Genetics of environmental sensitivity to psychiatric and neurodevelopmental phenotypes: evidence from GWAS of monozygotic twins.

Individual sensitivity to environmental exposures may be genetically influenced. This genotype-by-environment interplay implies differences in phenotypic variance across genotypes. However, environmental sensitivity genetic variants have proven challenging to detect. GWAS of monozygotic twin differences is a family-based variance analysis method, which is more robust to systemic biases that impact population-based methods. We combined data from up to 21,792 monozygotic twins (10,896 pairs) from 11 studies to conduct the largest GWAS meta-analysis of monozygotic phenotypic differences in children and adolescents/adults for seven psychiatric and neurodevelopmental phenotypes: attention deficit hyperactivity disorder (ADHD) symptoms, autistic traits, anxiety and depression symptoms, psychotic-like experiences, neuroticism, and wellbeing. The SNP-heritability of variance in these phenotypes were estimated (h2: 0% to 18%), but were imprecise. We identified a total of 13 genome-wide significant associations (SNP, gene, and gene-set), including genes related to stress-reactivity for depression, growth factor-related genes for autistic traits and catecholamine uptake-related genes for psychotic-like experiences. Monozygotic twins are an important new source of evidence about the genetics of environmental sensitivity.

Co-existing mental and somatic conditions in Swedish children with the avoidant restrictive food intake disorder phenotype.

Background: Avoidant restrictive food intake disorder (ARFID) is a feeding and eating disorder, characterized by limited variety and/or quantity of food intake impacting physical health and psychosocial functioning. Children with ARFID often present with a range of psychiatric and somatic symptoms, and therefore consult various pediatric subspecialties; large-scale studies mapping comorbidities are however lacking. To characterize health care needs of people with ARFID, we systematically investigated ARFID-related mental and somatic conditions in 616 children with ARFID and >30,000 children without ARFID. Methods: In a Swedish twin cohort, we identified the ARFID phenotype in 6-12-year-old children based on parent-reports and register data. From >1,000 diagnostic ICD-codes, we specified mental and somatic conditions within/across ICD-chapters, number of distinct per-person diagnoses, and inpatient treatment days between birth and 18th birthday (90 outcomes). Hazard ratios (HR) and incidence rate ratios (IRR) were calculated. Findings: Relative risks of neurodevelopmental, gastrointestinal, endocrine/metabolic, respiratory, neurological, and allergic disorders were substantially increased in ARFID (e.g., autism HR[CI95%]=9.7[7.5-12.5], intellectual disability 10.3[7.6-13.9], gastroesophageal reflux disease 6.7[4.6-9.9], pituitary conditions 5.6[2.7-11.3], chronic lower respiratory diseases 4.9[2.4-10.1], epilepsy 5.8[4.1-8.2]). ARFID was not associated with elevated risks of autoimmune illnesses and obsessive-compulsive disorder. Children with ARFID had a significantly higher number of distinct mental diagnoses (IRR[CI95%]=4.7[4.0-5.4]) and longer duration of hospitalizations (IRR[CI95%]=5.5[1.7-17.6]) compared with children without ARFID. Children with ARFID were diagnosed earlier with a mental condition than children without ARFID. No sex-specific differences emerged. Interpretation: This study yields the broadest and most detailed evidence of co-existing mental and somatic conditions in the largest sample of children with ARFID to date. Findings suggest a complex pattern of health needs in youth with ARFID, underscoring the critical importance of attention to the illness across all pediatric specialties. Funding: Fredrik and Ingrid Thurings Foundation, Mental Health Foundation.

Attention-Deficit/Hyperactivity Disorder and Major Depressive Disorder: Evidence From Multiple Genetically Informed Designs.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) are two highly prevalent disorders that frequently co-occur. Prior evidence from genetic and cohort studies supports an association between ADHD and MDD. However, the direction and mechanisms underlying their association remain unclear. As onset of ADHD occurs in early life, it has been hypothesized that ADHD may cause MDD. METHODS: We examined the association of ADHD with MDD using 3 different genetically informed methods to disentangle causality from confounding: 1) a nationwide longitudinal register-based full sibling comparison (N = 1,018,489) adjusting for shared familial confounding; 2) a prospective co-twin control study comprising 16,477 twins (5084 monozygotic and 11,393 dizygotic); and 3) a two-sample Mendelian randomization analysis using the largest available ADHD (N = 225,534) and MDD (N = 500,199) genome-wide association study summary statistics, adjusting for correlated and uncorrelated horizontal pleiotropy. RESULTS: Sibling and twin comparisons indicated that individuals with ADHD have an increased risk for subsequent development of MDD (hazard ratio = 4.12 [95% CI 3.62-4.69]) after adjusting for shared genetic and familial factors and that ADHD scores endorsed by parents are positively associated with subsequent MDD scores at ages 15 and 18 years (b = 0.07 [95% CI 0.05-0.08] and b = 0.09 [95% CI 0.08-0.11], respectively). Mendelian randomization analyses showed that genetic liability for ADHD is causally related to MDD (odds ratio = 1.15 [95% CI 1.08-1.23]). CONCLUSIONS: Our study provides consistent results across 3 different genetically informative approaches, strengthening the hypothesis that ADHD is causally related to MDD.

The genetics of gaming: A longitudinal twin study.

Background: Gaming is a popular past-time activity among children and adolescents, but it there is also a possible link to negative consequences such as psychological distress and lowered academic achievement. However, there are fundamental knowledge gaps remaining regarding central characteristics of gaming such as heritability, stability over time, and sex differences. We examined the genetic and environmental contribution to gaming behavior, including sex differences, continuity and change, in a longitudinal cohort of twins. Methods: This is the first longitudinal twin study on gaming, involving 32,006 twins in Sweden. Parents were asked about the twins' gaming at ages 9, 15 and 18. We used univariate and multivariate twin analyses to estimate the relative contribution of genetic and environmental influences at each time-point as well as across time. Sex-differences were also explored. Results: The results showed large sex differences, where genetics explained more of the variance for boys (31.3%-62.5% depending on age) than for girls (19.4%-23.4%). Genetic factors explained an increasing amount of the variance for boys (31.3% at age 9, 62.5% at age 15 and 53.9% at age 18). Shared environmental factors explained a larger proportion of the variance among girls, which remained relatively stable over time (70.5% at age 9, 61.8% at age 15 and 60.5% at age 18). The results also indicated that most of the variance came from genetic and environmental sources specific to each age. Conclusions: Compared to many other behavioral phenotypes, such as gambling, gaming was relatively unstable with a large degree of genetic innovation. There were large sex differences in the contribution of genetic and environmental factors. This suggests that excessive gaming could be the result of age- and sex-specific genetic and environmental factors, and should be taken into account when mapping gaming behaviors, since these behaviors might be under continual etiological transformation.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Genetic and environmental architecture of synaesthesia and its association with the autism spectrum-a twin study.

Synaesthesia is a sensory phenomenon where external stimuli, such as sounds or letters, trigger additional sensations (e.g. colours). Synaesthesia aggregates in families but its heritability is unknown. The phenomenon is more common in people on the autism spectrum compared with the general population and associated with higher autistic traits. Using classical twin design, we assessed the heritability of individual differences in self-reported synaesthesia and the genetic and environmental contributions to their association with autistic traits within a population twin cohort (n = 4262, age = 18 years). We estimated individual differences in synaesthesia to be heritable and influenced by environmental factors not shared between twins. The association between individual differences in synaesthesia and autistic traits was estimated to be predominantly under genetic influence and seemed to be mainly driven by non-social autistic traits (repetitive behaviours, restricted interests and attention to detail). Our study suggests that the link between synaesthesia and autism might reside in shared genetic causes, related to non-social autistic traits such as alterations in perception. Future studies building on these findings may attempt to identify specific groups of genes that influence both autism, synaesthesia and perception.

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.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Examining neurodevelopmental problems in 15q11.2 (BP1-BP2) copy number variation carriers at ages 9/12 and 18 in a Swedish twin sample.

BACKGROUND: Several copy number variations (CNVs) are associated with increased risk for neurodevelopmental and psychiatric disorders. The CNV 15q11.2 (BP1-BP2) deletion has been associated with learning difficulties, attention deficit hyperactivity disorder (ADHD), epilepsy, and brain morphology; however, many carriers present mild or no symptoms. Carrying the reciprocal duplication does not seem to confer risk for these disorders or traits. Our aim was to examine the impact of carrying either 15q11.2 deletion and reciprocal duplication on neurodevelopmental problems in a population-based sample of children. METHODS: Twins with genotype and phenotype information in the Child and Adolescent Twin Study in Sweden (CATSS) were included (N = 12,040). We included measures of neurodevelopmental problems (NDPs), including learning problems, from the questionnaire Autism-Tics, ADHD, and other Comorbidities inventory (A-TAC) at age 9/12, ADHD and autism spectrum disorder (ASD) questionnaires at age 18, as well as information about lifetime psychiatric diagnoses and epileptic seizures. We tested the association between these phenotypic measurements and carrying the 15q11.2 deletion, the reciprocal duplication, and other CNVs with previously reported strong associations with neurodevelopmental and psychiatric disorders (i.e., psychiatric CNVs). RESULTS: We identified 57 carriers of the 15q11.2 deletion, 75 carriers of the reciprocal duplication, and 67 carriers of other psychiatric CNVs. We did not find an increased risk for NDPs or psychiatric diagnoses in the 15q11.2 deletion carriers. For 15q11.2 duplication carriers, we found an increased risk for math learning problems and fewer self-reported ADHD symptoms at age 18 but not for other NDPs. In line with previous studies, we found an increased risk of NDPs and other evaluated phenotypes in carriers of psychiatric CNVs. CONCLUSIONS: Our results support previous findings that carrying 15q11.2 deletion does not have a large effect on NDPs in children.

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

BACKGROUND: Autism 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. METHODS: In 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. RESULTS: Similar 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). LIMITATIONS: Importantly, 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. CONCLUSIONS: Shared 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.

Importance: 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. Objective: To estimate the extent to which genetic and environmental factors contribute to the liability to the broad ARFID phenotype. Design, Setting, and Participants: 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. Main Outcomes and Measures: 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. Results: 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). Conclusions and Relevance: 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.

Multivariate analyses of molecular genetic associations between childhood psychopathology and adult mood disorders and related traits.

Ubiquitous associations have been detected between different types of childhood psychopathology and polygenic risk scores based on adult psychiatric disorders and related adult outcomes, indicating that genetic factors partly explain the association between childhood psychopathology and adult outcomes. However, these analyses in general do not take into account the correlations between the adult trait and disorder polygenic risk scores. This study aimed to further clarify the influence of genetic factors on associations between childhood psychopathology and adult outcomes by accounting for these correlations. Using a multivariate multivariable regression, we analyzed associations of childhood attention-deficit/hyperactivity disorder (ADHD), internalizing, and social problems, with polygenic scores (PGS) of adult disorders and traits including major depression, bipolar disorder, subjective well-being, neuroticism, insomnia, educational attainment, and body mass index (BMI), derived for 20,539 children aged 8.5-10.5 years. After correcting for correlations between the adult phenotypes, major depression PGS were associated with all three childhood traits, that is, ADHD, internalizing, and social problems. In addition, BMI PGS were associated with ADHD symptoms and social problems, while neuroticism PGS were only associated with internalizing problems and educational attainment PGS were only associated with ADHD symptoms. PGS of bipolar disorder, subjective well-being, and insomnia were not associated with any childhood traits. Our findings suggest that associations between childhood psychopathology and adult traits like insomnia and subjective well-being may be primarily driven by genetic factors that influence adult major depression. Additionally, specific childhood phenotypes are genetically associated with educational attainment, BMI and neuroticism.

A genetically informed Registered Report on adverse childhood experiences and 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.

Understanding the relationship between asthma and autism spectrum disorder: a population-based family and twin study.

BACKGROUND: There is some evidence that autism spectrum disorder (ASD) frequently co-occurs with immune-mediated conditions including asthma. We aimed to explore the familial co-aggregation of ASD and asthma using different genetically informed designs. METHODS: We first examined familial co-aggregation of asthma and ASD in individuals born in Sweden from 1992 to 2007 (n = 1 569 944), including their full- and half-siblings (n = 1 704 388 and 356 544 pairs) and full cousins (n = 3 921 890 pairs), identified using Swedish register data. We then applied quantitative genetic modeling to siblings (n = 620 994 pairs) and twins who participated in the Child and Adolescent Twin Study in Sweden (n = 15 963 pairs) to estimate the contribution of genetic and environmental factors to the co-aggregation. Finally, we estimated genetic correlations between traits using linkage disequilibrium score regression (LDSC). RESULTS: We observed a within-individual association [adjusted odds ratio (OR) 1.33, 95% confidence interval (CI) 1.28-1.37] and familial co-aggregation between asthma and ASD, and the magnitude of the associations decreased as the degree of relatedness decreased (full-siblings: OR 1.44, 95% CI 1.38-1.50, maternal half-siblings: OR 1.28, 95% CI 1.18-1.39, paternal half-siblings: OR 1.05, 95% CI 0.96-1.15, full cousins: OR 1.06, 95% CI 1.03-1.09), suggesting shared familial liability. Quantitative genetic models estimated statistically significant genetic correlations between ASD traits and asthma. Using the LDSC approach, we did not find statistically significant genetic correlations between asthma and ASD (coefficients between -0.09 and 0.12). CONCLUSIONS: Using different genetically informed designs, we found some evidence of familial co-aggregation between asthma and ASD, suggesting the weak association between these disorders was influenced by shared genetics.

Associations of impulsivity, hyperactivity, and inattention with nonsuicidal self-injury and suicidal behavior: longitudinal cohort study following children at risk for neurodevelopmental disorders into mid-adolescence.

BACKGROUND: The knowledge of how the separate Attention-Deficit/Hyperactivity Disorder (ADHD) subdimensions (impulsivity, hyperactivity, and inattention) are associated with nonsuicidal self-injury (NSSI) and suicidal behavior (SB) is limited. The objective of this study was to investigate the associations of childhood ADHD subdimensions with NSSI and SB in children at risk of neurodevelopmental disorders (NDDs; including ADHD). METHODS: The sample (N = 391) included twin pairs where at least one twin screened positive for at least one NDD or common comorbidity at age 9 or 12. Data on ADHD subdimensions was collected through a telephone interview with a caregiver/legal guardian at age 9 or 12, and data on NSSI and SB was collected through an in-person clinical assessment at age 15. The associations between the ADHD subdimensions and NSSI or SB were tested in three different models: (1) univariable, (2) together with the other ADHD subdimensions, and (3) in a confounder-adjusted model including other NDD symptoms in addition to ADHD subdimensions, for NSSI and SB separately. RESULTS: A total of 32 (8.2%) adolescents reported life-time engagement of NSSI, and 18 (4.6%) SB. Childhood impulsivity was associated with SB and childhood inattention with NSSI, in all models. Hyperactivity was not meaningfully associated with any of the outcomes. CONCLUSION: Impulsivity and inattention, but not hyperactivity, may be of particular importance in understanding SB and NSSI. Brief screening for impulsivity and inattention in childhood could facilitate detection of children vulnerable to NSSI and SB and indicate valuable information for preventive and intervention strategies.

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.

Sex Differences in Mental Health Problems and Psychiatric Hospitalization in Autistic Young Adults.

Importance: Psychiatric disorders are common among autistic children and adults. Little is known about sex differences in psychiatric disorders and hospitalization in early adulthood. Objective: To examine sex differences in psychiatric diagnoses and hospitalizations in autistic compared with nonautistic young adults. Design, Setting, and Participants: This population-based cohort study assessed all individuals born in Sweden between 1985 and 1997. A total of 1 335 753 individuals, including 20 841 autistic individuals (7129 [34.2%] female individuals), were followed up from age 16 through 24 years between 2001 and 2013. Analysis took place between June 2021 and August 2022. Exposures: Autism was defined as having received at least 1 clinical diagnosis of autism based on the International Classification of Diseases. Main Outcomes and Measures: The cumulative incidence of 11 psychiatric diagnoses up until age 25 years was estimated, and birth year-standardized risk difference was used to compare autistic female and male individuals directly. Sex-specific birth year-adjusted hazard ratios (HRs) with 95% CIs were calculated using Cox regression. Analyses were repeated for inpatient diagnoses to assess psychiatric hospitalization. Results: Of 1 335 753 individuals included in this study, 650 314 (48.7%) were assigned female at birth. Autism was clinically diagnosed in 20 841 individuals (1.6%; 7129 [34.2%] female) with a mean (SD) age of 16.1 (5.1) years (17.0 [4.8] years in female individuals and 15.7 [5.2] years in male individuals) for the first recorded autism diagnosis. For most disorders, autistic female individuals were at higher risk for psychiatric diagnoses and hospitalizations. By age 25 years, 77 of 100 autistic female individuals and 62 of 100 autistic male individuals received at least 1 psychiatric diagnosis. Statistically significant standardized risk differences were observed between autistic female and male individuals for any psychiatric disorder (-0.18; 95% CI, -0.26 to -0.10) and specifically for anxiety, depressive, and sleep disorders. Risk differences were larger among autistic than nonautistic individuals. Compared with nonautistic same-sex individuals, autistic female individuals (HR range [95% CI], 3.17 [2.50-4.04.]-20.78 [18.48-23.37]) and male individuals (HR range [95% CI], 2.98 [2.75-3.23]-18.52 [17.07-20.08]) were both at increased risk for all psychiatric diagnoses. Any psychiatric hospitalization was statistically significantly more common in autistic female individuals (32 of 100) compared with autistic male individuals (19 of 100). However, both autistic female and male individuals had a higher relative risk for psychiatric hospitalization compared with nonautistic female and male individuals for all disorders (female individuals: HR range [95% CI], 5.55 [4.63-6.66]-26.30 [21.50-32.16]; male individuals: HR range [95% CI], 3.79 [3.22-4.45]-29.36 [24.04-35.87]). Conclusions and Relevance: These findings highlight the need for profound mental health services among autistic young adults. Autistic female individuals, who experience more psychiatric difficulties at different levels of care, require increased clinical surveillance and support.

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.

Importance: 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. Objective: To assess etiological heterogeneity and exposure to environmental risks associated with psychotic experiences in adolescence using the twin design. Design, Setting, and Participants: 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. Main Outcomes and Measures: Primary outcome measures were exposure to environmental factors, as measured by a composite score, and psychotic experiences. Results: 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. Conclusions and Relevance: 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.