Using Multitissue Multiomics Systems Biology to Understand Tissue-specific Networks of Autism Spectrum Disorders

The genetic heterogeneity of autism spectrum disorder (ASD) has been a long-standing obstacle in our understanding of the pathogenic mechanisms of the disease, as the genetic risk of ASD is made up of numerous common variants and rare de novo or inherited variants. Previous studies have focused primarily on identifying rare variants and their impact on brain cortical cell types, and these mutations have been found to primarily affect neurodevelopment by perturbing neuronal functions. By contrast, common variants have been found to contribute substantially to ASD heritability, but remain understudied. This suggests a need to consider both rare and common variants of ASD to understand the genetic mechanisms of the disease. Furthermore, previous studies have implicated the subcortical areas of the brain and other organ and tissue systems such as the digestive and immune systems in ASD, but tissue-specific mechanisms remain poorly explored. To address these knowledge gaps, this thesis aims to identify gene networks and pathways informed by ASD common variants in both brain and peripheral tissues across the body and further examine whether these networks also capture genes informed by rare variants. We achieve this by integrating tissue level RNA sequencing data, genome wide association study (GWAS) summary statistics, and tissue-specific transcriptional regulatory networks using the multiomics integration method Mergeomics. Furthermore, we infer tissue-specific key regulatory genes governing the pathways and networks of ASD common variants by leveraging tissue-specific Bayesian gene regulatory networks. Lastly, we investigate whether the gene networks informed by ASD common variants converge with those of known ASD rare variants. Our multitissue multiomics systems studies incorporating both common and rare variants reveal the key tissues, biological pathways, and gene network regulators of ASD and identify key similarities and differences between ASD common and rare variants in tissue and network specificity.