Environmental etiologies of autism and other neurodevelopmental conditions : twin studies of the cumulative effect of early medical events

Abstract

Background: Neurodevelopmental conditions (NDC), such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), are characterized by alterations in the architecture, functioning, and maturation of the brain causing cognitive challenges and impairments in social, educational, occupational, and other important areas of life. NDC are common, with a prevalence of 10 to 15%. Heritability estimates leave space for environmental etiological contributions, but the exact etiology remains poorly understood. Observational studies of the etiology of NDC often suffer from familial confounding.

Objectives: The overarching aim of this thesis was to explore associations between environmental factors and ASD and other NDC, to identify early medical events associated with ASD and other NDC, and to test the hypothesis of a cumulative environmental effect.

Methods: A comprehensive systematic review of twin or sibling studies was performed to map all early environmental factors of NDC beyond familial confounding. Within a rare monozygotic (MZ) twin sample of ASD discordant twins, medical records were scrutinized for non-shared early medical events, and a co-twin control design was used to test the cumulative effect of early medical events in a larger twin sample discordant for autistic traits. In a large population-based twin cohort, the association of ASD and ASD symptoms, and the cumulative effect of early medical events identified in the systematic review (low birth weight, congenital malformations, and perinatal respiratory stress) were studied. Finally, confirmatory factor analysis was performed to model a common latent NDC factor to test if this cumulative effect acted through a common NDC pathway, ASD included.

Results: In total, 140 studies were included in the systematic review. Beyond familial confounding, advanced paternal age, low birth weight, congenital malformations, and perinatal respiratory stress were associated with ASD, and low birth weight, gestational age and low family income were associated with ADHD. The systematic review deemed several previously suspected factors, including pregnancy-related ones, due to familial confounding. A list of 31 non-shared early medical events were found within the discordant MZ sample and a cumulative effect on autistic traits was confirmed. In the large population-based twin cohort the within pair odds ratio (OR) for an ASD diagnosis when having exposure of three early medical events were 2.39, but not statistically significant (95%CI;0.62–9.24). Having a higher load of early exposure was consistently associated with autistic symptoms after adjusting for familial confounding and sex with OR 3.45 (1.66–7.15) for one exposure to OR 7.36 (1.99–27.18) for three exposures. Cumulative exposure to early medical events was also associated with a non-linear increase in the common latent NDC factor, from ß=0.12 (95%CI, 0.07–0.17) for one exposure to ß=0.62 (0.34–0.90) for three exposures. In a monozygotic twin difference analysis, with familial confounding being fully accounted for, the whole exposure effect was captured by the common latent factor, with residual associations fully attenuated for the respective symptoms of ASD, ADHD, tics and learning difficulties, at all levels of cumulative exposure.

Conclusions: This thesis advances our understanding of ASD and NDC in mainly four areas: 1. It comprehensively maps our present knowledge from twin and sibling studies on environmental etiologies of NDC; 2. Owing to environmental contributions, it places early medical events into the dimensional model of autism and the liability threshold model, associating them with symptoms of ASD continuously distributed in the general population; 3. It confirms the cumulative stress hypothesis of ASD in a large human sample, beyond familial confounding; 4. It suggests that this cumulative environmental effect of early medical events acts through a common latent NDC factor, that in turn affects neurodevelopment, ASD included. There is a critical need for more genetically informed studies of good quality in the quest of the environmental etiologies of NDC.