DEFINE - Defining endophenotypes from integrated neurosciences (360G-Wellcome-100202_Z_12_Z)

Our objective is to rebuild the foundations of psychiatry by breaking away from existing diagnostic categories to define a new biology of mental disorders. Recent genomic studies have identified a number of genetic risk factors for neurodevelopmental disorders. These implicate specific synaptic processes but do not respect current diagnostic boundaries and confer susceptibility across a spectrum of clinical phenotypes including schizophrenia, autism, attention deficit hyperactivity disorder (ADH D), and intellectual disability. Thus, in order to identify novel biomarkers and mechanisms, it will be necessary to jettison existing categorical classifications and instead take a radically different approach based on the genetic underpinnings of these conditions. By focusing upon the effects of high-penetrance mutations that each confers risk across a range of disorders we will be able to establish convergent effects on processes involved in synaptic plasticity and associated effects at a cir cuit level. This bottom-up approach will enable us to work across species and levels of complexity to identify cellular, animal and human endophenotypes that are signatures of risk across diagnostic categories. This will enable us to prioritise animal and cellular phenotypes for future drug development and identify biomarkers of fundamental disease processes for patient studies.