Abstract
Long non-coding RNAs (lncRNAs) are an emerging class of regulatory RNA that may be implicated in psychiatric disorders. Here we performed RNA-sequencing in the rostral anterior cingulate cortex of 26 depressed suicides and 24 matched controls. We first performed differential lncRNA expression analysis, and then conducted Weighted Gene Co-expression Network Analysis (WGCNA) to identify co-expression modules associating with depression and suicide. We identified 23 differentially expressed lncRNAs (FDR < 0.1) as well as their differentially expressed overlapping and antisense protein-coding genes. Several of these overlapping or antisense genes were associated with interferon signaling, which is a component of the innate immune response. Using WGCNA, we identified modules of highly co-expressed genes associated with depression and suicide and found protein-coding genes highly connected to differentially expressed lncRNAs within these modules. These protein-coding genes were located distal to their associated lncRNAs and were found to be part of several GO terms enriched in the significant modules, which include: cytoskeleton organization, plasma membrane, cell adhesion, nucleus, DNA-binding, and regulation of dendrite development and morphology. Altogether, we report that lncRNAs are differentially expressed in the brains of depressed individuals who died by suicide and may represent regulators of important molecular functions and biological processes.
Highlights
Depression is a leading cause of disability affecting 300 million people worldwide, according to estimates by World Health Organization[1], and the single most important risk factor for suicide[2]
We investigated associations between depression and module eigengenes while controlling for co-variates, as described previously:[39] eigengenes were used in a general linear model (GLM) using depression as a fixed factor while controlling for sample traits (Sex, substance use disorder (SUD), age, brain pH, post mortem interval (PMI), and RNA-integrity number (RIN)) as covariates
The expression data for 2670 long noncoding RNAs (lncRNAs) were included in downstream analysis, after filtering, with an average of 432 000 reads aligning to lncRNA genes per library
Summary
Depression is a leading cause of disability affecting 300 million people worldwide, according to estimates by World Health Organization[1], and the single most important risk factor for suicide[2]. An emerging class of non-coding RNAs, called long noncoding RNAs (lncRNAs), have recently become identified as important players involved in the mechanisms underlying disease, including mental health disorders[5]. LncRNAs are defined as RNA molecules greater than 200 bp in length with low protein-coding potential. They are found throughout the genome and are generally categorized based on their relation to other known genes. Recent investigations revealed that lncRNAs exhibit sequence conservation near their promoters, and high secondary structural conservation[7]. They show high tissue-specific[8] and
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