Contact PD/PI: Vladimirov Vladimir IAbstract: The objective of this proposal is to investigate the biological mechanisms by which microRNAs (miRNAs)contribute to major depressive disorder (MDD). MDD is a severe mental disorder and the single most commonrisk factor for suicide. Recent genome-wide association studies (GWAS) of large samples of MDD have for thefirst time identified robust genetic associations with major depression. However the biological mechanisms bywhich these increase the risk for major depression are still unknown. Additionally most genetic variantsassociated with MDD fall outside of the protein coding transcriptome suggesting that their functional impact islikely to affect gene expression levels rather than protein structure. MiRNA are highly expressed in the brain andwere shown to play an important role in the pathology of psychiatric disorders including MDD and their canonicalfunctions are to control gene expression levels. Despite their importance however profiling of miRNA expressionin large postmortem brain samples for various neuropsychiatric disorders including MDD across different brainregions currently do not yet exist. Thus in this application we propose to use miRNA sequencing to assess miRNA expression in one of thelargest postmortem brain samples of major depression in the world. The sample has been extensivelycharacterized clinically genetically and molecularly and provides a unique resource for examining theneurobiological mechanisms by which genetic factors contribute to major depression directly in the primaryaffected tissue. Our miRNA data will be integrated with an ongoing RNA sequencing data generated in the samesubjects to identify miRNA/mRNA pairs with important disease functions. Our aims are to: 1) carry out miRNAsequencing of the subgenual anterior cingulate cortex (sACC) and amygdala in 200 recurrent MDD cases and200 matched controls 2) test whether genome-wide significant SNPs from GWAS of MDD are associated withmiRNA expression across these key regions of the brain 3) identify miRNA whose expression is associated withmajor depression and suicide and perform a series of univariate multivariate (network) and data integrationanalyses to further elucidate miRNA role in the neuropathology of MDD 4) replicate our top miRNA (FDR 5%)in an independently ascertain postmortem brain sample of 50 MDD cases and 50 matched controls. In aim 4 wewill also perform series of exploratory analyses to identify the cellular mechanism by which risk MDD variantsaffect miRNA/mRNA interactions. We hypothesize that a major mechanism contributing to the etiology of majordepression is through the ability of risk MDD variants to affect miRNA expression and functions. By explicatingthe mechanisms by which risk MDD variants lead to increase risk of major depression we will provide noveltargets for intervention in the disease process and therefore a more rational basis for improved treatments.