Finally, the cross-sectional nature of the study is also a limitation, as longitudinal relationships between levels of the genotype-phenotype pathway and temporal sequencing of possible mediation could not be investigated. Future cross-level studies involving candidate genes would be wise to include multiple assessment points to clarify whether changes in molecular and neural systems measurements influence mood disorder progression. These studies can further elucidate whether molecular or neural system Inhibitors,research,lifescience,medical changes are influenced by genotype, as has

been shown for BDNF and changes in brain volumes during recovery from drinking (Mon et al. 2013). The present study greatly extends knowledge of the role of CACNA1C variation in brain structure, function, and vulnerability to mood dysregulation. It also provides a model, as well as a cautionary tale, Inhibitors,research,lifescience,medical that informs future cross-level studies evaluating the role of common genetic variation in complex neuropsychiatric diseases. Future large-scale multimodal studies will be needed to clarify

Inhibitors,research,lifescience,medical relationships between candidate genes, structural and functional brain characteristics, and cognitive processes related to mood disorder vulnerability. These types of studies, if well-powered, have the potential to identify specific molecular-neural systems relationships involved in mood disorder. In doing so, translational studies may identify sensitive neural treatment targets Inhibitors,research,lifescience,medical for genetically informed therapeutics, enhancing the speed of development and efficacy evaluation of new medicines. Acknowledgments This project was supported by a young investigator award from the Brain and Behavior Research Foundation and a career development award Inhibitors,research,lifescience,medical from the Case Western Reserve University/Cleveland Clinic CTSA Grant Number UL1 RR024989 provided by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health. The work was also partly supported

by grants MH 068766 and RR 020571 and with resources and the use of facilities at the CP724714 Michael E. DeBakey VA Medical Center. The sponsors had no role in the through design and conduct of the study, collection, or management of the data. The sponsors had no role in the analysis or interpretation of the data; or preparation, review, or approval of the manuscript. The views and opinions expressed in this article are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies, or US government. All authors participated in framing the research question, designing the analysis plan, and/or interpreting results. Dr. Frazier prepared the first draft of the manuscript. All authors participated in revising the manuscript after the first draft was prepared. Drs.