Project 458800

Autism spectrum disorder (ASD) is an early onset and life-long disorder that results in difficulties in social interaction and communication, and restricted and repetitive patterns of behaviour, which affects about 1% of the global population. ASD has a strong genetic component consisting of rare and common variants. Rare genetic events, such as deleted or duplicated regions of the genome (copy-number variants (CNVs)), that increase the risk for ASD also have been found to decrease intelligence (IQ). Common variants, on the other hand, have the opposite effect - while they increase the risk for ASD, they also increase IQ. The proposed project studies the combined effect of rare and common variants, and how they may interact together to increase the risk for ASD. Large-scale genetic and clinical data of 6,929 individuals with ASD and 32,663 unaffected controls will be used to carry out the study. First, CNVs across all individuals will be identified and will be given a deleteriousness score, known as LOEUF. A polygenic risk score (PRS) for IQ will be computed for each individual, which represents their genetic propensity for IQ that is conferred by common variants. Second, the effect of, and interaction between, rare (LOEUF for CNVs) and common (PRS for IQ) variant burden on ASD risk will be modelled. Finally, cases with ASD will be grouped according to their burden of rare and common variants. As such, the clinical factors that are shared amongst cases with ASD with similar genetic profiles can be assessed. These findings could shed light on the biological mechanisms underlying differences in the clinical manifestations of ASD. Taken together, studying the combined effect of rare and common genetic variants on ASD risk, which have opposite effects on IQ, could reveal the genetic factors that specifically underlie ASD. Ultimately, this may pave the way for developing early diagnostic tools and therapeutics that target core ASD symptoms, disentangled from cognition.