Physical comorbidity in twins with ASD or ADHD

Abstract: Background Individuals with autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) have an increased risk for a range of physical disorders, which can complicate the clinical management, and increase impairment and experienced burden. The potential shared aetiological pathways underlying the association between ASD and ADHD behavioural phenotypes and physical disorders have received growing scientific interest. However, the knowledge of clinical profiles and their associations with physical disorders in ASD and ADHD is still limited. In addition, the relative contributions of aetiological components to physical comorbidity in ASD and ADHD has not been systematically studied. Objectives The studies in this thesis aimed to achieve a better understanding of the association between ASD and ADHD phenotypes and physical disorders from both clinical and aetiological perspectives. More specifically the objectives were:  To explore the full range of co-occurring neurological disorders in ASD, by analyzing the association revealed in research of case-control and cohort design, as well as cross-sectional studies which reported prevalence.  To examine whether nonshared environmental factors contribute to the physical comorbidity in ASD and ADHD.  To estimate the magnitude of genetic and environmental components contributing to physical comorbidity in both clinical and subclinical phenotypes of ASD and ADHD Methods A systematic review and meta-analysis was conducted to estimate the odds of having neurological disorders compared to the general population, the overall prevalence of different comorbid neurological disorders, as well as the temporal association between early neurological disorders and a subsequent ASD diagnosis. Within a twin sample enriched for ASD and ADHD, the co-twin control design was adopted to examine the within pair association with physical comorbidity among monozygotic twins discordant for ASD and ADHD phenotypes. We also applied the classical twin design and structural equation modelling on a Swedish population-based twin cohort to estimate the phenotypic correlations and bivariate heritability between physical disorders in different organ systems and the clinical and subclinical variants of ASD and ADHD. Results Overall, individuals with ASD have significantly higher risk than the general population for epilepsy, macrocephaly, hydrocephalus, cerebral palsy, migraine/headache, and congenital abnormalities of the nervous system, with prevalence estimates ranging from 1.1% (0−3.3) (hydrocephalus) to 14.2% (11.3−17.2) (epilepsy). Neurological disorders showed within-twin pair association with clinical ASD diagnosis (odds ratio per neurological problem 3.15, p = 0.02), as well as autistic traits (β =10.44, p = 0.006). Digestive problems displayed an inverse within pair association with the severity of childhood ADHD symptoms (β = −2.72, p = 0.001). Clinical and subclinical ASD and ADHD exhibited similar patterns of association with physical disorders, with odds ratios ranging from 1.31 for asthma in subclinical ADHD to 8.03 for epilepsy in clinical ASD. Significant genetic correlation (ra) was found between ASD/ADHD in both clinical and subclinical phenotypes and epilepsy as well as gastrointestinal disorders. Conclusions Our findings underscore that ASD is a complex neurodevelopmental condition, which is linked to an increased susceptibility for a range of neurological disorders. Hence, neurological check-ups in ASD are imperative for individualized clinical management and tailored support provision. From the aetiological perspective, nonshared environmental factors might contribute to the overlap between neurological disorders and both clinical ASD and autistic traits, as well as the co-existence of gastrointestinal problems and ADHD symptoms among children. In addition, shared genetic effects contribute significantly to the comorbidity of clinical and subclinical ASD and ADHD with physical disorders across different organ systems. This support the notion that ASD and ADHD are quantitative extremes of continuously altered neurodevelopment. Moreover, the continuous genetic effects underlying the liability to physical comorbidity is in line with the concept of endophenotypes.

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