Adolescent Twin Study Research Articles

Association between bullying victimization and obsessive-compulsive disorder: a population-based, genetically informative study.

The extent to which bullying victimization is associated with an increased risk of obsessive-compulsive disorder (OCD) has received little empirical attention. This longitudinal, population-based, genetically informative study examined whether self-reported bullying victimization at age 15 was associated with a clinical diagnosis of OCD in the Swedish National Patient Register and with self-reported obsessive-compulsive symptoms (OCS) at ages 18 and 24 in 16,030 twins from the Child and Adolescent Twin Study in Sweden. Using a discordant twin design, including monozygotic (MZ) and dizygotic (DZ) twins, each twin was compared with their co-twin, allowing a strict control of genetic andenvironmental confounding. At the population level, adjusting for birth year and sex, each standard deviation (SD) increase in bullying victimization was associated with a 32% increase in the odds of an OCD diagnosis (OR, 1.32; 95% CI, 1.21-1.44), of 0.13 SD in OCS at age 18 (β, 0.13; 95% CI, 0.11-0.16), and of 0.11 SDin OCS at age 24 (β, 0.11; 95% CI, 0.07-0.16). While associations tended to persist in the within DZ-twin comparison models, the estimates attenuated and were no longer statistically significant in the within MZ-twin comparisons. These results suggest that the association between bullying victimization and OCD/OCS is likely due to genetic confounding and therefore incompatible with a strong causal effect. Other mechanisms, such as evocative gene-environment correlations, are more plausible explanations for the observed associations.

Trends in Body Mass Index Among Individuals With Neurodevelopmental Disorders

Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are increasingly common. Individuals with NDDs have heightened obesity risks, but long-term data on body mass index (BMI) trends over time in this population are lacking. To assess secular BMI changes from 2004 to 2020 among children with NDDs compared with those without NDDs. This repeated cross-sectional study used data from the Child and Adolescent Twin Study in Sweden. Children born between January 1, 1992, and December 31, 2010, were screened for neurodevelopmental symptoms using the Autism-Tics, ADHD, and Other Comorbidities inventory between July 2004 and April 2020 when they were 9 or 12 years of age. Data analysis was conducted between September 27, 2023, and January 30, 2024. BMI percentiles (15th, 50th, and 85th) were modeled using quantile regression and compared between youths with and without NDDs. Secular changes in BMI percentiles over time spanning 2004 to 2020 were evaluated and stratified by NDD subtype. The cohort included 24 969 Swedish twins (12 681 [51%] boys) born between 1992 and 2010, with mean (SD) age of 9 (0.6) years. Of these, 1103 (4%) screened positive for 1 or more NDDs, including ADHD, ASD, and/or learning disability. Results indicated that at the 85th BMI percentile, there was a greater increase in BMI from 2004 to 2020 among youths with NDDs compared with those without NDDs (β for interaction [βint] between NDD status and time, 1.67; 95% CI, 0.39-2.90). The greatest divergence was seen for ASD (βint, 2.12; 95% CI, 1.26-3.70) and learning disability (βint, 1.92; 95% CI, 0.65-3.82). Within the latest cohort (2016-2020), the 85th BMI percentile was 1.99 (95% CI, 1.08-2.89) points higher among children with NDDs compared with those without NDDs. In this repeated cross-sectional study, at the higher end of the BMI distribution, children with NDDs had significantly greater increases in BMI compared with peers without NDDs over a 16-year period, highlighting an increasing risk of overweight over time in youths with NDDs compared with those without NDDs. Targeted obesity prevention efforts for this high-risk population are needed.

Changes in parental attitudes toward attention-deficit/hyperactivity disorder impairment over time.

Over the last decades, the prevalence of Attention-deficit/hyperactivity disorder (ADHD) has increased. However, the underlying explanation for this increase remains unclear. We aimed to assess whether there has been a secular change in how parents perceive the impairment conferred by ADHD symptomatology. Data for this study were obtained from the Child and Adolescent Twin Study in Sweden, involving 27,240 individuals whose parents answered a questionnaire when the children were 9years old. We assessed the relationship between parentally perceived impairment caused by ADHD symptoms scores over time. The analysis was performed separately for five different birth cohorts, spanning three-year periods from 1995 to 2009 and for ADHD inattention and hyperactivity/impulsivity dimensions. We found a consistent upward trend of parents reporting impairment in relation to ADHD symptomatology across birth cohorts. Over a 12-year period, comparing those born 2007-2009 (assessed 2016-2018) with those born 1995-1997 (assessed 2004-2006), impairment scores increased by 27% at clinically relevant levels of ADHD symptomatology. Notably, when specifically evaluating the hyperactivity/impulsivity dimension, the disparity was even more striking, with an increase of up to 77%. This study revealed a significant secular change in parental perception of impairment attributed to ADHD symptomatology over recent decades, providing new insights into the increased prevalence of ADHD. It underscores the need to better understand the factors that have contributed to the increased perception of impairment related to ADHD symptoms.

Prevalence and heritability of parental-reported speech and/or language difficulties in a Swedish population-based twin sample.

Research on genetic and environmental influences on speech and/or language difficulties (SaLD) is sparse, with inconsistent heritability estimates. We aimed to estimate the prevalence of parental reported SaLD and the relative contributions of genetic and environmental factors for the phenotype using a Swedish population-based twin sample. We hypothesized that there would be a stronger genetic than environmental effect on SaLD. Data were collected from The Child and Adolescent Twin Study in Sweden. The study sample included 16,774 twin pairs (16,946 males, 16,602 females), of which 5141 were monozygotic, 5861 dizygotic (DZ), and 5772 opposite-sex DZ pairs. The language items in the Autism-Tics, Attention-Deficit Hyperactivity Disorder, and other Comorbidities inventory were used to categorize individuals as having parental-reported SaLD. A classical twin design was used to estimate the relative contribution of genetic and environmental factors to the liability of SaLD. The prevalence of SaLD was 7.85% (95% confidence interval (CI) [7.57%-8.15%]) and 7.27% (95% CI [6.99%-7.55%]) when excluding individuals with autism and intellectual disability (ID). We also found that SaLD were significantly more prevalent in males than females with a ratio of 2:1. The heritability was estimated to be 75% (95% CI [67%-83%]) for SaLD. Shared environment played a significant role with an estimated contribution of 22% (95% CI [14%-30%]). The heritability estimate was reduced to 70% but with overlapping CI when excluding individuals with autism and ID. We provide evidence that SaLD is common in the population and under strong genetic influence. Future studies should focus on mapping the genetic architecture of SaLD and related disorders.

Differential genetic associations between dimensions of eating disorders and alcohol involvement in late adolescent twins.

Twin studies have demonstrated shared genetic and environmental effects between eating disorders and alcohol involvement in adults and middle adolescents. However, fewer studies have focused on late adolescents or investigated a wide range of eating disorder dimensions and alcohol involvement subscales in both sexes. We examined genetic and environmental correlations among three eating disorder dimensions and two alcohol involvement subscale scores in late adolescent twins using bivariate twin models. Participants were 3568 female and 2526 male same-sex twins aged 18 years old from the Child and Adolescent Twin Study in Sweden. The Eating Disorder Inventory-2 (EDI) assessed the drive for thinness, bulimia, and body dissatisfaction. Alcohol involvement was assessed with the Alcohol Use Disorder Identification Test consumption (AUDIT-C) and problem (AUDIT-P) subscales. Only phenotypic and twin correlations in female twins met our threshold for twin modeling. The proportion of total variance for each trait accounted for by additive genetic factors ranged from 0.50 to 0.64 in female twins, with the rest explained by nonshared environmental factors and measurement error. Shared environmental factors played a minimal role in the variance of each trait. The strongest genetic correlation (ra ) emerged between EDI bulimia and AUDIT-P (ra = 0.46, 95% confidence interval: 0.37, 0.55), indicating that the proportion of genetic variance of one trait that was shared with the other trait was 0.21. Nonshared environmental correlations between eating disorder dimensions and alcohol involvement ranged from 0.03 to 0.13. We observed distinct patterns of genetic and environmental effects for co-occurring eating disorder dimensions and alcohol involvement in female vs. male twins, supporting sex-specific treatment strategies for late adolescents with comorbid eating disorders and alcohol use disorder. Our findings emphasize the importance of assessing family history of multiple eating disorder dimensions while treating late adolescents with problematic alcohol use, and vice versa, to improve detection and treatment.

A twin study of genetic and environmental contributions to attention-deficit/hyperactivity disorder over time.

Attention-deficit/hyperactivity disorder (ADHD) is an increasingly commonly diagnosed neurodevelopmental condition. One possibility is that this reflects a genuine increase in the prevalence of ADHD due to secular environmental changes, yet this hypothesis remains untested. We therefore investigated whether the genetic and environmental variance underlying ADHD, and traits of ADHD, has changed over time. We identified twins born from 1982 to 2008 from the Swedish Twin Registry (STR). We linked the STR with the Swedish National Patient Register and Prescribed Drug Register to identify diagnoses of ADHD and prescriptions of ADHD medication for these twins. We also utilized data collected from participants in the Child and Adolescent Twin Study in Sweden (CATSS), born from 1992 to 2008. Their parents completed a structured ADHD screening tool, which was used to measure traits of ADHD and assign broad screening diagnoses of ADHD. We used the classical twin design to test whether the degree to which variation in these measures was influenced by genetic and environmental variation changed over time. We included 22,678 twin pairs from the STR and 15,036 pairs from CATSS. The heritability of ADHD in the STR ranged from 66% to 86% over time, although these fluctuations were not statistically significant. We observed a modest increase in variance in ADHD traits, from 0.98 to 1.09. This was driven by small increases in the underlying genetic and environmental variance, with heritability estimated as 64%-65%. No statistically significant changes in variance in screening diagnoses were observed. The relative contribution of genetic and environmental factors to ADHD has remained stable over time, despite its increasing prevalence. Thus, changes in the underlying etiology of ADHD over time are unlikely to explain the increase in ADHD diagnoses.

Prevalence and heritability of alcohol use disorders in 18-year old Swedish twins.

Background: Heritability of alcohol use disorders (AUDs) varies widely, with reported estimates of 30-78% in twin studies. This variation might be due to methodological differences (e.g., using different thresholds for AUDs, age differences between samples). Aim: To investigate the heritability of AUDs in a nation-wide sample of male and female twins in late adolescence (18 years). Participants: The study is based on data from 8,330 18-year-old Swedish monozygotic (MZ) and dizygotic (DZ) twins from the Child and Adolescent Twin Study (Sweden). Method: Univariate sex-limitation twin analyses were performed using (a) total AUDIT score, (b) different AUDIT cut-offs (AUDIT-10: potentially harmful alcohol use and most likely alcohol dependent ; AUDIT-C: potential hazardous alcohol consumption/active alcohol use disorders), and (c) a risk-group classification for alcohol dependence based on AUDIT total score. Results: Prevalence of potential hazardous alcohol consumption/active alcohol use was 57.1%, and for potentially harmful alcohol use prevalence was 26.5%. Prevalence was higher among females (59.0% and 31.1% respectively) than males (54.4% and 20.0% respectively). Overall, the results of the univariate model fitting indicated that there were qualitative sex differences in the genetic and environmental influences on AUDs, with generally moderate heritability estimates ranging between 0.37 and 0.50. Discussion: At odds with previous research, a harmful/hazardous drinking pattern was more common in this age group among females than a low-risk drinking pattern (where males were overrepresented). Heritability estimates were moderate throughout all measures and cut-offs, with equally high contributions from shared and non-shared environment. Sex-limitation models revealed qualitative sex differences for AUDs, suggesting that different genetic and/or environmental factors influence variation in AUDs in males and females.

Genetic and environmental contributions to co-occurring physical health conditions in autism spectrum condition and attention-deficit/hyperactivity disorder

BackgroundAutism spectrum condition and attention-deficit/hyperactivity disorder (ADHD) are associated with a range of physical health conditions. The aim of this study was to examine the etiological components contributing to co-occurring physical health conditions in autism and ADHD.MethodsIn this nationwide Child and Adolescent Twin Study in Sweden, we analyzed data from 10,347 twin pairs aged 9 and 12. Clinical diagnoses of autism, ADHD, and physical health conditions were identified through the Swedish National Patient Register. Subclinical phenotypes of autism and ADHD were defined by symptom thresholds on a standardized parent-interview, the Autism–Tics, ADHD, and Other Comorbidities inventory. Associations between physical health conditions and autism/ADHD phenotypes were examined using generalized estimating equations. Bivariate twin models were applied to estimate the extent to which genetic and environmental risk factors accounted for physical health comorbidities.ResultsSimilar patterns of association with physical health conditions were found in clinical and subclinical autism/ADHD, with odds ratios ranging from 1.31 for asthma in subclinical ADHD to 8.03 for epilepsy in clinical autism. The estimated genetic correlation (ra) with epilepsy was 0.50 for clinical autism and 0.35 for subclinical autism. In addition, a modest genetic correlation was estimated between clinical autism and constipation (ra = 0.31), functional diarrhea (ra = 0.27) as well as mixed gastrointestinal disorders (ra = 0.30). Genetic effects contributed 0.86 for mixed gastrointestinal disorders in clinical ADHD (ra = 0.21). Finally, subclinical ADHD shared genetic risk factors with epilepsy, constipation, and mixed gastrointestinal disorders (ra = 0.30, 0.17, and 0.17, respectively).LimitationsImportantly, since medical records from primary care were not included in the registry data used, we probably identified only more severe rather than the full range of physical health conditions. Furthermore, it needs to be considered that the higher prevalence of physical health conditions among autistic children and children with ADHD could be associated with the increased number of medical visits.ConclusionsShared genetic effects contribute significantly to autism and ADHD phenotypes with the co-occurring physical health conditions across different organ systems, including epilepsy and gastrointestinal disorders. The shared genetic liability with co-occurring physical health conditions was present across different levels of autism and ADHD symptom severity.

Etiology of the Broad Avoidant Restrictive Food Intake Disorder Phenotype in Swedish Twins Aged 6 to 12 Years

Avoidant restrictive food intake disorder (ARFID) is characterized by an extremely limited range and/or amount of food eaten, resulting in the persistent failure to meet nutritional and/or energy needs. Its etiology is poorly understood, and knowledge of genetic and environmental contributions to ARFID is needed to guide future research. To estimate the extent to which genetic and environmental factors contribute to the liability to the broad ARFID phenotype. This nationwide Swedish twin study includes 16 951 twin pairs born between 1992 and 2010 whose parents participated in the Child and Adolescent Twin Study in Sweden (CATSS) at twin age 9 or 12 years. CATSS was linked to the National Patient Register (NPR) and the Prescribed Drug Register (PDR). Data were collected from July 2004 to April 2020, and data were analyzed from October 2021 to October 2022. From CATSS, NPR, and PDR, all parent reports, diagnoses, procedures, and prescribed drugs that were relevant to the DSM-5 ARFID criteria were extracted when twin pairs were aged 6 to 12 years and integrated into a composite measure for the ARFID phenotype (ie, avoidant/restrictive eating with clinically significant impact, such as low weight or nutritional deficiency, and with fear of weight gain as an exclusion). In sensitivity analyses, autism and medical conditions that could account for the eating disturbance were controlled for. Univariate liability threshold models were fitted to estimate the relative contribution of genetic and environmental variation to the liability to the ARFID phenotype. Of 33 902 included children, 17 151 (50.6%) were male. A total of 682 children (2.0%) with the ARFID phenotype were identified. The heritability of ARFID was 0.79 (95% CI, 0.70-0.85), with significant contributions from nonshared environmental factors (0.21; 95% CI, 0.15-0.30). Heritability was very similar when excluding children with autism (0.77; 95% CI, 0.67-0.84) or medical illnesses that could account for the eating disturbance (0.79; 95% CI, 0.70-0.86). Prevalence and sex distribution of the broad ARFID phenotype were similar to previous studies, supporting the use of existing epidemiological data to identify children with ARFID. This study of the estimated genetic and environmental etiology of ARFID suggests that ARFID is highly heritable, encouraging future twin and molecular genetic studies.

A genetically informed prediction model for suicidal and aggressive behaviour in teens

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

Intergenerational transmission of psychopathology: An examination of symptom severity and directionality.

The present study examined the intergenerational transmission of internalizing and externalizing symptom severity, which indexes comorbidity, and symptom directionality, which indicates differentiation toward externalizing versus internalizing problems. Data are from 854 male and female, same-sex adult twin pairs born between 1926 and 1971 (32-60 years old, M = 44.9 years, SD = 4.9 years) from the Twin and Offspring Study in Sweden and their adolescent offspring (11-22 years old, M = 15.7 years, SD = 2.4 years, 52% female). Children-of-twins models revealed additive (9%) and dominant (45%) genetic and nonshared environmental (47%) influences on twins' symptom severity, and additive genetic (39%) and nonshared environmental (61%) influences on twins' symptom directionality. Both comorbid problems and preponderance of symptoms of a particular - internalizing versus externalizing - spectrum were correlated across parent and child generations, although associations were modest especially for directionality (i.e., transmission of specific symptom type). By interpreting findings alongside a recent study of adolescent twins, we demonstrate that the intergenerational transmission of symptom severity and symptom directionality are both unlikely to be attributable to genetic transmission, are both likely to be influenced by direct phenotypic transmission and/or nonpassive rGE, and the intergenerational transmission of symptom severity is also likely to be influenced by passive rGE.

Examining protective factors for substance use problems and self-harm behavior during adolescence: A longitudinal co-twin control study.

Sports participation, physical activity, and friendship quality are theorized to have protective effects on the developmental emergence of substance use and self-harm behavior in adolescence, but existing research has been mixed. This ambiguity could reflect, in part, the potential for confounding of observed associations by genetic and environmental factors, which previous research has been unable to rigorously rule out. We used data from the prospective, population-based Child and Adolescent Twin Study in Sweden (n = 18,234 born 1994-2001) and applied a co-twin control design to account for potential genetic and environmental confounding of sports participation, physical activity, and friendship quality (assessed at age 15) as presumed protective factors for adolescent substance use and self-harm behavior (assessed at age 18). While confidence intervals widened to include the null in numerous co-twin control analyses adjusting for childhood psychopathology, parent-reported sports participation and twin-reported positive friendship quality were associated with increased odds of alcohol problems and nicotine use. However, parent-reported sports participation, twin-reported physical activity, and twin-reported friendship quality were associated with decreased odds of self-harm behavior. The findings provide a more nuanced understanding of the risks and benefits of putative protective factors for risky behaviors that emerge during adolescence.

Heritability of Psychotic Experiences in Adolescents and Interaction With Environmental Risk

Genetic risk factors are known to play a role in the etiology of psychotic experiences in the general population. Little is known about whether these risk factors interact with environmental risks for psychotic experiences. To assess etiological heterogeneity and exposure to environmental risks associated with psychotic experiences in adolescence using the twin design. This twin study, conducted from December 1, 2014, to August 31, 2020, included a UK-based sample of twin pairs aged 16 years. This investigation evaluated the extent to which the genetic variance underlying psychotic experiences and the magnitude of the heritability of psychotic experiences was moderated by exposure to 5 environmental risk factors (bullying, dependent life events, cannabis use, tobacco use, and low birth weight). Psychotic experiences were assessed by 5 self-reported measures and 1 parent-reported measure. Participants' exposure to environmental risks was assessed at birth and age 12 to 16 years. Structural equation models were used to assess differences in the variance in and heritability of psychotic experiences across these exposures, while controlling for gene-environment correlation effects. Analyses were repeated in an independent Swedish sample. Data analyses were performed from September 1, 2018, to August 31, 2020. Primary outcome measures were exposure to environmental factors, as measured by a composite score, and psychotic experiences. A total of 4855 twin pairs (1926 female same-sex pairs, 1397 male same-sex pairs, and 1532 opposite-sex pairs) were included from the Twins Early Development Study (TEDS), and 6435 twin pairs (2358 female same-sex pairs, 1861 male same-sex pairs, and 2216 opposite-sex pairs) were included from the Child and Adolescent Twin Study in Sweden (CATSS). Mean age of twins from TEDS was 16.5 years. Mean age of twins from CATSS was 18.6 years. More exposure to environmental risk factors was associated with having more psychotic experiences. The relative contribution of genetic influences to psychotic experiences was lower with increasing environmental exposure for paranoia (44%; 95% CI, 33%-53% to 38%; 95% CI, 14%-58%), cognitive disorganization (47%; 95% CI, 38%-51% to 32%; 95% CI, 11%-45%), grandiosity (41%; 95% CI, 29%-52% to 32%; 95% CI, 9%-48%), and anhedonia (49%; 95% CI, 42%-53% to 37%; 95% CI, 15%-54%). This pattern was replicated for the measure of psychotic experiences in the independent Swedish replication sample. The heritability of hallucinations and parent-rated negative symptoms remained relatively constant. Findings of this twin study suggest that environmental factors play a greater role in the etiology of psychotic experiences than genetic factors. The relative importance of environmental factors is even higher among individuals exposed to environmental risks for psychotic experiences, highlighting the importance of a diathesis-stress or bioecological framework for understanding adolescent psychotic experiences.

Measuring autism in males and females with a differential item functioning approach: Results from a nation-wide population-based study

Existing screening instruments for Autism Spectrum Disorder (ASD) might be prone to detect a male manifestation of ASD. Here, we examined the 17 items from the ASD domain in the Autism–Tics, ADHD and other Comorbidities inventory (A–TAC) for Differential Item Functioning (DIF). Data were obtained from the Child and Adolescent Twin Study in Sweden (CATSS) in which parents have responded to the A–TAC. Information regarding a registered diagnosis of ASD were retrieved from the National Patient Register. The cohort was divided into a developmental sample for evaluation of DIF, and a validation sample for examination of the diagnostic accuracy of the total ASD domain, and a novel male and female short form. Our main finding included the identification of DIF for six items, three favouring males and three favouring females. The full, 17 item, ASD domain and the male and female short form showed excellent ability to capture ASD diagnoses in both males and females up to the age of nine years. The full ASD domain in A–TAC is psychometrically largely equivalent across sex and the limited differences between males and females diminish the need for a sex-specific scoring when utilizing the 17 item total score.

Association of Obsessive-Compulsive Disorder and Obsessive-Compulsive Symptoms With Substance Misuse in 2 Longitudinal Cohorts in Sweden

Neurobiological models have postulated shared neural mechanisms between obsessive-compulsive disorder (OCD) and substance use disorders, but results from clinical and epidemiological studies are conflicting or even suggest that OCD may be protective against substance misuse. To investigate whether OCD and obsessive-compulsive symptoms are associated with substance misuse and the extent to which shared genetic and/or environmental factors account for this association. In this cohort study, individuals in the general population of Sweden born between January 1, 1932, and December 31, 1997 (population cohort), were followed up through Swedish nationwide registers from January 1, 1997, to December 31, 2013. The second cohort included twin participants in the Child and Adolescent Twin Study in Sweden (CATSS) followed up from ages 18 to 24 years. Data were analyzed from March 1, 2021, to March 31, 2022. Lifetime International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnosis of OCD in the National Patient Register (population cohort 1), and self-reported obsessive-compulsive symptoms at 18 years of age (CATSS cohort). Substance misuse was defined as registered substance use-related disorder, criminal conviction, or death (population cohort), and self-reported alcohol and drug dependence symptoms at 18 and 24 years of age (CATSS cohort). The general population cohort included 6 304 188 individuals (48.9% women and 51.1% men; median baseline age, 30.5 [IQR, 15.0-46.4] years), of whom 27 342 had an OCD diagnosis. Obsessive-compulsive disorder was associated with an elevated risk of substance misuse (hazard ratio, 3.68 [95% CI, 3.52-3.85]). In the 9230 individuals in the CATSS cohort (5551 women [60.1%] and 3679 men [39.9%]), obsessive-compulsive symptoms at 18 years of age were associated with increased symptoms of alcohol dependence (concurrent [n = 9219], β = 0.18 [95% CI, 0.16-0.20]; longitudinal [n = 3381], β = 0.10 [95% CI, 0.06-0.14]) and drug dependence (concurrent [n = 749], β = 0.19 [95% CI, 0.11-0.27]; longitudinal [n = 452], β = 0.15 [95% CI, 0.04-0.25]). Comorbid anxiety and depression did not entirely explain the associations in either cohort. Using data from full siblings and maternal half-siblings (population cohort) and monozygotic and dizygotic twins (CATSS cohort) provided estimates of the relative contribution of genetic and environmental influences to the covariance between OCD and obsessive-compulsive symptoms and substance misuse or dependence. The associations were explained by genetic (56%-68%) and nonshared environmental (32%-44%) factors. The findings of this Swedish population-based cohort study challenge the notion that OCD is protective against developing substance misuse. The association of OCD and obsessive-compulsive symptoms with substance misuse was largely explained by shared genetics but was also compatible with partial environmental mediation.

LARGE-SCALE INTEGRATION OF DNA METHYLATION AND GENE EXPRESSION ARRAY PLATFORMS IDENTIFIES BOTH cis AND trans RELATIONSHIPS

ABSTRACT Although epigenome-wide association studies (EWAS) have been successful in identifying DNA methylation (DNAm) patterns associated with disease states, any further characterization of etiologic mechanisms underlying disease remains elusive. This knowledge gap does not originate from a lack of DNAm-trait associations, but rather stems from study design issues that affect the interpretability of EWAS results. Despite known limitations in predicting the function of a particular CpG site, most EWAS maintain the broad assumption that altered DNAm results in a concomitant change of transcription at the most proximal gene. This study integrated DNAm and gene expression (GE) measurements in two cohorts, the Adolescent and Young Adult Twin Study (AYATS) and the Pregnancy, Race, Environment, Genes (PREG) study, to improve the understanding of epigenomic regulatory mechanisms. CpG sites associated with GE in cis were enriched in areas of transcription factor binding and areas of intermediate-to-low CpG density. CpG sites associated with trans GE were also enriched in areas of known regulatory significance, including enhancer regions. These results highlight issues with restricting DNAm-transcript annotations to small genomic intervals and question the validity of assuming a cis DNAm-GE pathway. Based on these findings, the interpretation of EWAS results is limited in studies without multi-omic support and further research should identify genomic regions in which GE-associated DNAm is overrepresented. An in-depth characterization of GE-associated CpG sites could improve predictions of the downstream functional impact of altered DNAm and inform best practices for interpreting DNAm-trait associations generated by EWAS.

Childhood-onset versus adolescent-onset anxiety and depression: Epidemiological and neurodevelopmental aspects

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

Internalizing symptoms in adolescence are modestly affected by symptoms of anxiety, depression, and neurodevelopmental disorders in childhood

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

Association of cumulative early medical factors with autism and autistic symptoms in a population-based twin sample

Although highly heritable, environment also contributes to the etiology of autism spectrum disorder (ASD), with several specific environmental factors previously suggested. A registry-linked population-based twin cohort of 15,701 pairs (586 individuals with an ASD diagnosis), was established within the Child and Adolescent Twin Study in Sweden. Participants were evaluated for autistic symptoms at age 9 using the Autism-Tics, ADHD and other Comorbidities parental interview. A series of binary cut-offs indicated whether participants scored over various ASD symptom percentiles. Three early medical factors previously associated with ASD, beyond familial confounding (low birth weight, congenital malformations and perinatal hypoxia), were summed up creating an individual cumulative exposure load. A series of unconditional logistic regressions between all individuals and conditional regressions within twin pairs were performed for each outcome and exposure level. Between all individuals increasing cumulative early exposure loads were associated with increasing risk of ASD diagnosis (OR 3.33 (95%CI 1.79–6.20) for three exposures) and autistic symptoms (ranging from OR 2.12 (1.57–2.86) for three exposures at the 55th symptom percentile cut-off to OR 3.39 (2.2–5.24) at the 95th). Within twin pairs, the association between three exposures and an ASD diagnosis remained similar, but not statistically significant (OR 2.39 (0.62–9.24)). Having a higher load of early cumulative exposure was consistently associated with autistic symptoms after adjusting for familial confounding and sex (OR 3.45 (1.66–7.15) to OR 7.36 (1.99–27.18)). This study gives support to the cumulative stress hypothesis of ASD, and the dimensional model regarding environmental exposures, after adjustment for familial confounding.

Association of Etiological Factors for Hypomanic Symptoms, Bipolar Disorder, and Other Severe Mental Illnesses

Subsyndromal hypomanic symptoms are relatively common in the general population and are linked to the onset of bipolar disorder. Little is known about their etiology and whether this is shared with the etiology of bipolar disorder or other mental illnesses. To examine the genetic and environmental architecture of hypomanic symptoms in a nonclinical youth sample and compare estimates at varying severity levels and their association with diagnosed bipolar disorder. This cohort study used phenotypic and genetic data from the Child and Adolescent Twin Study in Sweden and included individuals with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis of psychiatric disorders from national registries for residents of Sweden. Associations between hypomania and polygenic risk scores for bipolar disorder, major depressive disorder and schizophrenia were also investigated. Analysis began November 2018 and ended October 2021. Hypomanic symptoms were assessed using the parent-rated Mood Disorders Questionnaire when the twins were aged 18 years. Bipolar disorder diagnosis and/or lithium prescription were ascertained from national registries for residents of Sweden. Polygenic risk scores for psychiatric disorders were calculated using independent discovery genetic data. A total of 8568 twin pairs aged 18 years (9381 [54.7%] female) were included in the study. The hypomania heritability estimate was 59% (95% CI, 52%-64%) for male individuals and 29% (95% CI, 16%-44%) for female individuals. Unique environmental factors accounted for 41% (95% CI, 36%-47%) of the hypomania variance in male individuals and 45% (95% CI, 40%-50%) in female individuals. Shared environmental factors were only detected for female individuals and explained 26% (95% CI, 13%-38%) of the variance. The heritability estimates were fairly consistent across different hypomania severity groups. Moderate genetic (0.40; 95% CI, 0.21-0.58) and shared environmental (0.41; 95% CI, 0.03-0.75) correlations between hypomania and diagnosed bipolar disorder were found. Hypomania was significantly associated with the polygenic risk scores for schizophrenia (β = 0.08; SE = 0.026; P = .002) and major depressive disorder (β = 0.09; SE = 0.027; P = .001) but not bipolar disorder (β = 0.017; SE = 0.03; P = 0.57) (bipolar disorder I [β = 0.014; SE = 0.029; P = .64] or bipolar disorder II [β = 0.045; SE = 0.027; P = .10]). Higher heritability for hypomania was found for male compared with female individuals. The results highlight the shared etiologies between hypomanic symptoms, bipolar disorder, major depression, and schizophrenia in youths. Future research should focus on identifying specific shared genetic and environmental factors. These findings support a possible dimensional model of bipolar disorder, with hypomania representing a continuous trait underlying the disorder.