be to continue efforts to examine phenotypes thought to be more proximal to a genetic substrate than are clinically-defined categories.155 Putative “intermediate” or “endophenotypes” related to depression include emotion-based attention biases,156,157 impaired reward function,158 and deficits in domains of executive functioning, such as learning and memory.159 Investigation of endophenotypes is consistent with the National Institute on Mental Health (NIMH) Research Domain Criteria Initiative (RDoC;),160-163 which aims to provide a bottom-up characterization of psychopathology incorporating genetics, neural circuitry, and behavioral phenotypes. Endophenotypes have not yet been the subject of large-scale studies that might fully evaluate their power relative. One exception is the ENIGMA consortium, through which GWAS meta-analyses of structural MRI phenotypes yielded a genome-wide significant association with hippocampal volume,164 one of the best-established biomarkers of depression risk. However, this result still required sample sizes in the thousands, challenging the view that endophenotype-based studies will be more powerful than studies of major depressive disorder itself.
