Differential ADAR editing landscapes in major depressive disorder and suicide

Abstract

Neuropsychiatric 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.

Alterations in RNA editing in skeletal muscle following exercise training in individuals with Parkinson’s disease

“…Importantly, albeit consistent with the bulk of PD research to-date, the lack of female samples creates an obstacle in furthering our understanding of PD, its progression, and how sex impacts its manifestation [22,86]. While we acknowledge that the extremely small sample size of post-training PD females (n = 1) and other groups makes it difficult to draw conclusions on the effects of exercise training on ADAR editing in PD, we identified intriguing trends that warrant further data collection and research.…”

“…Briefly, this program consisted of thrice weekly sessions of strength, power, endurance, balance, and functional training lasting between 35-45 minutes. Because the Lavin et al [22] study included only a handful of female samples (Older Females = 3, PD Females = 3, Younger Females = 3, and Post-Training Females = 1), and our prior studies have suggested sex-specific differences in ADAR editing patterns [86], we focused our analyses on male samples. Nonetheless, the results of a preliminary analysis on this small subset are discussed briefly in our results.…”

“…The Lavin et al study [22] also included 10 female samples: 3 Older Females, 3 PD Females, 3 Younger Females, and 1 Post-Training PD Female. This sample number was not robust enough to make valid comparisons between groups and considering our previous findings that ADAR editing may vary between the sexes [86], we are not including an in-depth analysis of female samples along with this research. However, we did conduct a basic analysis of female data, with some intriguing results that we believe warrant future analysis and research.…”

Alterations in RNA editing in skeletal muscle following exercise training in individuals with Parkinson’s disease

“…The transcriptomics dataset used in this study included samples from various subgroups from the skeletal muscle RNA-seq study of Lavin et al (6) and our prior studies have suggested sex-specific differences in ADAR editing patterns (62), we focused our analyses on male samples. Table 1…”