Endophenotype 2.0: updated definitions and criteria for endophenotypes of psychiatric disorders, incorporating new technologies and findings.

Recent genetic studies have linked numerous loci to psychiatric disorders. However, the biological pathways that connect these genetic associations to psychiatric disorders' specific pathophysiological processes are largely unclear. Endophenotypes, first defined over five decades ago, are heritable traits, independent of disease state that are associated with a disease, encompassing a broad range of neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, and neuropsychological characteristics. Considering the advancements in genetics and genomics over recent decades, we propose a revised definition of endophenotypes as 'genetically influenced phenotypes linked to disease or treatment characteristics and their related events.' We also updated endophenotype criteria to include (1) reliable measurement, (2) association with the disease or its related events, and (3) genetic mediation. 'Genetic mediation' is introduced to differentiate between causality and pleiotropic effects and allows non-linear relationships. Furthermore, this updated Endophenotype 2.0 framework expands to encompass genetically regulated responses to disease-related factors, including environmental risks, illness progression, treatment responses, and resilience phenotypes, which may be state-dependent. This broadened definition paves the way for developing new endophenotypes crucial for genetic analyses in psychiatric disorders. Integrating genetics, genomics, and diverse endophenotypes into multi-dimensional mechanistic models is vital for advancing our understanding of psychiatric disorders. Crucially, elucidating the biological underpinnings of endophenotypes will enhance our grasp of psychiatric genetics, thereby improving disease risk prediction and treatment approaches.