Cross-disorder analysis of autism and adhd using rare variants: insights from danish ipsych exomes

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 seeks to extend these findings, employing a significantly larger iPSYCH exome dataset for gene discovery and to estimate the heritability attributable to the rare variant burden in ASD and ADHD, and to determine the rare variant genetic correlation between these disorders. We investigated an extended iPSYCH case-cohort exome dataset linked with the Danish health register system, including individuals diagnosed with ASD and/or ADHD, alongside controls. We apply multivariate Poisson regression models to systematically estimate rare variant burdens across all genes, constrained genes with pLI > 0.9, and multiple gene sets associated with different disorders including ASD, neurodevelopmental disorders, and schizophrenia. These estimates are undertaken separately for distinct groups: (i) individuals diagnosed with ASD alone (ASD-only), (ii) individuals diagnosed with ADHD alone (ADHD-only), (iii) individuals diagnosed with both ASD and ADHD (ASD+ADHD), and (iv) a control group without any of diagnoses including ASD, ADHD, schizophrenia, bipolar disorder, affective disorder and anorexia and intellectual disability (ID), stratified further by the presence or absence of ID. We use burden heritability regression to estimate the burden heritability of ASD and ADHD respectively, and the rare variant genetic correlation between the two disorders. For gene discovery, we combine individuals diagnosed with ASD and/or ADHD into a single case group and use TADA+ to integrate with family data and Swedish PAGE case-control data from the most recent ASD exome study (Fu et al., 2022). Post quality control, exomes of 25,457 individuals were included, encompassing 7,556 individuals with ASD-only, 5,536 with ADHD-only, 3,359 with ASD+ADHD, and 9,005 controls. Our preliminary results echoed our earlier work (Satterstrom et al., 2019). We observed similar rates of rare PTVs in constrained genes between ASD and ADHD (mean = 0.228 and se = 0.0055 for ASD-only; mean = 0.23 and se = 0.0067 for ADHD-only; mean = 0.242 and se = 0.0086 for ASD+ADHD), while all these three case groups showed a significant excess compared to controls (mean = 0.168 and se = 0.0044). Our c-alpha tests found no significant differences between ASD-only and ADHD-only groups for rare PTVs in constrained genes (P= 0.48). However, when comparing either case group to controls, significant differences were observed (P = 9.74 × 10-7 for ASD-only versus controls; P = 3.16 × 10-10 for ADHD-only versus controls). Our preliminary findings suggest shared genetic underpinnings across ASD and ADHD. It motivates us to merge individuals diagnosed with ASD and/or ADHD into a single group to enhance gene discovery. In our presentation, we will expound upon the results of our ongoing analyses as listed in the method section. The application of multivariate Poisson regression, rare variant burden heritability, and TADA+ is novel in this context. We hope that these methods will further our understanding of the shared genetic foundation of ASD and ADHD.