BACKGROUND:Despite proven heritability, little is known about the genetic architecture of mood disorders. Although a number of family and case-control studies have examined the genetics of mood disorders, none have carried out joint linkage-association studies and sought to validate the results with gene expression analyses in an independent cohort. METHODS:We present findings from a large candidate gene study that combines linkage and association analyses using families and singletons, providing a systematic candidate gene investigation of mood disorder. For this study, 876 individuals were recruited, including 83 families with 313 individuals and 563 singletons. This large-scale candidate gene analysis included 130 candidate genes implicated in addictive and other psychiatric disorders. These data showed significant genetic associations for 28 of these candidate genes, although none remained significant after correction for multiple testing. To evaluate the functional significance of these 28 candidate genes in mood disorders, we examined the transcriptional profiles of these genes within the dorsolateral prefrontal cortex and anterior cingulate for 21 cases with mood disorders and 25 nonpsychiatric controls, and carried out a pathway analysis to identify points of high connectivity suggestive of particular molecular pathways that may be dysregulated. RESULTS:Two primary gene candidates were supported by the linkage-association, gene expression profiling, and network analysis: neurotrophic tyrosine kinase receptor, type 2 (NTRK2), and the opioid receptor, κ1 (OPRK1). CONCLUSION:This study supports a role for NTRK2 and OPRK1 signaling in the pathophysiology of mood disorder. The unique approach incorporating evidence from multiple experimental and computational modalities enhances confidence in these findings.