In summary, we have used advanced statistical modelling to demonstrate both considerable similarities yet also fundamental differences in the genetic architecture of ADHD, BIP, schizophrenia and MD, alongside cognitive and personality traits. Despite extensive genetic overlap and few trait-specific variants, there were distinct patterns of genetic correlations with widespread mixed effect directions. This suggests that it is the specific distribution of effect sizes of highly pleiotropic variants that predominantly contribute to the development of mental disorders and related traits, rather than a set of disorder-specific variants. This represents a conceptual advance in our understanding of the genetic risk of mental disorders, suggesting that normative and pathological mental traits, and the biological processes underlying them, exist on the same dimensions in genomic space. These findings place greater emphasis on efforts to improve the specificity of psychiatric diagnostic categories, potentially offering a means to test the genetic heterogeneity of hypothesized sub-groups through estimates of polygenicity. This may aid efforts to refine the current nosological system, with potential for improved translation of genetic findings into clinically meaningful prediction and stratification tools, and improved drug target identification.
