Exploring the genetic architecture of autism spectrum disorder

Autism spectrum disorder (ASD) is one of the most common neurodevelopmental disorders affecting approximately 1% of the global population.Individuals with ASD have impairments in social interaction and communication, and restricted and repetitive patterns of behaviour, interests, and activities.The spectrum of clinical presentation can vary between subjects with ASD and most individuals have at least one co-occurring psychiatric or medical condition.The early onset (<3 years), lifelong persistence, economic burden, and lack of therapeutics for ASD warrants a need to elucidate its etiology and in turn, mitigate its impact.The role of genetic risk factors in ASD have been firmly established, with an estimated heritability of 65-91%, and an accompanying complex genetic architecture.Like other complex traits, different classes of genetic variants with varying frequencies and penetrance have been implicated in the genetic liability for ASD.Early efforts focused on identifying rare, large-effect genetic risk factors.Yet, there remains insufficient evidence for ASD-specific genes to date.Gaining insight into the complex genetic architecture of ASD is fundamental to understanding the mechanisms of the disorder.Today, large-scale genetic and clinical data are available to power statistical models of the disorder.Yet, the clinical and genetic heterogeneity of the disorder remains a challenge to overcome despite the substantial increases in sample size over the last decade.As such, approaches that leveragerather than reducethe complexity of ASD can be useful to uncover the genetic underpinnings of the disorder.In this thesis, we used the genetic and clinical data of tens of thousands of individuals from families with ASD and the general population to characterize the heterogeneous risk factors of ASD.First, we identified a rare inherited copy-number variant (CNV) encompassing the CNTN5 gene shared by all four affected brothers of a multiplex family with ASD.We validated the role of this variant in a large case-control study, which confirmed its association with ASD risk and other neuropsychiatric conditions.This study underscored the importance of characterizing variants of intermediate effect size in the etiology of ASD to elucidate its complete genetic architecture.Second, we explored the genetic liability for ASD conferred through common variants.In this study, we combined multiple polygenic risk scores (PRSs) for ASD-related traits to capture the CH.Statistical analyses and result interpretation were performed by ZS, VRB, ED, JPR, PA, and CEC.Data analysis and manuscript writing was performed by ZS.

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