Defining the Genetic, Genomic, Cellular, and Diagnostic Architectures of Psychiatric Disorders

Studies of the genetics of psychiatric disorders have become one of the most exciting and fast-moving areas in human genetics. A decade ago, there were few reproducible findings, and now there are hundreds. In this review, we focus on the findings that have illuminated the genetic architecture of psychiatric disorders and the challenges of using these findings to inform our understanding of pathophysiology. The evidence is now overwhelming that psychiatric disorders are "polygenic"-that many genetic loci contribute to risk. With the exception of a subset of those with ASD, few individuals with a psychiatric disorder have a single, deterministic genetic cause; rather, developing a psychiatric disorder is influenced by hundreds of different genetic variants, consistent with a polygenic model. As progressively larger studies have uncovered more about their genetic architecture, the need to elucidate additional architectures has become clear. Even if we were to have complete knowledge of the genetic architecture of a psychiatric disorder, full understanding requires deep knowledge of the functional genomic architecture-the implicated loci impact regulatory processes that influence gene expression and the functional coordination of genes that control biological processes. Following from this is cellular architecture: of all brain regions, cell types, and developmental stages, where and when are the functional architectures operative? Given that the genetic architectures of different psychiatric disorders often strongly overlap, we are challenged to re-evaluate and refine the diagnostic architectures of psychiatric disorders using fundamental genetic and neurobiological data.