A pilot integrative genomics study of GABA and glutamate neurotransmitter systems in suicide, suicidal behavior, and major depressive disorder

Abstract

Gamma-amino butyric acid (GABA) and glutamate are the major inhibitory and excitatory neurotransmitters in the mammalian central nervous system, respectively, and have been associated with suicidal behavior and major depressive disorder (MDD). We examined the relationship between genotype, brain transcriptome, and MDD/suicide for 24 genes involved in GABAergic and glutamatergic signaling. In part 1 of the study, 119 candidate SNPs in 24 genes (4 transporters, 4 enzymes, and 16 receptors) were tested for associations with MDD and suicidal behavior in 276 live participants (86 nonfatal suicide attempters with MDD and 190 non-attempters of whom 70% had MDD) and 209 postmortem cases (121 suicide deaths of whom 62% had MDD and 88 sudden death from other causes of whom 11% had MDD) using logistic regression adjusting for sex and age. In part 2, RNA-seq was used to assay isoform-level expression in dorsolateral prefrontal cortex of 59 postmortem samples (21 with MDD and suicide, 9 MDD without suicide, and 29 sudden death non-suicides and no psychiatric illness) using robust regression adjusting for sex, age, and RIN score. In part 3, SNPs with subthreshold (uncorrected) significance levels below 0.05 for an association with suicidal behavior and/or MDD in part 1 were tested for eQTL effects in prefrontal cortex using the Brain eQTL Almanac (www.braineac.org). No SNPs or transcripts were significant after adjustment for multiple comparisons. However, a protein coding transcript (ENST00000414552) of the GABA A receptor, gamma 2 (GABRG2) had lower brain expression postmortem in suicide (P = 0.01) and evidence for association with suicide death (P = 0.03) in a SNP that may be an eQTL in prefrontal cortex (rs424740, P = 0.02). These preliminary results implicate GABRG2 in suicide and warrant further investigation and replication in larger samples.

Sex-Specific Effects of Stress on Mood-Related Gene Expression

“…We found that Gabarapl1 expression was increased by chronic stress in the PFC and NAc, consistent with results in human MDD in which expression is increased in Brodmann area 9 (BA9), BA10, BA20, and BA46 [84, 85]. Consistent with what we observed for the effects of stress on Gabra2 expression in the PFC and NAc, subjects with MDD have increased Gabra2 expression in the cerebellum [86].…”

“…Our results for Gria1 are consistent with reports in the literature. For instance, GRIA1 expression is increased in BA9 [84, 87] and BA21 [85] in MDD subjects. We also saw increased Gria1 expression in the PFC and NAc of chronically stressed mice.…”

Analyzing the genes and pathways related to major depressive disorder via a systems biology approach

“…Neuroendocrine and immune system interactions play an important role in stress response (Ashley & Demas, 2017;Dantzer, 2018). By comparing our results with that of a meta-analysis on genes implicated in MDD (Gatt et al, 2015;Manoharan et al, 2016;Yin et al, 2016), we found that most of the pathways reported earlier were also identified in the current study. Both stress and inflammatory cytokine activation have been reported to have adverse effect on the neurogenesis and neural plasticity (Syed et al, 2018).…”

Genomewide association studies of suicide attempts in US soldiers

“…Although twin studies have documented genetic influences on suicide-related phenotypes (heritability ~30% – 55%) [Tidemalm et al 2011], it is clear that suicidality is a multi-determined, genetically complex trait, as is the case for virtually all mental and behavioral disorders [Gelernter 2015]. Thus, a great many genes and genomic processes (e.g., epistasis and epigenetic variation) are likely to contribute to risk for suicidality, but none have been firmly established [Niculescu et al 2015a; Oquendo et al 2014; Sokolowski et al 2014; Turecki 2014; Yin et al 2016]. …”