height: OR=1.21, 95 % CI=1.13-1.31) stimulants for ADHD were introduced in Sweden and was of similar magnitude in both cohorts. The association between ADHD and shorter height attenuated after adjustment for prenatal factors, psychiatric disorders and SES. Relatives of individuals with ADHD had an increased risk of shorter height (below average height in full siblings: OR=1.14, 95 % CI=1.09-1.19; maternal half siblings: OR=1.10, 95 % CI=1.01-1.20; paternal half siblings: OR=1.15, 95 % CI=1.07-1.24, first full cousins: OR=1.10, 95 % CI=1.08-1.12).

CONCLUSION: Our findings suggest that ADHD is associated with shorter height. On a population level, this association was present both before and after ADHD-medications were available in Sweden. The association between ADHD and height was partly explained by prenatal factors, psychiatric comorbidity, low SES and a shared familial liability for ADHD.

BACKGROUND: Consistent evidence suggests a strong association between attention-deficit/hyperactivity disorder (ADHD) and subjectively reported sleep problems. However, the prevalence of clinically ascertained sleep disorder diagnoses and sleep medication prescriptions in individuals with ADHD remains unclear.

OBJECTIVE: To determine the rates of sleep disorder diagnoses and sleep medication prescriptions in children, adolescents and adults with ADHD.

METHODS: We linked Swedish national registers to create a cohort of individuals born 1945-2008. We estimated the absolute and relative risks (using logistic regression models) of different sleep disorder diagnoses and medication prescriptions in individuals with and without ADHD. The analyses were performed across five different age groups: children (5-11 years), adolescents (12-17 years), young adults (18-30 years), middle-aged adults (31-45 years) and older adults (46-60 years).

FINDINGS: Among individuals with ADHD (N=145 490, 2.25% of the cohort), 7.5% had a sleep disorder diagnosis and 47.5% had been prescribed sleep medication. Individuals with ADHD, across all age groups, had a statistically significantly increased risk of having any sleep disorder diagnosis (ORrange=6.4-16.1) and any sleep medication prescription (ORrange=12.0-129.4) compared with individuals without ADHD. While rates of sleep disorders were highest in older adults, the relative risks were highest in youth.

CONCLUSIONS: Individuals with ADHD have a substantially increased risk of sleep disorder diagnoses and sleep medication prescriptions, from childhood into older adulthood.

CLINICAL IMPLICATIONS: More clinical efforts are needed to tackle impairing sleep problems in individuals with ADHD via systematic sleep assessment, appropriate diagnosis, and pharmacological and non-pharmacological interventions. Sleep medication use should be informed by sleep disorder diagnosis.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is associated with an increased risk of poor mental health. However, the understanding of ADHD-related burden and impairments in women during the postpartum period is limited. The aim with the present study was to examine the risk of depression and anxiety disorders during the postpartum period among women with and without an ADHD diagnosis.

METHODS: We used register-based data to identify women who gave birth to their first and/or second child between 2005 and 2013 in Sweden (n = 773,047), of which 0.5 % (n = 3515) had a diagnosis of ADHD prior to pregnancy. Diagnoses of depression and anxiety disorders up to one year after delivery were collected from the national patient register.

RESULTS: A total of 16.76 % of the women with an ADHD diagnosis were also diagnosed with depression disorders in the postpartum period, prevalence ratio (PR) 5.09 (95 % confidence interval (CI), 4.68-5.54). A total of 24.92 % of the women with an ADHD diagnosis were also diagnosed with anxiety disorders in the postpartum period, PR 5.41 (5.06-5.78). Stratified results revealed that having a diagnosis of ADHD increased the risk for both depression and anxiety disorders postpartum, beyond other well-known risk factors.

LIMITATIONS: There is a potential risk of surveillance bias as women diagnosed with ADHD are more likely to have repeated visits to psychiatric care and might have an enhanced likelihood of also being diagnosed with depression and anxiety disorders postpartum, compared to women without ADHD.

CONCLUSIONS: ADHD is an important risk factor for both depression and anxiety disorders postpartum. Therefore, ADHD needs to be considered in the maternal care, regardless of sociodemographic factors and the presence of other psychiatric disorders.

Background: Attention-deficit/hyperactivity disorder (ADHD) has been associated with an increased risk of tobacco smoking, and more difficulties with smoking cessation compared to non-ADHD individuals. Women with ADHD may therefore show elevated rates of smoking during pregnancy.

Aims: To examine the association between ADHD and smoking habits among pregnant women in Sweden and Norway.

Methods: Women pregnant for the first time were identified in Sweden (n = 622,037), and Norway (n = 293,383), of which 1.2% (n = 7,444), and 1.7% (n = 4,951) were defined as having ADHD, respectively. Data on smoking habits were collected early and late in pregnancy.

Results: In Sweden, ADHD was associated with an increased risk of smoking early in pregnancy, adjusted risk ratio (adjRR) 2.69 (95% confidence interval, 2.58-2.81), and late in pregnancy, adjRR 2.95 (2.80-3.10). Similar findings were observed in the Norwegian data, early in pregnancy, adjRR 2.31 (2.21-2.40), and late in pregnancy, adjRR 2.56 (2.42-2.70). Women with ADHD were more likely to continue smoking during pregnancy, compared to women without ADHD, both in Sweden adjRR 1.13 (1.10-1.17), and in Norway, adjRR 1.16 (1.12-1.20). Having a sibling diagnosed with ADHD was associated with an increased risk of smoking early and late in pregnancy, in both Sweden and Norway.

Conclusions: Women with ADHD are considerably more likely to smoke early and late in (their first) pregnancy and are less likely to stop smoking between the two time points. Smoking, early and late in pregnancy, co-aggregates in families with ADHD. Smoking prevention and intervention programs should be targeted towards women with ADHD, specifically during their childbearing years, to ensure better mother and child outcomes.

Background: Attention-deficit/hyperactivity disorder (ADHD) frequently co-occurs with other psychiatric disorders. Twin studies have established that these co-occurrences are in part due to shared genetic risks. However, the strength of these genetic overlaps and the potential heterogeneity accounted for by type of psychiatric symptoms, age, and methods of assessment remain unclear. We conducted a systematic review to fill this gap.

Methods: We searched PubMed, PsycINFO, Embase, and Web of Science until March 07, 2019. Genetic correlations (r(g)) were used as effect size measures.

Results: A total of 31 independent studies fulfilled the inclusion criteria. The pooled estimates showed that the associations between ADHD and other psychiatric symptoms were partly explained by shared genetic factors, with a pooled genetic correlation of 0.50, 95% confidence interval: 0.46-0.60. The genetic correlations (r(g)) between ADHD and externalizing (r(g) = .49 [0.37-0.61]), internalizing (r(g) = .50 [0.39-0.69]), and neurodevelopmental (r(g) = .56 [0.47-0.66]) symptoms were similar in magnitude. The genetic correlations in childhood and adulthood werer(g) = .53 (0.43-0.63) andr(g) = .51 (0.44-0.56), respectively. For methods of assessment, the genetic correlations were also similar in strength, self-reportsr(g) = .52 (0.47-0.58), other informantsr(g) = .55 (0.41-0.69), and combined ratersr(g) = .50 (0.33-0.65).

Conclusions: These findings indicate that the co-occurrence of externalizing, internalizing, and neurodevelopmental disorder symptoms in individuals with ADHD symptoms in part is due to a shared genetic risk.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder (Wilens, Biederman & Spencer 2002) and affects approximately 5% of children (Polanczyk, de Lima, Horta, Biederman & Rohde 2007). About half of those diagnosed in childhood continue to have the diagnosis and symptoms in adulthood (Kessler et al. 2006). The co-occurrence of ADHD with other psychiatric disorder symptoms (Burt et al. 2001; Cole et al. 2009; Polderman et al. 2014) has been suggested to be partly explained by a shared genetic vulnerability (Polderman et al. 2014). However, the strength of the genetic overlap is currently unclear. Also, no study has examined whether the genetic correlations differs between age groups (childhood versus adulthood), by rater (self-report, other informant, combined (parent-teacher, parent-twin, teacher-twin)), or by type of psychiatric disorder symptoms (externalizing, internalizing, neu-rodevelopmental). To address this gap, we conducted a systematic literature search to identify relevant twin studies, in PubMed, PsycINFO, and EMBASE. A total of 31 articles were identified and included in the present study. The pooled estimates showed that the comorbidity between ADHD and diverse psychiatric disorder symptoms were explained by shared genetic effectsrg= 0.50 (0.43–0.56). A similar shared genetic overlap between ADHD and psychiatric disorder symptoms was observed in both childhood rg= 0.51(0.42–0.61) and adulthood rg= 0.47 (0.40–0.53). Similar results werealso found for self-reports rg= 0.49 (0.42–0.55), other informants rg= 0.50 (0.40–0.60), and combined raters rg= 0.51 (0.30–0.69). Further, the strength of the genetic correlations of ADHD with the externalizing rg= 0.49 (0.39–0.59), internalizing rg= 0.55 (0.40–0.68) and neurodevelopmental rg= 0.47 (0.40–0.53) spectrums were similar in magnitude. These findings emphasize the presence of a shared genetic liability between ADHD and externalizing, internalizing and neurodevelopmental disorder symptoms, independent of age and rater.

References

Burt, S. A., Krueger, R. F., McGue, M., Iacono, W. G. (2001).Sources of covariation among attention-deficit/hyperactivity disorder,oppositional defiant disorder, and conduct disorder: the importance ofshared environment.Journal of Abnormal Psychology, 4, 516–525.

Cole, J., Ball, H. A., Martin, N. C., Scourfield, J., McGuffin, P.(2009). Genetic overlap between measures of hyperactivity/inatten-tion and mood in children and adolescents.J Am Acad Child AdolescPsychiatry48, 1094–1101.

Kessler, R. C., Adler, L., Barkley, R., Biederman, J., Conners, C.K., Demler, O., Faraone, S. V., Greenhill, L. L., Howes, M. J., Secnik,K., Spencer, T., Ustun, T. B., Walters, E. E., Zaslavsky, A. M. (2006).The prevalence and correlates of adult ADHD in the United States:results from the National Comorbidity Survey Replication.Am JPsychiatry, 163, 716–723.

Polanczyk, G., de Lima, M. S., Horta, B. L., Biederman, J., Rohde,L. A. (2007). The worldwide prevalence of ADHD: a systematicreview and metaregression analysis.Am J Psychiatry, 164, 942-8.

Polderman, T. J., Hoekstra, R. A., Posthuma, D., Larsson, H.(2014). The co-occurrence of autistic and ADHD dimensions inadults: an etiological study in 17,770 twins.Transl Psychiatry2014;4: e435.

Wilens, T. E., Biederman, J., Spencer, T. J. (2002). Attentiondeficit/hyperactivity disorder across the lifespan.Annual Review Med53:113–131.

We mapped the evidence on the type and strength of associations between a broad range of mental and physical conditions in children and adolescents, by carrying out an umbrella review, i.e., a quantitative synthesis of previous systematic reviews and meta-analyses. We also assessed to which extent the links between mental and physical conditions vary across disorders or, by contrast, are transdiagnostic. Based on a pre-established protocol, we retained 45 studies, encompassing around 12.5 million of participants. In analyses limited to the most rigorous estimates, we found evidence for the following associations: ADHD-asthma, ADHD-obesity, and depression-asthma. A transdiagnostic association was confirmed between asthma and anxiety/ASD/depression/bipolar disorder, between obesity and ADHD/ASD/depression, and between dermatitis and ASD/ADHD. We conclude that obesity and allergic conditions are likely to be associated with mental disorders in children and adolescents. Our results can help clinicians explore potential links between mental and physical conditions in children/adolescent and provide a road map for future studies aimed at shading light on the underlying factors.

Human data supporting a role for endoplasmic reticulum (ER) stress and calcium dyshomeostasis in heart disease is scarce. Darier disease (DD) is a hereditary skin disease caused by mutations in the ATP2A2 gene encoding the sarcoendoplasmic-reticulum Ca2⁺ ATPase isoform 2 (SERCA2), which causes calcium dyshomeostasis and ER stress. We hypothesized that DD patients would have an increased risk for common heart disease. We performed a cross-sectional case-control clinical study on 25 DD patients and 25 matched controls; and a population-based cohort study on 935 subjects with DD and matched comparison subjects. Main outcomes and measures were N-terminal pro-brain natriuretic peptide, ECG and heart diagnosis (myocardial infarction, heart failure and arrythmia). DD subjects showed normal clinical heart phenotype including heart failure markers and ECG. The risk for heart failure was 1.59 (1,16-2,19) times elevated in DD subjects, while no major differences were found in myocardial infarcation or arrhythmias. Risk for heart failure when corrected for cardivascular risk factors or alcohol misuse was 1.53 (1.11-2.11) and 1.58 (1,15-2,18) respectively. Notably, heart failure occurred several years earlier in DD patients as compared to controls. We conclude that DD patients show a disease specific increased risk of heart failure which should be taken into account in patient management. The observation also strenghtens the clinical evidence on the important role of SERCA2 in heart failure pathophysiology.

Background: Genetic and environmental factors are important in the etiology of substance use. However, little is known about the stability of these factors across development. We aimed to answer three crucial questions about this etiology that have never been addressed in a single study: (1) Is there a general vulnerability to substance consumption from early adolescence to young adulthood? (2) If so, do the genetic and environmental influences on this vulnerability change across development? (3) Do these developmental processes differ in males and females?

Method: Subjects included 1480 twin pairs from the Swedish Twin Study of Child and Adolescent Development who have been followed since 1994. Prospective, self-reported regular smoking, alcohol intoxication and illicit drug use were assessed at ages 13-14, 16-17 and 19-20 years. Structural modeling was performed with the program Mx.

Results: An underlying common factor accounted for the association between smoking, alcohol and illicit drug consumption for the three age groups. Common genetic and shared environmental effects showed substantial continuity. In general, as participants aged, the influence of the shared environment decreased, and genetic effects became more substance specific in their effect.

Conclusions: The current report answers three important questions in the etiology of substance use. The genetic and environmental risk for substance consumption is partly mediated through a common factor and is partly substance specific. Developmentally, evidence was strongest for stability of common genetic effects, with less evidence for genetic innovation. These processes seem to be the same in males and females.

BACKGROUND: Alcohol involvement has familial associations with bulimic symptoms (i.e., binge eating, inappropriate compensatory behaviors), with several studies indicating a genetic overlap between the two. It is unclear whether overlapping familial risk with alcohol involvement extends to other eating disorder symptoms. Understanding the genetic overlap between alcohol involvement and other eating disorder symptoms may aid in more targeted interventions for comorbid alcohol use-eating disorder symptoms. Thus, we investigated associations between alcohol involvement and 2 core eating disorder symptoms: drive for thinness and body dissatisfaction in adolescent female and male twins.

METHODS: We assessed 3 levels of alcohol involvement: alcohol use in the last month, having ever been intoxicated, and alcohol intoxication frequency via self-report. The Eating Disorder Inventory-II assessed drive for thinness and body dissatisfaction. Sex-specific biometrical twin modeling examined the genetic overlap between alcohol involvement and eating disorder symptoms.

RESULTS: Phenotypic associations between alcohol involvement, drive for thinness, and body dissatisfaction were significantly greater in girls compared with boys. A majority of the associations between alcohol involvement, drive for thinness, and body dissatisfaction in girls, but not boys, met our threshold for twin modeling (phenotypic r > 0.20). Moderate genetic correlations were observed between the 3 aspects of alcohol involvement and drive for thinness. Moderate genetic correlations were observed between alcohol use and intoxication frequency and body dissatisfaction.

CONCLUSIONS: Together with the literature on alcohol involvement and bulimic symptoms, these findings suggest a generalized association between alcohol involvement and eating disorder symptoms in girls, whereas this association may be symptom specific in boys. Genetic correlations indicate that the amount and direction of this genetic overlap differs across specific symptoms. When intervening on comorbid alcohol involvement and eating disorder symptoms, it may be important to target-specific eating disorder symptoms.

Objective: Twin studies have shown that genetic factors in part explain the established relation between alcohol use (i.e., problematic use or abuse/dependence) and eating disorder symptoms in adolescent and adult females. However, studies have yet to elucidate if there are similar shared genetic factors between other aspects of substance involvement, such as illicit drug use and repeated cigarette smoking.

Method: For those sex-specific phenotypic correlations above our threshold of.20, we used a behavioral genetic design to examine potential shared genetic overlap between self-reported lifetime illicit drug use and repeated cigarette smoking and the eating disorder symptoms of drive for thinness (DT), bulimia (BU), and body dissatisfaction (BD), as assessed with the Eating Disorder Inventory-II in 16- to 17-year-old female and male twin pairs.

Results: Only phenotypic correlations with illicit drug use met our threshold for twin modeling. Small to moderate genetic correlations were observed between illicit drug use and BU in both girls and boys and between illicit drug use and in girls.

Conclusions: Similar etiological factors are at play in the overlap between illicit drug use and certain eating disorder symptoms in girls and boys during adolescence, such that genetic factors are important for covariance. Specifically, illicit drug use was associated with bulimia nervosa symptoms in girls and boys, which parallels previous substance use research finding a genetic overlap between alcohol use and bulimia nervosa symptoms. Future research should prospectively examine developmental trajectories to further understand the etiological overlap between substance involvement and eating disorder symptoms.

Twin studies show the established relation between bulimic symptoms and problematic alcohol involvement in adult females is partly due to shared familial factors, specifically shared genetic effects. However, it is unclear if similar shared etiological factors exist during adolescence or in males. We examined the familial overlap (i.e., genetic and common environmental correlations) between bulimic symptoms and various levels of alcohol involvement in 16- to 17-year-old female and male same-sex twin pairs using sex-specific biometrical twin modeling. Bulimic symptoms were assessed with the Eating Disorder Inventory-2. Alcohol involvement included alcohol use in the last month, having ever been intoxicated, and alcohol intoxication frequency. Results revealed 3 distinct patterns. First, in general, phenotypic correlations indicated statistically similar associations between bulimic symptoms and alcohol involvement in girls and boys. Second, common environmental overlap was significant for the bivariate associations including having ever been intoxicated. Third, moderate genetic correlations were observed between all bulimic symptoms and alcohol involvement in girls and moderate common environmental correlations were observed in boys for the more risky/deviant levels of involvement. Similar to adults, there is familial overlap between bulimic symptoms and alcohol involvement in adolescent girls and boys. These results could inform symptom-and sex-specific, developmentally targeted prevention and intervention programs for the comorbidity between bulimic symptoms and alcohol involvement.

Body dissatisfaction is a significant mental health symptom present in adolescent girls and boys. However, it is often either disregarded in adolescent boys or examined using assessments that may not resonate with males. The present study addresses these issues, examining the manifestation, etiology, and correlates of 3 facets of body dissatisfaction in adolescent boys. Adolescent male twins aged 16- to 17-years-old from the Swedish Twin Study of Child and Adolescent Development were included along with a female comparison group: 915 monozygotic and 671 dizygotic same-sex twins. Body dissatisfaction was defined using measures of height dissatisfaction, muscle dissatisfaction, and the body dissatisfaction subscale of the Eating Disorder Inventory (EDI-BD). We examined the prevalence of body dissatisfaction, whether the facets of body dissatisfaction were phenotypically and etiologically distinct, and associations with specific externalizing and internalizing symptoms. For boys, muscle dissatisfaction scores were greater than height dissatisfaction scores. Results also indicated that height and muscle dissatisfaction were phenotypically and etiologically distinct from the EDI-BD. Unique associations were observed with externalizing and internalizing symptoms: muscle dissatisfaction with symptoms of bulimia nervosa and the EDI-BD with internalizing symptoms, body mass index, and drive for thinness. The facets of body dissatisfaction were also largely distinct in girls and unique between-sex associations with externalizing and internalizing symptoms emerged. Overall, male-oriented aspects of body dissatisfaction are distinct from female-oriented aspects of body dissatisfaction. To capture the full picture of male body dissatisfaction, multiple facets must be addressed.

To increase the number of pre-registered observational studies, Journal of Child Psychology and Psychiatry (JCPP) Advances is delighted to now invite Registered Reports. Registered Reports are a format of article in which the study protocol is pre-registered and peer-reviewed before the research is conducted. If the protocol is of high quality and the proposed research topic is important, JCPP Advances will commit to publishing the study regardless of the results. This article format crucially addresses publication bias, as decisions on publication are entirely independent of the results.

Children exposed to adverse childhood experiences (ACEs) have an elevated risk of mental health problems, but it is unclear whether these associations reflect genetic confounding. We tested (1) whether children with genetic liability to psychopathology are more likely to experience ACEs, and (2) the extent to which the associations between ACEs and mental health are genetically confounded. Par-ticipants were 6411 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). ACEs (including maltreatment, domestic violence, and parental psychopathology, substance abuse, criminality, and separation) were prospectively measured through parent reports at multiple assessments between birth and age 9. Internalizing and externalizing problems at age 9 were assessed through parent reports on the Development and Wellbeing Assessment. We derived polygenic scores for a range of psychiatric disorders. Children with greater genetic liability to psychopathology had a small elevation in risk of ACEs (pooled odds ratio = 1.05, 95% CI 1.01–1.09). Measured polygenic scores accounted for a very small proportion of the associations between ACEs with internalizing problems (pooled average across ACEs = 3.6%) and externalizing problems (pooled average = 4.8%). However, latent polygenic scores capturing SNP heritability in mental health outcomes explained a larger proportion of the associations between ACEs with internalizing problems (pooled average = 63%) and externalizing problems (pooled average = 17%). Risk of mental health problems in children exposed to ACEs is partly, but not completely driven by pre-existing genetic liability to psychopathology. Assuming the absence of nongenetic confounding, these findings are consistent with a partly causal effect of ACEs on mental health.

Children who experience adversities have an elevated risk of mental health problems. However, the extent to which adverse childhood experiences (ACEs) cause mental health problems remains unclear, as previous associations may partly reflect genetic confounding. In this Registered Report, we used DNA from 11,407 children from the United Kingdom and the United States to investigate gene-environment correlations and genetic confounding of the associations between ACEs and mental health. Regarding gene-environment correlations, children with higher polygenic scores for mental health problems had a small increase in odds of ACEs. Regarding genetic confounding, elevated risk of mental health problems in children exposed to ACEs was at least partially due to pre-existing genetic risk. However, some ACEs (such as childhood maltreatment and parental mental illness) remained associated with mental health problems independent of genetic confounding. These findings suggest that interventions addressing heritable psychiatric vulnerabilities in children exposed to ACEs may help reduce their risk of mental health problems.

BACKGROUND: An increasing number of women of reproductive age are treated with attention-deficit hyperactivity disorder (ADHD) medication; however, patterns of ADHD medication use for women in the perinatal period have not been well described.

OBJECTIVE: This study aimed to describe ADHD medication use patterns from 1 year before pregnancy to 1 year after delivery, and to describe sociodemographic characteristics and clinical features by medication trajectories.

METHODS: The population-based cohort study included pregnancies in Denmark between 1997 and 2020, from the Medical Birth Register, by women who filled at least one prescription for ADHD medication from 12 months before pregnancy until 12 months after delivery. We applied group-based trajectory modeling to classify women into subgroups based on the identification of heterogeneous ADHD medication treatment patterns, and described the characteristics associated with these groups.

RESULTS: Overall, we included 4717 pregnancies leading to liveborn singletons by 4052 mothers with a mean (standard deviation) age of 27.5 (5.6) years. We identified four treatment trajectories across pregnancy and the postpartum period: continuers (23.3%), discontinuers (41.8%), interrupters who ceased filling prescriptions during pregnancy but resumed postpartum (17.2%), and postpartum initiators (17.7%). Continuers were older at the time of conception, gave birth in more recent years, were more likely to smoke during pregnancy, and used other psychotropic medications during pregnancy. A large proportion of continuers used methylphenidate (89.1%) compared with the other groups (75.9-84.1%) and had switched ADHD medication type during the whole period (16.4% vs. 7.4-14.8%).

CONCLUSION: We found that approximately 60% of women discontinued or interrupted their ADHD medication around pregnancy, and those who continued differed in sociodemographic and clinical factors that may reflect more severe ADHD.

Attention Deficit Hyperactivity Disorder (ADHD) medication is increasingly being used during pregnancy. Concerns have been raised as to whether ADHD medication has long-term adverse effects on the offspring. The authors investigated whether in utero exposure to ADHD medication was associated with adverse long-term neurodevelopmental and growth outcomes in offspring. The population-based cohort study in the Danish national registers included 1,068,073 liveborn singletons from 1998 to 2015 followed until any developmental diagnosis, death, emigration, or December 31, 2018. Children of mothers who continued ADHD medication (methylphenidate, amphetamine, dexamphetamine, lisdexamphetamine, modafinil, atomoxetine, clonidine) during pregnancy and children of mothers who discontinued ADHD medication before pregnancy were compared using Cox regression. Main outcomes were neurodevelopmental psychiatric disorders, impairments in vision or hearing, epilepsy, seizures, or growth impairment during childhood or adolescence. In total, 898 children were exposed to ADHD medication during pregnancy compared to 1270 children whose mothers discontinued ADHD medication before pregnancy. After adjustment for demographic and psychiatric characteristics of the mother, no increased risk of any offspring developmental disorders was found combined (aHR 0.97, 95% CI 0.81 to 1.17) or for separate subcategories. Similarly, no increased risk was found for any sub-categories of outcomes in the negative control or sibling controlled analyses. Neurodevelopment and growth in offspring do not differ based on antenatal exposure to ADHD medication. These findings provide reassurance for women with ADHD who depend on ADHD medication for daily functioning and who consider continuing medication in pregnancy.

Background: Self-harm among young adults is a common and increasing phenomenon in many parts of the world. The long-term prognosis after self-harm at young age is inadequately known. We aimed to estimate the risk of mental illness and suicide in adult life after self-harm in young adulthood and to identify prognostic factors for adverse outcome.

Method: We conducted a national population-based matched case-cohort study. Patients aged 18-24 years (n = 13 731) hospitalized after self-harm between 1990 and 2003 and unexposed individuals of the same age (n = 137 310 ) were followed until December 2009. Outcomes were suicide, psychiatric hospitalization and psychotropic medication in short-term (1-5 years) and long-term (>5 years) follow-up.

Results: Self-harm implied an increased relative risk of suicide during follow-up [hazard ratio (HR) 16.4, 95% confidence interval (CI) 12.9-20.9). At long-term follow-up, 20.3% had psychiatric hospitalizations and 51.1% psychotropic medications, most commonly antidepressants and anxiolytics. There was a six-fold risk of psychiatric hospitalization (HR 6.3, 95% CI 5.8-6.8) and almost three-fold risk of psychotropic medication (HR 2.8, 95% CI 2.7-3.0) in long-term follow-up. Mental disorder at baseline, especially a psychotic disorder, and a family history of suicide were associated with adverse outcome among self-harm patients.

Conclusion: We found highly increased risks of future mental illness and suicide among young adults after self-harm. A history of a mental disorder was an important indicator of long-term adverse outcome. Clinicians should consider the substantially increased risk of suicide among self-harm patients with psychotic disorders.

BACKGROUND: Self-harm is common in youth and an important risk factor for suicide. Certain self-harm methods might indicate a higher risk of suicide. The main aim of this study was to determine whether some methods of self-harm in adolescents (10-17 years) and young adults (18-24 years) are associated with a particularly high risk of suicide. A secondary aim was to ascertain how different self-harm methods might affect the probability of psychiatric follow-up.

METHOD: Five Swedish registers were linked in a national population-based cohort study. All nonfatal self-harm events recorded in specialist health care, excluding psychiatry and primary care services, among 10-24 year olds between 2000 and 2009 were included. Methods were classified as poisoning, cutting/piercing, violent method (gassing, hanging, strangulation/suffocation, drowning, jumping and firearms), other and multiple methods. Hazard Ratios (HR) for suicide were calculated in Cox regression models for each method with poisoning as the reference. Odds Ratios (OR) for psychiatric inpatient care were determined in logistic regression models. Analyses were adjusted for important covariates and stratified by age group and treatment setting (inpatient/outpatient).

RESULTS: Among adolescents with initial medical hospitalisation, use of a violent method was associated with a near eightfold increase in HR for suicide compared to self-poisoning in the adjusted analysis [HR 7.8; 95% confidence interval (CI) 3.2-19.0]. Among hospitalised young adult women, adjusted HRs were elevated fourfold for both cutting [4.0 (1.9-8.8)] and violent methods [3.9 (1.5-10.6)]. Method of self-harm did not affect suicide risk in young adult men. Adolescents using violent methods had an increased probability of psychiatric inpatient care following initial treatment for self-harm.

CONCLUSIONS: Violent self-harm requiring medical hospitalisation may signal particularly high risk of future suicide in adolescents (both sexes) and in young adult women. For the latter group this is the case for cutting requiring hospitalisation as well.

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.

Several studies have, with conflicting results, investigated the relationship between the Val⁶⁶Met polymorphism in brain-derived neurotrophic factor (BDNF) and attention deficit hyperactivity disorder (ADHD). We assessed longitudinal, quantitative phenotypes of hyperactivity-impulsivity and inattention in order to determine whether the Val⁶⁶Met polymorphism is associated with age-specific and/or persistent symptoms of hyperactivity-impulsivity and/or inattention in a community-based cohort of 1236 Swedish individuals for which ADHD symptom data were collected when the participants were aged 8-9, 13-14 and 16-17 yr. The Met allele was associated with symptoms of ADHD at ages 8-9 and 13-14 yr. A multivariate regression analysis revealed that the observed effect of the Met allele on ADHD symptoms reflects an influence on persistent hyperactivity-impulsivity symptoms. The present findings support the hypothesis that BDNF is involved in the pathogenesis of ADHD. The results highlight the importance of distinguishing between hyperactivity-impulsivity and inattention, respectively, and demonstrate the value of using a longitudinal approach in genetic studies of ADHD symptoms.

Purpose: Parental history of criminal offending is a major risk factor for later criminal behavior in children. Extensive research has also shown low resting heart rate (RHR), a moderately heritable biological variable, to be prospectively predictive of criminal behavior. Despite its status as a replicable risk factor, limited research exists on RHR's role in the intergenerational transmission of crime. Specifically, it remains unclear whether parent-child resemblance for biological characteristics such as RHR might play a role in intergenerational crime transmission.

Method: The current study was undertaken to clarify the role of RHR in the intergenerational transmission of crime, and test for moderating effects of socioeconomic status (SES) on its role, in a large Swedish population-based sample of fathers and their sons combined (N similar to 266,000).

Results: Beyond replicating prior work documenting paternal crime history and RHR as predictors of later offspring crime, we show tfhat father-son resemblance for RHR accounts in part for father-to-son crime transmission, and that familial SES does not moderate this transmission.

Conclusions: Our findings have important implications for understanding the role of biological and environmental influences in the intergenerational transmission of crime.

The Swedish National Patient Register (NPR) includes population-level longitudinal data, and determining the validity of NPR diagnoses is critical to undergirding the research and policy recommendations they inform. Sweden also has the integrated "Riksa & BULL;t " and "Stepwise " National Quality Registers (QR), with data from specialized eating disorder (ED) treatment based on structured, valid assessment methods. To validate NPR ED diagnoses, we compared ICD-10-based anorexia nervosa (AN), bulimia nervosa (BN), and unspecified ED in NPR to DSM-IV-based AN, BN, and ED not otherwise specified category (EDNOS) in QR. Patients' first diagnoses registered in QR between February 2008 and August 2013 were compared with NPR diagnoses entered within & PLUSMN;1 month (N = 2074). QR registration includes the semi-structured DSM-IV-based Structured ED Interview. Each ED diagnosis was analyzed separately for degree of match using several indices: overall agreement, sensitivity, positive predictive value, specificity, negative predictive value, area under the curve, and Cohen's kappa. Results showed moderate to excellent agreement depending on estimate (e.g. positive predictive values AN: 0.747; BN:.836; EDNOS: 0.761), except for a somewhat low sensitivity for BN, and EDNOS agreement was overall the lowest. Case prevalence in the NPR and QR was highly similar for AN, and within five percentage points for BN and EDNOS. Generalizability is hampered by limited age range and diagnostic resolution as well as few males. Available data precluded study of presence/absence of ED, and complementary approaches are considered for future research. We conclude that NPR ED diagnoses have acceptable validity and are appropriate for use in research.

BACKGROUND AND HYPOTHESIS: Recent research showed that young people who presented to hospital with self-harm in Finland had a significantly elevated risk of later psychosis. We investigated the prospective relationship between hospital presentation for self-harm and risk of psychosis in an unprecedentedly large national Swedish cohort.

STUDY DESIGN: We used inpatient and outpatient healthcare registers to identify all individuals born between 1981 and 1993 who were alive and living in Sweden on their 12th birthday and who presented to hospital one or more times with self-harm. We compared them with a matched cohort, followed up for up to 20 years, and compared the cumulative incidence of psychotic disorders. Furthermore, we examined whether the strength of the relationship between hospital presentation for self-harm and later psychosis changed over time by examining for cohort effects.

STUDY RESULTS: In total, 28 908 (2.0%) individuals presented to hospital with self-harm without prior psychosis diagnosis during the follow-up. For individuals who presented to hospital with self-harm, the cumulative incidence of diagnosed psychosis was 20.7% at 20 years follow-up (hazard radio = 13.9, 95% CI 13.3-14.6, P-value <5 × 10-308). There was no evidence of a dilution of the effect over time: while the incidence of hospital self-harm presentation increased, this did not result in an attenuation over time of the strength of the relationship between hospital self-harm presentation and subsequent psychosis.

CONCLUSIONS: Individuals who present to hospital with self-harm in their teens and 20s represent an important risk group for psychosis prediction and prevention.

Objective: Irritable and oppositional behaviors are increasingly considered as distinct dimensions of oppositional defiant disorder. However, few studies have explored this multidimensionality across the broader spectrum of disruptive behavior problems (DBPs). This study examined the presence of dimensions and distinct subgroups of childhood DBPs, and the cross-sectional and longitudinal associations between these dimensions.

Method: Using factor mixture models (FMMs), the presence of dimensions and subgroups of DBPs was assessed in the Generation R Study at ages 6 (n = 6,209) and 10 (n = 4,724) years. Replications were performed in two population-based cohorts (Netherlands Twin Registry, n = 4,402, and Swedish Twin Study of Child and Adolescent Development, n = 1,089) and a clinical sample (n = 1,933). We used cross-lagged modeling in the Generation R Study to assess cross-sectional and longitudinal associations between dimensions. DBPs were assessed using mother-reported responses to the Child Behavior Checklist.

Results: Empirically obtained dimensions of DBPs were oppositional behavior (age 6 years), disobedient behavior, rule-breaking behavior (age 10 years), physical aggression, and irritability (both ages). FMMs suggested that one-class solutions had the best model fit for all dimensions in all three population-based cohorts. Similar results were obtained in the clinical sample. All three dimensions, including irritability, predicted subsequent physical aggression (range, 0.08-0.16).

Conclusion: This study showed that childhood DBPs should be regarded as a multidimensional phenotype rather than comprising distinct subgroups. Incorporating multidimensionality will improve diagnostic accuracy and refine treatment. Future studies need to address the biological validity of the DBP dimensions observed in this study; herein lies an important opportunity for neuro-imaging and genetic measures.

The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about the regulation of receptor and transporter density levels. This lack of knowledge obscures interpretation of differences in protein availability reported in psychiatric patients. In this study, we used positron emission tomography (PET) in a twin design to estimate the relative contribution of genetic and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [(11)C]raclopride binding to the D2- and D3-dopamine receptor and [(11)C]WAY100635 binding to the serotonin 5-HT1A receptor. Heritability, shared environmental effects and individual-specific non-shared effects were estimated for regional D2/3 and 5-HT1A receptor availability in projection areas. We found a major contribution of genetic factors (0.67) on individual variability in striatal D2/3 receptor binding and a major contribution of environmental factors (pairwise shared and unique individual; 0.70-0.75) on neocortical 5-HT1A receptor binding. Our findings indicate that individual variation in neuroreceptor availability in the adult brain is the end point of a nature-nurture interplay, and call for increased efforts to identify not only the genetic but also the environmental factors that influence neurotransmission in health and disease.

ADHD is defined by symptoms of hyperactivity, impulsivity and inattention, prevalent in 5-7 % of youth and 2-3 % of adults and caused by an interplay of multiple genetic and environmental risk factors. The ADHD-phenotype was first described in the medical literature in 1775. While neuroimaging studies show altered structure and function of the brain, and neuropsychological tests low capacity of executive functions on a group level, neither assessment can be used to diagnose ADHD on an individual level. ADHD poses increased risk for somatic and psychiatric comorbidities as well as low quality of life, social impairment, professional underachievement, and hazardous behaviors such as substance misuse, injuries, and premature death. The consequences of undiagnosed and untreated ADHD pose a great economic burden on society worldwide. Research strongly suggests that several medications are safe and effective by reducing negative outcomes associated with ADHD across the lifespan.

Background: Given the frequency with which families change residences, the effects of childhood relocations have gained increasing research attention. Many researchers have demonstrated that childhood relocations are associated with a variety of adverse outcomes. However, drawing strong causal claims remains problematic due to uncontrolled confounding factors.

Method: We utilized longitudinal, population-based Swedish registers to generate a nationally representative sample of offspring born 1983-1997 (n = 1 510 463). Using Cox regression and logistic regression, we examined the risk for numerous adverse outcomes after childhood relocation while controlling for measured covariates. To account for unmeasured genetic and environmental confounds, we also compared differentially exposed cousins and siblings.

Results: In the cohort baseline model, each annual relocation was associated with risk for the adverse outcomes, including suicide attempt [hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.19-1.20]. However, when accounting for offspring and parental covariates (HR 1.08, 95% CI 1.07-1.09), as well as genetic and environmental confounds shared by cousins (HR 1.07, 95% CI 1.05-1.09) and siblings (HR 1.00, 95% CI 0.97-1.04), the risk for suicide attempt attenuated. We found a commensurate pattern of results for severe mental illness, substance abuse, criminal convictions, and low academic achievement.

Conclusions: Previous research may have overemphasized the independent association between relocations and later adverse outcomes. The results suggest that the association between childhood relocations and suicide attempt, psychiatric problems, and low academic achievement is partially explained by genetic and environmental confounds correlated with relocations. This study demonstrates the importance of using family-based, quasi-experimental designs to test plausible alternate hypotheses when examining causality.

Importance: Hypertensive disorders of pregnancy (HDP) have been associated with poorer neurodevelopmental outcomes in offspring, but the role of familial confounding in these associations is unclear.

Objective: To investigate associations of maternal HDP with risks in offspring of autism spectrum disorders (ASDs), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID), as well as variation in overall cognitive performance in offspring.

Design, Setting, and Participants: This Swedish register-based study used data from a birth cohort divided into 1 085 024 individuals born between 1987 and 1996 and followed up until December 31, 2014, and 285 901 men born between 1982 and 1992 who attended assessments for military conscription, including a cognitive function test. Statistical analysis was performed from April 1, 2019, to June 1, 2020.

Exposures: Diagnoses of HDP, which were provided by the Medical Birth Register.

Main Outcomes and Measures: Diagnoses of ASDs, ADHD, and ID were extracted from the National Patient Register. Cognitive function was assessed using written tests and summarized as a single 9-point score. Whole-cohort and within-sibship analyses were performed; the latter accounted for unmeasured familial confounding factors shared by siblings.

Results: The study included 1 085 024 individuals (556 912 male participants [51.3%]) born between 1987 and 1996 and 285 901 men born between 1982 and 1992 who attended assessments for military conscription. The prevalence of maternal HDP was 4.0% in the 1987-1996 birth cohort (n = 42 980) and 5.1% in the military conscription cohort (n = 14 515). A total of 15 858 participants received a diagnosis of ASD, 36 852 received a diagnosis of ADHD, and 8454 received a diagnosis of ID. The mean (SD) cognitive score among the men in the conscription cohort was 5.1 (1.9). In whole-cohort analyses with multivariable adjustment, HDP were associated with offspring ASDs (hazard ratio [HR], 1.22; 95% CI, 1.13-1.31), ADHD (HR, 1.10; 95% CI, 1.05-1.16), and ID (HR, 1.39; 95% CI, 1.27-1.53). Analyses comparing siblings discordant for HDP were less statistically powered but indicated estimates of similar magnitude for ASDs (HR, 1.19; 95% CI, 1.00-1.42) and possibly ADHD (HR, 1.09; 95% CI, 0.95-1.24), but not for ID (HR, 1.04; 95% CI, 0.83-1.29). Hypertensive disorders of pregnancy were associated with somewhat lower cognitive scores in whole-cohort analysis (mean difference comparing offspring exposed with those unexposed, -0.10; 95% CI, -0.13 to -0.07), but in within-sibship analysis, the association was null (mean difference, 0.00; 95% CI, -0.09 to 0.08).

Conclusions and Relevance: The study results suggest that HDP are associated with small increased risks of ASDs and possibly ADHD in offspring, whereas associations with ID and cognitive performance are likely confounded by shared familial (environmental or genetic) factors.

Importance: There are limited data concerning the risk of metabolic and cardiovascular disorders among individuals with Tourette syndrome (TS) or chronic tic disorder (CTD).

Objective: To investigate the risk of metabolic and cardiovascular disorders among individuals with TS or CTD over a period of 40 years.

Design, Settings, and Participants: This longitudinal population-based cohort study included all individuals living in Sweden between January 1, 1973, and December 31, 2013. Families with clusters of full siblings discordant for TS or CTD were further identified. Data analyses were conducted from August 1, 2017, to October 11, 2018.

Exposures: Previously validated International Classification of Diseases diagnoses of TS or CTD in the Swedish National Patient Register.

Main Outcomes and Measures: Registered diagnoses of obesity, dyslipidemia, hypertension, type 2 diabetes, and cardiovascular diseases (including ischemic heart diseases, arrhythmia, cerebrovascular diseases and transient ischemic attack, and arteriosclerosis).

Results: Of the 14 045 026 individuals in the cohort, 7804 individuals (5964 males [76.4%]; median age at first diagnosis, 13.3 years [interquartile range, 9.9-21.3 years]) had a registered diagnosis of TS or CTD in specialist care. Of 2 675 482 families with at least 2 singleton full siblings, 5141 families included siblings who were discordant for these disorders. Individuals with TS or CTD had a higher risk of any metabolic or cardiovascular disorders compared with the general population (hazard ratio adjusted by sex and birth year [aHR], 1.99; 95% CI, 1.90-2.09) and sibling controls (aHR for any disorder, 1.37; 95% CI, 1.24-1.51). Specifically, individuals with TS or CTD had higher risks for obesity (aHR, 2.76; 95% CI, 2.47-3.09), type 2 diabetes (aHR, 1.67; 95% CI, 1.42-1.96), and circulatory system diseases (aHR, 1.76; 95% CI, 1.67-1.86). The risk of any cardiometabolic disorder was significantly greater in males than in females (aHR, 2.13; 95% CI, 2.01-2.26 vs aHR, 1.79; 95% CI, 1.64-1.96), as was the risk of obesity (aHR, 3.24; 95% CI, 2.83-3.70 vs aHR, 1.97; 95% CI, 1.59-2.44). The risks were already evident from childhood (the groups were significantly different by age 8 years) and were significantly reduced with the exclusion of individuals with comorbid attention-deficit/hyperactivity disorder (aHR, 1.52; 95% CI, 1.42-1.62), while excluding other comorbidities did not significantly affect the results. Compared with patients with TS or CTD who were not taking antipsychotics, patients with a longer duration of antipsychotic treatment (>1 year) had significantly lower risks of metabolic and cardiovascular disorders.

Conclusions and Relevance: The findings of this study suggest that TS and CTD are associated with a substantial risk of metabolic and cardiovascular disorders. The results highlight the importance of carefully monitoring cardiometabolic health in patients with TS or CTD across the lifespan, particularly in those with comorbid attention-deficit/hyperactivity disorder.

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 < 0.0001). These differences remained when the groups were matched by age at first OCD diagnosis and after various sensitivity analyses. The observed familial patterns of OCD in relation to tics were not seen in relation to other neuropsychiatric comorbidities. Tic-related OCD is a particularly familial subtype of OCD. The results have important implications for ongoing gene-searching efforts.

Objective: To synthesize the current knowledge on possible environmental risk factors for Obsessive-Compulsive Disorder (OCD).

Method: We conducted a systematic review following PRISMA guidelines. The Embase, PubMed and Scopus databases were searched up until October 6, 2015, employing relevant keywords and MeSH terms.

Results: 128 studies met inclusion criteria. Potential environmental risk factors for OCD have been identified in the broad areas of perinatal complications, reproductive cycle, and stressful life events. There is limited evidence regarding other potential risk factors, such as parental age, season of birth, socioeconomic status, parental rearing practices, infections, traumatic brain injury, substance use or vitamin deficiency. In general, studies were of limited methodological quality.

Conclusions: At present, no environmental risk factors have convincingly been associated with OCD. We propose a roadmap for future studies, consisting of longitudinal, population-based research, employing quasi-experimental family and twin designs to identify risk factors that are not only associated with the disorder but also contribute to its causation either directly or moderating the effect of genes.

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.

Importance: Perinatal complications may increase the risk of obsessive-compulsive disorder (OCD). Previous reports were based on small, retrospective, specialist clinic-based studies that were unable to rigorously control for unmeasured environmental and genetic confounding.

Objective: To prospectively investigate a wide range of potential perinatal risk factors for OCD, controlling for unmeasured factors shared between siblings in the analyses.

Design, Setting, and Participants: This population-based birth cohort study included all 2 421 284 children from singleton births in Sweden from January 1, 1973, to December 31, 1996, who were followed up through December 31, 2013. From the 1 403 651 families in the cohort, differentially exposed siblings from the 743 885 families with siblings were evaluated; of these, 11 592 families included clusters of full siblings that were discordant for OCD. Analysis of the data was conducted from January, 26, 2015, to September, 5, 2016.

Exposures: Perinatal data were collected from the Swedish Medical Birth Register and included maternal smoking during pregnancy, labor presentation, obstetric delivery, gestational age (for preterm birth), birth weight, birth weight in relation to gestational age, 5-minute Apgar score, and head circumference.

Main Outcomes and Measures: Previously validated OCD codes (International Statistical Classification of Diseases and Health Related Problems, Tenth Revision, code F42) in the Swedish National Patient Register.

Results: Of 2 421 284 individuals included in the cohort, 17 305 persons were diagnosed with OCD. Of these, 7111 were men (41.1%). The mean (SD) age of individuals at first diagnosis of OCD was 23.4 (6.5) years. An increased risk for OCD remained after controlling for shared familial confounders and measured covariates (including sex, year of birth, maternal and paternal age at birth, and parity), for smoking 10 or more cigarettes per day during pregnancy (hazard ratio [HR], 1.27; 95% CI, 1.02-1.58), breech presentation (HR, 1.35; 95% CI, 1.06-1.71), delivery by cesarean section (HR, 1.17; 95% CI, 1.01-1.34), preterm birth (HR, 1.24; 95% CI, 1.07-1.43), birth weight 1501 to 2500 g (HR, 1.30; 95% CI, 1.05-1.62) and 2501 to 3500 g (HR, 1.08; 95% CI, 1.01-1.16), being large for gestational age (HR, 1.23; 95% CI, 1.05-1.45), and Apgar distress scores at 5 minutes (HR, 1.50; 95% CI, 1.07-2.09). Gestational age and birth weight followed inverse dose-response associations, whereby an increasingly higher risk for OCD was noted in children with a shorter gestational age and lower birth weight. We also observed a dose-response association between the number of perinatal events and increased OCD risk, with HRs ranging from 1.11 (95% CI, 1.07-1.15) for 1 event to 1.51 (95% CI, 1.18-1.94) for 5 or more events.

Conclusions and Relevance: A range of perinatal risk factors is associated with a higher risk for OCD independent of shared familial confounders, suggesting that perinatal risk factors may be in the causal pathway to OCD.

It is increasingly recognized that children with asthma are at a higher risk of other non-allergic concurrent diseases than the non-asthma population. A plethora of recent research has reported on these comorbidities and progress has been made in understanding the mechanisms for comorbidity. The goal of this review was to assess the most recent evidence (2016-2021) on the extent of common comorbidities (obesity, depression and anxiety, neurodevelopmental disorders, sleep disorders and autoimmune diseases) and the latest mechanistic research, highlighting knowledge gaps requiring further investigation. We found that the majority of recent studies from around the world demonstrate that children with asthma are at an increased risk of having at least one of the studied comorbidities. A range of potential mechanisms were identified including common early life risk factors, common genetic factors, causal relationships, asthma medication and embryologic origins. Studies varied in their selection of population, asthma definition and outcome definitions. Next, steps in future studies should include using objective measures of asthma, such as lung function and immunological data, as well as investigating asthma phenotypes and endotypes. Larger complex genetic analyses are needed, including genome-wide association studies, gene expression-functional as well as pathway analyses or Mendelian randomization techniques; and identification of gene-environment interactions, such as epi-genetic studies or twin analyses, including omics and early life exposure data. Importantly, research should have relevance to clinical and public health translation including clinical practice, asthma management guidelines and intervention studies aimed at reducing comorbidities.

BACKGROUND: Maternal psychological stress during pregnancy and postnatally has been shown to be associated with offspring atopic diseases (asthma, atopic dermatitis and allergic rhinitis). The aim of this study was to assess whether this association may be attributable to the child's own mental health disorders.

METHOD: The study population included 15,092 twin children born 2002-2010 in Sweden. Questionnaire data at age 9 years was linked to national patient- and prescription registers. Maternal mental health during pregnancy and 3 years postnatally were identified from diagnosis and medication data (depression, anxiety and stress disorders). Atopic diseases in children were identified from questionnaires, diagnosis and medication data. Child mental health status (depression and anxiety) was identified from questionnaires. Three-way decomposition methods tested for mediation or interaction by child mental health disorders.

RESULTS: Maternal mental health disorders were associated with most child atopic diseases including asthma aRR1.36 (95% CI 1.12, 1.60), and child mental health disorders, aRR1.73 (95% CI 1.56, 1.92). Children with mental health disorders were comorbid for atopic diseases with only asthma reaching statistical significance, aRR1.29 (95% CI 1.14, 1.47). Three-way decomposition found that mediation or interaction by child mental health disorders did not account for the mother mental health and child atopy associations except in parent-report asthma, where child mental health disorders mediated 13.4% (95% CI 2.1, 24.7) of the effect, but not for objectively defined (diagnosis and medication) asthma.

CONCLUSION: The associations between maternal mental health and child asthma and allergic diseases do not appear to be attributable to child mental health disorders.

Background: Developmental Origins of Health and Disease Hypothesis (DOHaD) studies are often observational in nature and are therefore prone to biases from loss to follow-up and unmeasured confounding. Register-based studies can reduce these issues since they allow almost complete follow-up and provide information on fathers that can be used in a negative control analysis to assess the impact of unmeasured confounding.

Aim: The aim of this study was to propose a causal model for testing DOHaD using paternal exposure as a negative control, and its application to maternal distress in pregnancy and offspring asthma.

Methods: A causal diagram including shared and parent-specific measured and unmeasured confounders for maternal (fetal) and paternal exposures is proposed. The case study consisted of all children born in Sweden from July 2006 to December 2008 (n=254,150). Information about childhood asthma, parental distress and covariates was obtained from the Swedish national health registers. Associations between maternal and paternal distress during pregnancy and offspring asthma at age five years were assessed separately and with mutual adjustment for the other parent's distress measure, as well as for shared confounders.

Results: Maternal distress during pregnancy was associated with offspring asthma risk; mutually adjusted odds ratio (OR) (OR 1.32, 95% CI 1.23, 1.43). The mutually adjusted paternal distress-offspring asthma analysis (OR 1.05, 95% CI 0.97, 1.13) indicated no evidence for unmeasured confounding shared by the mother and father.

Conclusions: Using paternal exposure in a negative control model to test the robustness of fetal programming hypotheses can be a relatively simple extension of conventional observational studies but limitations need to be considered.

BACKGROUND: Children with asthma and atopic diseases have an increased risk of depression or anxiety. Each of these diseases have strong genetic and environmental components, therefore it seems likely that there is a shared liability rather than causative risk.

OBJECTIVE: To investigate the existence and nature of familial aggregation for the comorbidity of atopic diseases and depression or anxiety.

METHODS: Participants came from the Childhood and Adolescent Twin Study in Sweden (CATSS), n= 14197. Current and ever asthma, eczema, hayfever and food-allergy were reported by parents. Internalizing disorders were identified using validated questionnaires. Familial co-aggregation analysis compared monozygotic MZ twins and same-sex dizygotic DZ twins for atopic disease in one twin with internalizing disorder in the other to test for genetic liability. Several familial liability candidates were also tested including parental education, recent maternal psychological stress, childhood family trauma and parental country of birth.

RESULTS: Familial co-aggregation analysis found that if one twin had at least one current atopic disease the partner twin was at risk of having an internalizing disorder regardless of their own atopic status (Adjusted OR 1.22 (95% CI 1.08, 1.37). Similar results were found for each atopic disease ever and current. MZ associations were not higher than DZ associations suggesting that the liability is not genetic in nature. Including other familial candidates to the models made little difference to effect estimates.

CONCLUSIONS AND CLINICAL RELEVANCE: Atopic diseases and depression or anxiety tend to occur together in families, therefore when treating for one disease the physician should consider comorbidity in both the individual and the individual's siblings. We did not find evidence to support a genetic explanation for comorbidity and further exploration is needed to disentangle the environmental and epigenetic reasons for familial aggregation.

Background: Previous research has found that maternal stress during pregnancy increases the risk of offspring asthma. However, whether this association is consistent with a causal interpretation has never been tested. The objective is to determine whether there is a critical exposure period for maternal depression or anxiety on offspring asthma or whether cumulative exposure is most important, and to investigate evidence of confounding.

Methods: The study population included all children born in Sweden from July 2006 to December 2009 (n = 360 526). Information about childhood asthma, maternal depression or anxiety (diagnosis or medication) and covariates was obtained from the Swedish national health registers. The associations between exposure periods (pre-conception, pregnancy, postnatal or current) and childhood asthma were estimated using structured life course approach hypothesis testing. Paternal and cousin analyses were used to test for evidence of confounding from shared genes and environment.

Results: For childhood asthma, cumulative exposure best described the effect of exposure to maternal depression or anxiety up to a maximum of any two exposure periods [adjusted odds ratio 1.44, 95% confidence interval (CI) 1.38, 1.52]. The hypotheses of a critical period were not supported. The paternal and cousin analyses indicated minimal influence from familial confounding.

Conclusions: These findings support an association between cumulative exposure to maternal depression or anxiety and asthma development in offspring. This association is unique for maternal depression or anxiety and not due to familial confounding. The clinical implication is that effective psychological management of women with chronic distress may reduce offspring asthma risk.

It is increasingly recognized that children with asthma are at a higher risk of other non-allergic concurrent diseases than the non-asthma population. A plethora of recent research has reported on these comorbidities and progress has been made in understanding the mechanisms for comorbidity. The goal of this review was to assess the most recent evidence (2016-2021) on the extent of common comorbidities (obesity, depression and anxiety, neurodevelopmental disorders, sleep disorders and autoimmune diseases) and the latest mechanistic research, highlighting knowledge gaps requiring further investigation. We found that the majority of recent studies from around the world demonstrate that children with asthma are at an increased risk of having at least one of the studied comorbidities. A range of potential mechanisms were identified including common early life risk factors, common genetic factors, causal relationships, asthma medication and embryologic origins. Studies varied in their selection of population, asthma definition and outcome definitions. Next, steps in future studies should include using objective measures of asthma, such as lung function and immunological data, as well as investigating asthma phenotypes and endotypes. Larger complex genetic analyses are needed, including genome-wide association studies, gene expression-functional as well as pathway analyses or Mendelian randomization techniques; and identification of gene-environment interactions, such as epi-genetic studies or twin analyses, including omics and early life exposure data. Importantly, research should have relevance to clinical and public health translation including clinical practice, asthma management guidelines and intervention studies aimed at reducing comorbidities.

Background: Attention-deficit/hyperactivity disorder (ADHD) affects 10–30% of children with epilepsy, making it one of the most common comorbidities in epilepsy. Stimulant medications are first line pharmacological treatment of ADHD, yet there areconcerns regarding the safety of stimulant treatment in patients with comorbid ADHD and epilepsy. This is due to the long held view that stimulants may lower the seizure threshold and increase seizure frequency [1]. Evidence for such an effect are however inconsistent and largely based on studies with small sample sizes, highly selected patient populations and observational studies that have not sufficiently addressed issues of confounding [2]. The aim of this pharmacoepidemiological register based study wastherefore to estimate the risk of seizures in relation to ADHD medication use in a population based cohort of individuals with a history of seizures.

Methods: Using Swedish national registers, we identified a cohort of 62,361 individuals (48% female) born in Sweden between 1960 and 2004, with at least one seizure episode according to ICD codes. Each individual was followed from January 1st 2006, their first seizure or age five, up until December 31st 2013 or death, whichever came first. We identified periods of ADHD medication use (methylphenidate, amphetamine, dexamphetamine, lisdexamfetamine, and atomoxetine) from the Swedish National Prescribed Drug Register. A period was defined as on-medication when two consecutive prescriptions where no more than 183 days apart, and off-medication if more than 183 daysapart. We obtained information on medical visit for unplanned seizures events from the Swedish National Patient register using ICD codes. We estimated the population level association between ADHD medications and the rate of seizures during medicated and non-medication periods using a cox proportional hazards regression model. To adjust for individual-specific confounding that may influence both seizure risk and the likelihood of receiving ADHD medication, we used a stratified Cox regression model to estimate the rate of seizures during medicated and non-medicated periods, within the same individual.

Preliminary Result: A total of 59,749 seizure events occurred during 361,501 person years of follow-up. ADHD medications were not associated with the rate of seizures at the population level (HR = 1.06, 95%CI 0.91–1.23). In the within-individual analysis, ADHD medication periods were associated with a reduced rate of seizures (HR = 0.70, 95%CI 0.62–0.79), compared to non-medicated periods. Estimates did not differ across sex, nor in age restricted analyses including only ages 5 and 20 years. All analyses were adjusted for age as a time-varying covariate. Population level analyses were additionally adjusted for sex.

Conclusions: Our findings suggest that ADHD medications are not associated with an increased risk of seizures. Rather, results from the within-individual analysis, which adjusts for factors that are constant within the individual, such as genetic factors and underlying disorder severity, suggest a protective effect of ADHD medication treatment on seizure rates. Next, we will study the effect of concurrent antiepileptic medication use and whether the observed effect differs by stimulant and non-stimulant ADHD medications. We will also further investigate possible mechanisms contributing to the observed protective effect of ADHD medications on seizure rates.

References

[1] Williams, A.E., Giust, J.M., Kronenberger, W.G., Dunn, D.W., 2016. Epilepsy and attention-deficit hyperactivity disorder: links, risks, and challenges. Neuropsychiatr Dis Treat 12, 287–296.

[2] Ravi, M., Ickowicz, A., 2016. Epilepsy, Attention-Deficit/Hyperactivity Disorder and Methylphenidate: Critical Examination of Guiding Evidence. Journal of the Canadian Academy of Child and Adolescent Psychiatry 25 (1), 50.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) affects 10%-30% of individuals with epilepsy, yet concerns remain regarding the safety of ADHD medication in this group. The objective of this study was to examine the risk of acute seizures associated with ADHD medication in individuals with epilepsy.

METHODS: A total of 21 557 individuals with a seizure history born between 1987 and 2003 were identified from Swedish population registers. Within this study population, we also identified 6773 youth (<19 years of age) who meet criteria for epilepsy, and 1605 youth with continuous antiepileptic drug (AED) treatment. ADHD medication initiation and repeated medication periods were identified from the Swedish Prescribed Drug Register between January 1, 2006 and December 31, 2013. Acute seizures were identified via unplanned visits to hospital or specialist care with a primary seizure discharge diagnosis in the Swedish National Patient Register during the same period. Conditional Poisson regression was used to compare the seizure rate during the 24 weeks before and after initiation of ADHD medication with the rate during the same 48 weeks in the previous year. Cox regression was used to compare the seizure rate during ADHD medication periods with the rate during nonmedication periods. Comparisons were made within-individual to adjust for unmeasured, time?constant confounding.

RESULTS: Among 995 individuals who initiated ADHD medication during follow-up, within-individual analyses showed no statistically significant difference in the rate of seizures during the 24 weeks before and after medication initiation, compared to the same period in the previous year. In the full study population 11 754 seizure events occurred during 136 846 person-years and 1855 individuals had at least one ADHD medication period. ADHD medication periods were associated with a reduced rate of acute seizures (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.57-0.94), compared to nonmedication periods within the same individual. Similar associations were found in youth with epilepsy and continuous AED treatment, when adjusting for AEDs, and across sex, age, and comorbid neurodevelopmental disorders.

SIGNIFICANCE: We found no evidence for an overall increased rate of acute seizures associated with ADHD medication treatment among individuals with epilepsy. These results suggest that epilepsy should not automatically preclude patients from receiving ADHD medications.