The genetic architecture of neuropsychiatric traits: mechanism, polygenicity, and genome function

Recent progress in genome science has enabled advances in our understanding of the molecular basis underlying susceptibility to a broad spectrum of complex traits, including neuropsychiatric disorders. Methodologically, genome-wide association studies have been remarkably successful in identifying trait-associated variation, but the ever-increasing repository of reproducible genetic associations has highlighted an important gap, namely crucial insight into the underlying mechanisms for most of the identified genetic loci. Here we develop analytic methods that improve on existing approaches and present molecular data that may serve as intermediate phenotypes to higher-order clinical traits with the goal of helping to dissect, more precisely, the functional consequences of the discovered variants. We explore the challenges (methodological and translational) that emerge from the recognition of the polygenicity of neuropsychiatric disease predisposition and the implications on the types of analyses that can advance our understanding of the genetic architecture of neuropsychiatric disorders. Finally, we present research aimed at leveraging our current understanding of regulatory variation in the genome and developing an integrative approach to systematize this knowledge into elucidating the cellular and biological consequences of trait-associated variation