Characterizing Genetic Pathways Unique to Autism Spectrum Disorder at Multiple Levels of Biological Analysis

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by atypical patterns of social functioning and repetitive/restricted behaviors. ASD commonly co-occurs with ADHD and, despite their clinical distinctiveness, the two share considerable genetic overlap. Given their shared genetic liability, it is unclear which genetic pathways confer unique risk for ASD independent of ADHD. We applied Genomic Structural Equation Modeling (SEM) to GWAS summary statistics for ASD and ADHD, decomposing the genetic signal for ASD into that which is unique to ASD (uASD)and that which is shared with ADHD. We computed genetic correlations betweenuASDand 75 external traits to estimate genetic overlap betweenuASDand other clinically relevant phenotypes. We went on to apply Stratified Genomic SEM to identify classes of genes enriched foruASD. Finally, we implemented Transcriptome-Wide SEM (T-SEM) to explore patterns of gene-expression associated withuASD. We observed positive genetic correlations betweenuASDand several external traits, most notably those relating to cognitive/educational outcomes and internalizing psychiatric traits. Stratified Genomic SEM showed that heritability foruASDwas significantly enriched in genes involved in evolutionarily conserved processes, as well as for a histone mark in the germinal matrix. T-SEM revealed 83 unique genes with expression associated withuASD,many of which were novel. These findings delineate the unique biological underpinnings of ASD which exist independent of ADHD and demonstrate the utility of Genomic SEM and its extensions for disambiguating shared and unique risk pathways for genetically overlapping traits.