Differential ADAR editing landscapes in major depressive disorder and suicide

AbstractNeuropsychiatric disorders, including depression and suicide, are becoming an increasing public health concern. Rising rates of both depression and suicide, exacerbated by the current COVID19 pandemic, have only hastened our need for objective and reliable diagnostic biomarkers. These can aide clinicians treating depressive disorders in both diagnosing and developing treatment plans. While differential gene expression analysis has highlighted the serotonin signaling cascade among other critical neurotransmitter pathways to underly the pathology of depression and suicide, the biological mechanisms remain elusive. Here we propose a novel approach to better understand molecular underpinnings of neuropsychiatric disorders by examining patterns of differential RNA editing by adenosine deaminases acting on RNA (ADARs). We take advantage of publicly available RNA-seq datasets to map ADAR editing landscapes in a global gene-centric view. We use a unique combination of Guttman scaling and random forest classification modeling to create, describe and compare ADAR editing profiles focusing on both spatial and biological sex differences. We use a subset of experimentally confirmed ADAR editing sites located in known protein coding regions, the excitome, to map ADAR editing profiles in Major Depressive Disorder (MDD) and suicide. Using Guttman scaling, we were able to describe significant changes in editing profiles across brain regions in males and females with respect to cause of death (COD) and MDD diagnosis. The spatial distribution of editing sites may provide insight into biological mechanisms under-pinning clinical symptoms associated with MDD and suicidal behavior. Additionally, we use random forest modeling including these differential profiles among other markers of global editing patterns in order to highlight potential biomarkers that offer insights into molecular changes underlying synaptic plasticity. Together, these models identify potential prognostic, diagnostic and therapeutic biomarkers for MDD diagnosis and/or suicide.