CROSS-DISORDER RARE VARIANT ANALYSIS OF AUTISM AND ADHD

Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are heterogeneous neurodevelopmental disorders with high heritability and frequent co-occurrence. Our previous work on the first phase of iPSYCH exomes (Satterstrom et al., 2019) suggested a similar burden of rare protein-truncating variants (PTVs) across ASD and ADHD and identified MAP1A as a shared risk gene implicated by rare PTVs in both disorders. This study aims to 1) extend these findings, employing a significantly larger iPSYCH exome dataset for gene discovery, 2) estimate the burden heritability explained by rare coding variants in ASD and ADHD, and 3) assess the burden genetic correlation between the two disorders.

We analyzed exomes of 25,208 individuals from iPSYCH, encompassing 7,119 individuals diagnosed with ASD alone (ASD-only), 5,598 with ADHD alone (ADHD-only), 3,794 with both ASD and ADHD (ASD+ADHD), and 8,697 controls. We used multivariate Poisson regression models to systematically evaluate rare variant burdens in different gene sets across the three case groups and controls, stratified further by the presence or absence of intellectual disability (ID). The gene sets included all genes, genes intolerant to loss-of-function variants (pLI > 0.9), and gene sets associated with different disorders including ID, ASD, ADHD, schizophrenia, and a broader group of neurodevelopmental disorders. We applied c-alpha tests to assess whether the distribution of rare deleterious variants differs between ASD and ADHD. We employed burden heritability regression to estimate the burden heritability of ASD and ADHD, respectively, and the burden genetic correlation between the two disorders. For gene discovery, we combined individuals diagnosed with ASD and/or ADHD into a single case group and applied TADA+ to integrate with family data and Swedish PAGES case-control data from a recent large-scale ASD rare variant study (Fu et al., 2022).

We observed similar burdens of class I variants including rare PTVs and rare deleterious missense variants (MPC > 3) in constrained genes across the three case groups, while they all showed a significant excess compared to controls: OR = 1.35, 95% CI = [1.26, 1.45] for ASD-only; OR = 1.35, CI = [1.25, 1.45] for ADHD-only; and OR = 1.39, CI = [1.28, 1.52] for ASD+ADHD. The c-alpha tests indicated no significant differences in the distribution of class I variants in constrained genes between ASD-only and ADHD-only groups (P= 0.39) while, when comparing the case groups to controls, significant differences were observed. The burden heritability of class I variants on the liability scale was estimated to 1.87% (SE = 0.51%) for ASD and 2.42% (s.e. = 0.72%) for ADHD. The class I variant burden genetic correlation between ASD and ADHD was 0.31 (s.e. = 0.26), which approximates the point estimate of their common-variant genetic correlation of 0.42 (s.e. = 0.05) (Demontis et al., 2023).

Our findings suggest substantial sharing of rare variant risk between ASD and ADHD, reinforcing the results of our earlier work (Satterstrom et al., 2019). This motivated us to merge individuals diagnosed with ASD and/or ADHD into a single group to enhance the discovery of rare variant risk genes shared between the disorders. This gene discovery analysis is ongoing, and the results will be presented at the conference.