LAUSR

Overall Abstract Attention Deficit Hyperactivity Disorder (ADHD) is a childhood behavioral disorder affecting 5% of school-age children and 2.5% of adults. The disorder is diagnosed more frequently in males than in females, in particular in children where the diagnosis rate is 3-7 times higher in males compared to females. Results from more than 30 twin studies indicate that the heritability (h^2) of ADHD is 70-80%, and a very recent genome-wide association study (GWAS) of 20,183 ADHD cases and 35,191 controls succeeded in identifying the first 12 genome-wide significant loci based on a large international collaboration anchored at the PGC-ADHD and iPSYCH-Broad consortia. This GWAS also found that the proportion of variance attributable to genome-wide common variants (liability-scale SNP heritability, h_SNP^2) is around 22%. Thus, the h_SNP^2 accounts for between a third and a quarter of the overall h^2, leaving a substantial part of the h^2 unaccounted for, which could potentially be explained in part by rare risk variants contributing to the etiology. Furthermore, analysis of the recent ADHD GWAS data revealed strong genetic correlations with other psychiatric disorders, including autism spectrum disorder and major depression, both showing genetic correlations of 0.3-0.4. In this symposium, we examine the genetic architecture of ADHD by assessing both the common and rare variant contributions. First, we expand upon the results from the aforementioned GWAS by incorporating additional samples of non-European ancestry to advance locus discovery, improve fine-mapping of the identified loci, and evaluate transferability of ADHD risk prediction across ancestries. Second, we examine the difference in prevalence between males and females using Swedish whole population registry data and Swedish twin data. Third, we report on cross-disorder studies between ADHD and, respectively, autism and major depression, using the largest and newly updated GWAS data from the PGC based studies of these disorders. Fourth, we present results from analyses of rare variants identified by whole exome sequencing of several thousand cases and controls, focusing on the impact on ADHD risk of ultra-rare deleterious variants.