In this cross-trait genetic analysis of ADHD, BIP, MD, schizophrenia, and cognitive and personality traits, we systematically quantified genetic architecture beyond genome-wide genetic correlations. We found marked differences in polygenicity but extensive genetic overlap across all mental disorders, cognitive, and personality traits, with few disorder-specific variants. These findings were supported by LAVA local correlations which also revealed patterns of mixed effect directions concealed by estimates of genome-wide genetic correlations. This indicates that, rather than a predominance of disorder-specific risk variants, there may be a set of highly pleiotropic variants which influence the risk of diverse mental disorders and related traits. By extension, phenotypic specificity may be largely driven by the distribution of effect sizes and effect directions across this pool of pleiotropic variants rather than variants unique to each phenotype.17 Building on previous work highlighting extensive overlap across mental disorders,13,17 this represents a conceptual advance in our understanding of the genetic architecture of mental disorders, which may inform strategies for genetic discovery, biological characterization, and psychiatric nosology, providing the foundations for the development of precision psychiatry and treatment stratification across diagnostic boundaries.
