Identification of biobehavioral markers of neurodevelopmental disorders in twins

Sammanfattning: Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are complex neurodevelopmental disorders (NDD), heterogeneous in phenotypes and etiology. The exact mechanisms driving the phenotypes are still largely unknown. The overall aim of this thesis is to find new leads for ASD and ADHD etiology, focusing on environmental factors through the examination of discordant twins. For this purpose, two ASD enriched and well characterized twin cohorts were investigated; the Roots of Autism and ADHD Twin Study of Sweden (RATSS) and the Californian Autism Twin Study (CATS). In study I, we are discussing the background the aims and the rationale for the RATSS program. In study II, the association between ASD and IQ is examined. There is a robust and negative phenotypic correlation between IQ and ASD, categorical as well as dimensional, underpinned by genetic and non-shared environmental (NSE) factors. The role of non-shared environment in ASD, focusing on early medical events, is explored in Study III. There is an association between the total load of early medical events and ASD, both categorically as well as dimensionally defined. The association is particularly driven by behavioral dysregulation in infants (feeding and sleeping problems, excessive crying and worriedness) as a function of NSE factors. In study IV, we test the hypothesis of a link between ASD and pre- and postnatal dysregulation of metals. ASD cases demonstrate higher lead levels during a period of 20 weeks before and 30 weeks after birth, lower manganese levels 17 weeks prenatally to 30 weeks postnatally, and a reduction in zinc 10 weeks prenatally to five weeks postnatally. In study V we study executive functioning as a behavioral marker of ADHD. There is a link between ADHD on one hand, and foresighted planning and inhibitory control on the other hand, mediated by NSE factors. In summary, the findings support ASD to be continuously distributed in the population with clinical phenotypes being the extremes of these continuums. They point to a cumulative multifactor threshold model, including both genetic and NSE components in the etiology of ASD. More specifically, the results support that systemic pre- and postnatal elemental dysregulation increase ASD risk, and an association between early medical events and ASD risk. The findings also indicate low IQ to be a behavioral marker for ASD, and poor executive functioning to be a behavioral marker for ADHD. Both these association are underpinned by NSE factors.