Molecular pixelation: spatial proteomics of single cells by sequencing.

The spatial distribution of cell surface proteins governs vital processes of the immune system such as intercellular communication and mobility. However, fluorescence microscopy has limited scalability in the multiplexing and throughput needed to drive spatial proteomics discoveries at subcellular level. We present Molecular Pixelation (MPX), an optics-free, DNA sequence-based method for spatial proteomics of single cells using antibody-oligonucleotide conjugates (AOCs) and DNA-based, nanometer-sized molecular pixels. The relative locations of AOCs are inferred by sequentially associating them into local neighborhoods using the sequence-unique DNA pixels, forming >1,000 spatially connected zones per cell in 3D. For each single cell, DNA-sequencing reads are computationally arranged into spatial proteomics networks for 76 proteins. By studying immune cell dynamics using spatial statistics on graph representations of the data, we identify known and new patterns of spatial organization of proteins on chemokine-stimulated T cells, highlighting the potential of MPX in defining cell states by the spatial arrangement of proteins.

Exploring the genetic etiology across the continuum of the general psychopathology factor: a Swedish population-based family and twin study.

Psychiatric comorbidity can be accounted for by a latent general psychopathology factor (p factor), which quantifies the variance that is shared to varying degrees by every dimension of psychopathology. It is unclear whether the entire continuum of the p factor shares the same genetic origin. We investigated whether mild, moderate, and extreme elevations on the p factor shared the same genetic etiology by, first, examining the linearity of the association between p factors across siblings (N = 580,891 pairs). Second, we estimated the group heritability in a twin sample (N = 17,170 pairs), which involves testing whether the same genetic variants influence both extreme and normal variations in the p factor. In both samples, the p factor was based on 10 register-based psychiatric diagnoses. Results showed that the association between siblings' p factors appeared linear, even into the extreme range. Likewise, the twin group heritabilities ranged from 0.42 to 0.45 (95% CI: 0.33-0.57) depending on the thresholds defining the probands (2-3.33 SD beyond the mean; >2 SD beyond the mean; >4.33 SD beyond the mean; and >5.33 SD beyond the mean), and these estimates were highly similar to the estimated individual differences heritability (0.41, 95% CI: 0.39-0.43), indicating that scores above and below these thresholds shared a common genetic origin. Together, these results suggest that the entire continuum of the p factor shares the same genetic origin, with common genetic variants likely playing an important role. This implies, first, genetic risk factors for the aspect that is shared between all forms of psychopathology (i.e., genetic risk factors for the p factor) might be generalizable between population-based cohorts with a higher prevalence of milder cases, and clinical samples with a preponderance of more severe cases. Second, prioritizing low-cost genome-wide association studies capable of identifying common genetic variants, rather than expensive whole genome sequencing that can identify rare variants, may increase the efficiency when studying the genetic architecture of the p factor.

Childhood and adolescence outcomes in offspring to parents with bipolar disorder: the impact of lifetime parental comorbidity, parental sex, and bipolar subtype.

BACKGROUND: Offspring of parents with bipolar disorder have increased risks of their own psychopathology. However, a large-scale survey of psychiatric, somatic, and adverse social outcomes up to adulthood, which could aid in prioritizing and tailoring prevention, is lacking. It also remains to clarify how risks are modified by other parental factors. METHODS: Swedish population registers were linked to compare offspring having (N = 24,788) and not having (N = 247,880) a parent with bipolar disorder with respect to psychiatric diagnoses and psychotropic medication, birth-related and somatic conditions, social outcomes, accidents, suicide attempts, and mortality. Individuals were followed until age 18. We estimated the influence of lifetime parental psychiatric comorbidity, bipolar disorder subtype, and sex on outcomes. RESULTS: Children of parents with bipolar disorder had 2-3 times higher risks of all psychiatric diagnoses, except for bipolar disorder, for which the risk was 11-fold. Significantly increased risks were also found for several somatic conditions, low school grades, criminal behavior, victimization, accidents, and suicidal behavior. Adjusting for lifetime parental psychiatric comorbidity attenuated most associations. Offspring of a parent with bipolar disorder type 2 had statistically significantly higher risks of attention deficit hyperactivity disorder, respiratory tract conditions, and accidents compared with offspring of a parent with bipolar disorder type 1. Offspring of mothers with bipolar disorder had higher risks of several psychiatric diagnoses, respiratory tract conditions, low school grades, and accidents compared with offspring of fathers with bipolar disorder. Having two parents with bipolar disorder entailed the highest risks of psychiatric outcomes in offspring. CONCLUSIONS: Early intervention and family support are particularly warranted for the offspring of a parent with bipolar disorder in the presence of lifetime parental psychiatric comorbidity, when the parent has bipolar disorder type 2, or when the mother or both parents have bipolar disorder.

Neurodevelopmental disorders and subsequent risk of violent victimization: exploring sex differences and mechanisms.

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

Proximity Extension Assay in Combination with Next-Generation Sequencing for High-throughput Proteome-wide Analysis.

Understanding the dynamics of the human proteome is crucial for developing biomarkers to be used as measurable indicators for disease severity and progression, patient stratification, and drug development. The Proximity Extension Assay (PEA) is a technology that translates protein information into actionable knowledge by linking protein-specific antibodies to DNA-encoded tags. In this report we demonstrate how we have combined the unique PEA technology with an innovative and automated sample preparation and high-throughput sequencing readout enabling parallel measurement of nearly 1500 proteins in 96 samples generating close to 150,000 data points per run. This advancement will have a major impact on the discovery of new biomarkers for disease prediction and prognosis and contribute to the development of the rapidly evolving fields of wellness monitoring and precision medicine.

Associations between psychiatric polygenic risk scores and general and specific psychopathology symptoms in childhood and adolescence between and within dizygotic twin pairs.

BACKGROUND: Although polygenic risk scores (PRS) predict psychiatric problems, these associations might be attributable to indirect pathways including population stratification, assortative mating, or dynastic effects (mediation via parental environments). The goal of this study was to examine whether PRS-psychiatric symptom associations were attributable to indirect versus direct pathways. METHODS: The sample consisted of 3,907 dizygotic (DZ) twin pairs. In childhood, their parents rated them on 98 symptoms. In adolescence (n = 2,393 DZ pairs), both the parents and the twins rated themselves on 20 symptoms. We extracted one general and seven specific factors from the childhood data, and one general and three specific factors from the adolescent data. We then regressed each general factor model onto ten psychiatric PRS simultaneously. We first conducted the regressions between individuals (ß) and then within DZ twin pairs (ßw ), which controls for indirect pathways. RESULTS: In childhood, the PRS for ADHD predicted general psychopathology (ß = 0.09, 95% CI: [0.06, 0.12]; ßw = 0.07 [0.01, 0.12]). Furthermore, the PRS for ADHD predicted specific inattention (ß = 0.04 [0.00, 0.08]; ßw = 0.09 [0.01, 0.17]) and specific hyperactivity (ß = 0.07 [0.04, 0.11]; ßw = 0.09 [0.01, 0.16]); the PRS for schizophrenia predicted specific learning (ß = 0.08 [0.03, 0.13]; ßw = 0.19 [0.08, 0.30]) and specific inattention problems (ß = 0.05 [0.01, 0.09]; ßw = 0.10 [0.02, 0.19]); and the PRS for neuroticism predicted specific anxiety (ß = 0.06 [0.02, 0.10]; ßw = 0.06 [0.00, 0.12]). Overall, the PRS-general factor associations were similar between individuals and within twin pairs, whereas the PRS-specific factors associations amplified by 84% within pairs. CONCLUSIONS: This implies that PRS-psychiatric symptom associations did not appear attributable to indirect pathways such as population stratification, assortative mating, or mediation via parental environments. Rather, genetics appeared to directly influence symptomatology.

Psychological distress after esophageal cancer surgery and the predictive effect of dispositional optimism: a nationwide population-based longitudinal study.

PURPOSE: To examine the trajectory of psychological distress from 1 to 2 years after esophageal cancer surgery, and whether dispositional optimism could predict the risk of postoperative psychological distress. METHODS: This Swedish nationwide longitudinal study included 192 patients who had survived for 1 year after esophageal cancer surgery. We measured dispositional optimism with the Life Orientation Test-Revised (LOT-R) 1 year post-surgery and psychological distress with the Hospital Anxiety and Depression Scale 1, 1.5, and 2 years post-surgery. Latent growth curve models were used to assess the trajectory of postoperative psychological distress and to examine the predictive validity of dispositional optimism. RESULTS: One year after surgery, 11.5% (22 of 192) patients reported clinically significant psychological distress, and the proportion increased to 18.8% at 1.5 years and to 25.0% at 2 years post-surgery. Higher dispositional optimism predicted a lower probability of self-reported psychological distress at 1, 1.5, and 2 years after esophageal cancer surgery. For each point increase in the LOT-R sum score, the odds of psychological distress decreased by 44% (OR, 0.56; 95% CI, 0.40 to 0.79). CONCLUSION: The high prevalence and longitudinal increase of self-reported psychological distress after esophageal cancer surgery indicate the unmet demands for timely psychological screening and interventions. Measuring dispositional optimism may help identify patients at higher risk of developing psychological distress, thereby contributing to the prevention of postoperative psychological distress.

Dispositional optimism and all-cause mortality after esophageal cancer surgery: a nationwide population-based cohort study.

PURPOSE: To examine the association between dispositional optimism and all-cause mortality after esophageal cancer surgery and whether pathological tumor stage and the COVID-19 pandemic modified this association. METHODS: This nationwide, population-based prospective cohort study included 335 patients undergoing esophageal cancer surgery in Sweden between January 1, 2013, and December 31, 2019. Dispositional optimism was measured 1 year post-surgery using Life Orientation Test-Revised (LOT-R). A higher LOT-R sum score represents higher dispositional optimism. Mortality information was obtained from the Swedish Register of the Total Population. All patients were followed up until death or until December 31, 2020, whichever occurred first. Cox regression with adjustments for confounders was used. RESULTS: The median follow-up was 20.8 months, during which 125 (37.3%) patients died. Among the included 335 patients, 219 (65.4%) patients had tumor pathologically staged Tis-II, and 300 (89.6%) patients entered the cohort before the COVID-19 pandemic. Both tumor stage and the COVID-19 pandemic were effect modifiers. For each unit increase in LOT-R sum score, the risk of all-cause mortality decreased by 11% (HR 0.89, 95% CI 0.81 to 0.98) among patients with tumor staged Tis-II before the COVID-19 pandemic. This association was non-significant in patients with tumor staged III-IV (HR 0.99, 95% CI 0.92 to 1.07) and during the COVID-19 pandemic (HR 1.08, 95% CI 0.94 to 1.25). CONCLUSION: Assessing dispositional optimism may help predict postoperative survival, especially for patients with early and intermediate esophageal cancer. Increasing dispositional optimism might be a potential intervention target to improve survival after esophageal cancer surgery.

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.

Higher Dispositional Optimism Predicts Better Health-Related Quality of Life After Esophageal Cancer Surgery: A Nationwide Population-Based Longitudinal Study.

PURPOSE: To assess whether higher dispositional optimism could predict better health-related quality of life (HRQL) after esophageal cancer surgery. METHODS: This Swedish nationwide longitudinal study included 192 patients who underwent esophagectomy for cancer. The exposure was dispositional optimism measured by the Life Orientation Test-Revised (LOT-R) at 1 year post-surgery. Patients were categorized into four subgroups (very low, moderately low, moderately high, and very high dispositional optimism) based on the quartile of the LOT-R sum score. The outcome was HRQL assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) and Quality of Life Questionnaire-Esophago-Gastric module 25 (QLQ-OG25) at 1, 1.5, and 2 years post-surgery. Linear mixed-effects models, adjusted for potential confounders, were used to examine the mean score difference (MSD) with 95% confidence interval of HRQL among the four patient subgroups. RESULTS: Patients with very high dispositional optimism reported clinically relevantly better global quality of life, emotional function, and social function (MSD range 10-16) and less severe symptoms in pain, dyspnea, diarrhea, eating difficulty, anxiety, dry mouth, trouble with taste, worry about weight loss, and self-doubt about body image (MSD range - 9 to - 22) than patients with lower dispositional optimism. Patients with moderately high dispositional optimism reported clinically and statistically significantly better global quality of life (MSD 10) and less severe diarrhea (MSD - 9) than patients with lower dispositional optimism. Adjusted MSDs were constant over the three time points in all aspects except for eating difficulty. CONCLUSIONS: Measuring dispositional optimism could help identify patients at higher risk of poor HRQL recovery after esophageal cancer surgery.

Overlap between attention-deficit hyperactivity disorder and neurodevelopmental, externalising and internalising disorders: separating unique from general psychopathology effects.

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

The contribution of common genetic risk variants for ADHD to a general factor of childhood psychopathology.

Common genetic risk variants have been implicated in the etiology of clinical attention-deficit/hyperactivity disorder (ADHD) diagnoses and symptoms in the general population. However, given the extensive comorbidity across ADHD and other psychiatric conditions, the extent to which genetic variants associated with ADHD also influence broader psychopathology dimensions remains unclear. The aim of this study was to evaluate the associations between ADHD polygenic risk scores (PRS) and a broad range of childhood psychiatric symptoms, and to quantify the extent to which such associations can be attributed to a general factor of childhood psychopathology. We derived ADHD PRS for 13,457 children aged 9 or 12 from the Child and Adolescent Twin Study in Sweden, using results from an independent meta-analysis of genome-wide association studies of ADHD diagnosis and symptoms. We estimated associations between ADHD PRS, a general psychopathology factor, and several dimensions of neurodevelopmental, externalizing, and internalizing symptoms, using structural equation modeling. Higher ADHD PRS were statistically significantly associated with elevated neurodevelopmental, externalizing, and depressive symptoms (R2 = 0.26-1.69%), but not with anxiety. After accounting for a general psychopathology factor, on which all symptoms loaded positively (mean loading = 0.50, range = 0.09-0.91), an association with specific hyperactivity/impulsivity remained significant. ADHD PRS explained ~ 1% (p value < 0.0001) of the variance in the general psychopathology factor and ~ 0.50% (p value < 0.0001) in specific hyperactivity/impulsivity. Our results suggest that common genetic risk variants associated with ADHD, and captured by PRS, also influence a general genetic liability towards broad childhood psychopathology in the general population, in addition to a specific association with hyperactivity/impulsivity symptoms.

Sexual orientation and adolescent suicide attempt and self-harm: a co-twin control study.

BACKGROUND: Research has demonstrated that individuals who identify as a sexual minority (e.g., gay/lesbian, bisexual) are at increased risk for suicidality-related outcomes. However, previous research is primarily limited by the lack of adjustment for unmeasured (i.e., genetic and environmental) confounding factors and previous psychopathology. METHODS: Using the Child and Adolescent Twin Study in Sweden, we employed a co-twin control design to examine the extent to which the association between sexual orientation and adolescent suicide attempt and self-harm (SA/SH) was independent of genetic and environmental factors shared by twins, as well as measured symptoms of childhood psychopathology. RESULTS: Adolescents who identified as a sexual minority (i.e., gay/lesbian, bisexual, or other sexual orientation) were at two-fold increased odds for SA/SH (OR, 2.01 [95% confidence interval, 1.63-2.49) compared to heterosexual adolescents. When adjusting for all genetic and shared environmental factors that make twins similar and for measured childhood psychopathology, the association remained positive but attenuated to OR, 1.55 (1.11-2.16). CONCLUSIONS: Identifying as a sexual minority was associated with approximately 50% increased odds of SA/SH in adolescence after adjusting for unmeasured genetic and environmental factors shared by twins and for childhood psychopathology. The results support that environmental factors specifically associated with identifying as a sexual minority likely increase risk for SA/SH. Our findings highlight the need to monitor suicidality risk among this group.

Associations between conduct problems in childhood and adverse outcomes in emerging adulthood: a longitudinal Swedish nationwide twin cohort.

BACKGROUND: We examined whether childhood conduct problems predicted a wide range of adverse outcomes in emerging adulthood and whether the association with internalizing problems remained after adjusting for general comorbidity and externalizing problems. METHODS: Participants were 18,649 twins from the Child and Adolescent Twin Study in Sweden. At age 9/12, parents rated their children on eight conduct problems. Adverse outcomes were retrieved from national registers in emerging adulthood (median follow-up time = 9.2 years), including diagnoses of six psychiatric disorders, prescriptions of antidepressants, suicide attempts, criminality, high school ineligibility, and social welfare recipiency. We estimated risk for the separate outcomes and examined if conduct problems predicted an internalizing factor above and beyond a general comorbidity and an externalizing factor. We used twin analyses to estimate genetic and environmental contributions to these associations. RESULTS: On the average, each additional conduct symptom in childhood was associated with a 32% increased risk of the adverse outcomes in emerging adulthood (mean hazard ratio = 1.32; range = 1.16, 1.56). A latent childhood conduct problems factor predicted the internalizing factor in emerging adulthood (ßboys  = .24, standard error, SE = 0.03; ßgirls  = .17, SE = 0.03), above and beyond its association with the externalizing (ßboys  = 0.21, SE = 0.04; ßgirls  = 0.17, SE = 0.05) and general factors (ßboys  = 0.45, SE = 0.03; ßgirls  = 0.34, SE = 0.04). These associations were differentially influenced by genetic and environmental factors. CONCLUSIONS: It is important to monitor boys and girls with conduct problems not only for future externalizing problems, but also for future internalizing problems. Prevention of specific outcomes, however, might require interventions at different levels.

Volitional eye movement control and ADHD traits: a twin study.

BACKGROUND: Top-down volitional command of eye movements may serve as a candidate endophenotype of ADHD, an important function underlying goal-directed action in everyday life. In this twin study, we examined the relation between performance on a response inhibition eye-tracking paradigm and parent-rated ADHD traits in a population-based twin sample. We hypothesized that altered eye movement control is associated with the severity of ADHD traits and that this association is attributable to genetic factors. METHODS: A total of 640 twins (320 pairs, 50% monozygotic) aged 9-14 years) from the Child and Adolescent Twin Study in Sweden (CATSS) participated. Twins performed the antisaccade task indexing inhibitory alterations as either direction errors (following exogenous cues rather than instructions) or premature anticipatory eye movements (failure to wait for cues). We calculated the associations of eye movement control and ADHD traits using linear regression mixed-effects models and genetic and environmental influences with multivariate twin models. RESULTS: Premature anticipatory eye movements were positively associated with inattentive traits (ß = .17; 95% CI: 0.04, 0.31), while controlling for hyperactive behaviors and other covariates. Both premature anticipatory eye movements and inattention were heritable (h2  = 0.40, 95% CI: 0.22, 0.56; h2  = 0.55; 95% CI: 0.42, 0.65; respectively), and their genetic correlation was small but statistically significant (r = .19, 95% CI: 0.02, 0.36). However, the genetic correlation did not remain significant after adjusting for covariates (age, sex, hyperactivity traits, IQ). No link was found between direction errors and ADHD traits. CONCLUSIONS: This study indicates that there is a specific, genetically influenced, relation between top-down eye movement control and the inattentive traits typical of ADHD.

A Nordic-Baltic perspective on indications for proton therapy with strategies for identification of proper patients.

The beneficial effects of protons are primarily based on reduction of low to intermediate radiation dose bath to normal tissue surrounding the radiotherapy target volume. Despite promise for reduced long-term toxicity, the percentage of cancer patients treated with proton therapy remains low. This is probably caused by technical improvements in planning and delivery of photon therapy, and by high cost, low availability and lack of high-level evidence on proton therapy. A number of proton treatment facilities are under construction or have recently opened; there are now two operational Scandinavian proton centres and two more are under construction, thereby eliminating the availability hurdle. Even with the advantageous physical properties of protons, there is still substantial ambiguity and no established criteria related to which patients should receive proton therapy. This topic was discussed in a session at the Nordic Collaborative Workshop on Particle Therapy, held in Uppsala 14-15 November 2019. This paper resumes the Nordic-Baltic perspective on proton therapy indications and discusses strategies to identify patients for proton therapy. As for indications, neoplastic entities, target volume localisation, size, internal motion, age, second cancer predisposition, dose escalation and treatment plan comparison based on the as low as reasonably achievable (ALARA) principle or normal tissue complication probability (NTCP) models were discussed. Importantly, the patient selection process should be integrated into the radiotherapy community and emphasis on collaboration across medical specialties, involvement of key decision makers and knowledge dissemination in general are important factors. An active Nordic-Baltic proton therapy organisation would also serve this purpose.

Genetic and environmental contribution to the overlap between ADHD and ASD trait dimensions in young adults: a twin study.

BACKGROUND: Traits of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are strongly associated in children and adolescents, largely due to genetic factors. Less is known about the phenotypic and aetiological overlap between ADHD and ASD traits in adults. METHODS: We studied 6866 individuals aged 20-28 years from the Swedish Study of Young Adult Twins. Inattention (IA) and hyperactivity/impulsivity (HI) were assessed using the WHO Adult ADHD Self-Report Scale-V1.1. Repetitive and restricted behaviours (RRB) and social interaction and communication (SIC) were assessed using the Autism-Tics, ADHD, and other Comorbidities inventory. We used structural equation modelling to decompose covariance between these ADHD and ASD trait dimensions into genetic and shared/non-shared environmental components. RESULTS: At the phenotypic level, IA was similarly correlated with RRB (r = 0.33; 95% Confidence Interval (CI) 0.31-0.36) and with SIC (r = 0.32; 95% CI 0.29-0.34), whereas HI was more strongly associated with RRB (r = 0.38; 95% CI 0.35-0.40) than with SIC (r = 0.24; 95% CI 0.21-0.26). Genetic and non-shared environmental effects accounted for similar proportions of the phenotypic correlations, whereas shared environmental effects were of minimal importance. The highest genetic correlation was between HI and RRB (r = 0.56; 95% 0.46-0.65), and the lowest was between HI and SIC (r = 0.33; 95% CI 0.23-0.43). CONCLUSIONS: We found evidence for dimension-specific phenotypic and aetiological overlap between ADHD and ASD traits in adults. Future studies investigating mechanisms underlying comorbidity between ADHD and ASD may benefit from exploring several symptom-dimensions, rather than considering only broad diagnostic categories.

Childhood neurodevelopmental disorders and risk of coercive sexual victimization in childhood and adolescence - a population-based prospective twin study.

BACKGROUND: Autism spectrum disorder (ASD), Attention-deficit/Hyperactivity disorder (ADHD), and other related neurodevelopmental disorders (NDDs) have, in some previous studies, been shown to increase the risk of being sexually victimized. However, no studies have examined whether the association is driven by a general NDD phenotype versus specific diagnoses, nor the etiology of the association. METHOD: Using a genetically informative, prospective design, we examined the association between ASD and ADHD in childhood and coercive sexual victimization up to age 18. A total of 4,500 children participating in the Child and Adolescent Twin Study in Sweden (CATSS) were rated by their parents on NDDs at age 9 or 12 years, and self-reported at age 18 on lifetime experiences of coercive sexual touching and/or coercive sex. First, we regressed sexual victimization on the NDDs. Second, we regressed sexual victimization on general and specific NDD symptoms identified via a bifactor model. Third, we decomposed the observed associations into genetic and environmental parts. RESULTS: In females, ASD was associated with an almost threefolded increased risk of coercive sexual victimization, and ADHD with a doubled risk. In males, the risk associated with ASD and ADHD was of the same magnitude but not significant. When controlling for overall NDD symptom load ASD or ADHD, no longer uniquely predicted coercive sexual victimization. The association between the NDD general factor and coercive sexual victimization was due to shared genetics. CONCLUSIONS: General NDD symptom load, rather than specific ASD or ADHD symptoms, seems to be a moderate vulnerability factor for coercive sexual victimization. We speculate that an evocative gene-environment correlation might account for this observation, such that sexual perpetrators actively target NDD individuals.

Childhood attention-deficit/hyperactivity disorder symptoms and the development of adolescent alcohol problems: A prospective, population-based study of Swedish twins.

Children with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of problematic alcohol and other substance use in adolescence. This study used data from an ongoing, prospective, population-based twin study of Swedish children and adolescents to evaluate the extent to which the association between ADHD symptoms and alcohol problems reflects a unique source of genetic or environmental risk related to ADHD versus a broader predisposition to youth externalizing behavior. We used all available data from same-sex monozygotic (MZ) and dizygotic (DZ) twins on ADHD symptoms in childhood (age 9/12; N = 15,549) and alcohol problems in late adolescence (age 18; N = 2,564). Consistent with prior longitudinal studies, the phenotypic association between hyperactive/impulsive ADHD symptoms and alcohol problems was small in magnitude, whereas the association for inattentive symptoms was even weaker. Additive genetic influences explained 99.8% of the association between hyperactive/impulsive symptoms and alcohol problems. Furthermore, we found that the genetic risk specifically associated with hyperactive/impulsive symptoms was attenuated when estimated in the context of externalizing behavior liability during childhood, of which ADHD symptoms were specific expressions. In sensitivity analyses exploring hyperactivity in mid-adolescence, we found a similar pattern of genetic associations. These results are consistent with previous findings of genetically driven overlap in the etiology of ADHD and problematic alcohol use. At least some of this co-occurrence may result from a general predisposition to externalizing behaviors in youth. © 2015 Wiley Periodicals, Inc.

The association between childhood autistic traits and adolescent psychotic experiences is explained by general neuropsychiatric problems.

Studies suggest associations between childhood autistic traits and adolescent psychotic experiences. However, recent research suggests that a general neuropsychiatric problems factor predicts adverse outcomes better than specific diagnostic entities. To examine if the alleged association between autistic traits and psychotic experiences could rather be explained by a general neuropsychiatric problems factor comprising symptoms of ADHD, tic disorder, developmental coordination disorder, and learning disorder, we conducted a prospective cohort study based on the Child and Adolescent Twin Study in Sweden. In addition, we examined the genetic and environmental influences on the associations. A total of 9,282 twins with data on childhood autistic traits and other neuropsychiatric problems, and follow-up data on psychotic experiences at ages 15 and/or 18 years were included. First, psychotic experiences were regressed on autistic traits and second, the general neuropsychiatric problems factor was added to the model. Auditory hallucinations were analyzed separately from the other psychotic experiences. Finally, twin analyses were employed to disentangle genetic from environmental influences in the observed associations. Replicating prior research, significant associations were found between autistic traits in childhood and auditory hallucinations at ages 15 and 18. However, after controlling for the general neuropsychiatric problems factor, the associations between autistic traits and auditory hallucinations disappeared, whereas the association between the general neuropsychiatric problems factor and auditory hallucinations persisted after controlling for autistic traits. Twin analyses revealed that the association between the general neuropsychiatric problems factor and auditory hallucinations was driven by shared genetic influences. © 2015 Wiley Periodicals, Inc.