Project Summary Autism spectrum disorder (ASD) is one of the most common and highly inherited of all developmental disorders, with heritability exceeding 0.80. Although remarkable advances in genetics have identified rare de novo mutations in select brain genes, by definition, none of these relate to the pronounced heritability of autism relevant to the vast proportion of cases in the population. Given that heritability has been shown to be a function of additive genetic risk, inferring an impractically large number of genetic targets for intervention, an important strategy is to identify convergent mechanisms of polygenic risk factors by elucidating intermediate phenotypes (i.e., endophenotypes) through which they exert their causal influence. Our group has identified two such candidates that appear highly contributory but not sufficient for ASD: (i) the social behavioral phenotype indexed by quantitative (subclinical) autistic traits in parents (QAT-p); and (ii) variation in social visual engagement (SVE), an eye-tracking measure based on viewing of dynamic social scenes. Both can be ascertained in the first year of life using rapid acquisition methods of less than 20 minutes. Our team’s prior work strongly supports a developmental model in which autism arises from joint additive genetic effects of these and other neurodevelopmental liabilities, suggesting that targeting a discrete group of early-contributing liabilities before autism develops offers the greatest opportunity for high-impact, personalized intervention for children at risk for common, polygenic forms of ASD. The primary objective of this research program is to validate wearable-sensor methodology (bilateral, wrist-worn accelerometers) for quantifying two additional endophenotypes: hyperactivity (HYP, as an early marker of liability to Attention Deficit Hyperactivity Disorder, which is strongly comorbid with autism) and impairment in motor coordination (MOT). We will examine HYP and MOT in three distinct samples. Aim I will study 120 pairs of infant twins first assessed at 6 months of age and then followed at ages 18 and 36 months to evaluate early associations between HYP, MOT, QAT, and SVE, as well as their heritability and ability to predict quantitative variation in autistic traits among the twins. Aim II will study a cohort of 50 toddlers diagnosed with idiopathic ASD to determine whether novel sensor-based metrics of HYP and MOT show differences between the twins and children with ASD. Aim III will study a legacy cohort of 120 infants at elevated risk for autism due to prematurity and/or cerebellar injury, in whom we will explore relationships between cerebellar structure and function in the first year of life and a) sensor-based indices of HYP and MOT, b) quantitative autistic traits, and c) performance-based indices of motor ability at age three years. This project is expected to yield a rich, comprehensive understanding of motor endophenotypes in infants and children and ...