Molecular and Genetic Characterization of Depression: Overlap with Other Psychiatric Disorders and Aging

Ding, Ying; Chang, Lun‐Ching; Wang, Xingbin; Guilloux, Jean‐Philippe; Parrish, Jenna N; Oh, Heung Bum; French, Beverly J.; Lewis, David A.; Tseng, George C.; Sibille, Etienne

doi:10.1159/000369974

Cited by 58 publications

(79 citation statements)

References 45 publications

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“…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]. While single-nucleotide polymorphisms (SNPs) in the Gabbr2 gene are associated with MDD, human postmortem studies have not found altered expression of this gene in the brain (e.g., [85, 87]). Since we found increased expression of Gabbr2 in the PFC of XX mice but not XY mice, it is tempting to speculate that human postmortem studies might find an effect on Gabbr2 expression if analyses were stratified by sex.…”

Section: Discussionsupporting

confidence: 71%

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

et al. 2019

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Women are twice as likely as men to be diagnosed with major depressive disorder (MDD). Recent studies report distinct molecular changes in depressed men and women across mesocorticolimbic brain regions. However, it is unclear which sex-related factors drive distinct MDD-associated pathology. The goal of this study was to use mouse experimental systems to investigate sex-specific mechanisms underlying the distinct molecular profiles of MDD in men and women. We used unpredictable chronic mild stress to induce an elevated anxiety-/depressive-like state and “four core genotypes” (FCG) mice to probe for sex-specific mechanisms. As predicted, based on previous implications in mood, stress impacted the expression of several dopamine-, GABA-, and glutamate-related genes. Some of these effects, specifically in the prefrontal cortex, were genetic sex-specific, with effects in XX mice but not in XY mice. Stress also impacted gene expression differently across the mesocorticolimbic circuit, with increased expression of mood-related genes in the prefrontal cortex and nucleus accumbens, but decreased expression in basolateral amygdala. Our results suggest that females are sensitive to the effects of chronic stress, partly due to their genetic sex, independent of gonadal hormones. Furthermore, these results point to the prefrontal cortex as the node in the mesocorticolimbic circuitry with the strongest female-specific effects.

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Section: Discussionsupporting

confidence: 71%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…MDD also shows substantial heritability (approx. 0.37) [9, 10] and polygenic inheritance [11, 12]. However, promis ing genetic risk candidates for SCZ and MDD had not been well implicated until the emergence of recent large-scale genome-wide association studies (GWAS) [13-21].…”

Section: Introductionmentioning

confidence: 99%

VRK2, a Candidate Gene for Psychiatric and Neurological Disorders

Yue

2018

Complex Psychiatry

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Recent large-scale genetic approaches, such as genome-wide association studies, have identified multiple genetic variations that contribute to the risk of mental illnesses, among which single nucleotide polymorphisms (SNPs) within or near the vaccinia related kinase 2 (VRK2) gene have gained consistent support for their correlations with multiple psychiatric and neurological disorders including schizophrenia (SCZ), major depressive disorder (MDD), and genetic generalized epilepsy. For instance, the genetic variant rs1518395 in VRK2 showed genome-wide significant associations with SCZ (35,476 cases and 46,839 controls, p = 3.43 × 10^–8) and MDD (130,620 cases and 347,620 controls, p = 4.32 × 10^–12) in European populations. This SNP was also genome-wide significantly associated with SCZ in Han Chinese population (12,083 cases and 24,097 controls, p = 3.78 × 10^–13), and all associations were in the same direction of allelic effects. These studies highlight the potential roles of VRK2 in the central nervous system, and this gene therefore might be a good candidate to investigate the shared genetic and molecular basis between SCZ and MDD, as it is one of the few genes known to show genome-wide significant associations with both illnesses. Furthermore, the VRK2 gene was found to be involved in multiple other congenital deficits related to the malfunction of neurodevelopment, adding further support for the involvement of this gene in the pathogenesis of these neurological and psychiatric illnesses. While the precise function of VRK2 in these conditions remains unclear, preliminary evidence suggests that it may affect neuronal proliferation and migration via interacting with multiple essential signaling pathways involving other susceptibility genes/proteins for psychiatric disorders. Here, we have reviewed the recent progress of genetic and molecular studies of VRK2, with an emphasis on its role in psychiatric illnesses and neurological functions. We believe that attention to this important gene is necessary, and further investigations of VRK2 may provide hints into the underlying mechanisms of SCZ and MDD.

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“…This leads to the idea that BPD and MDD may have common genetic risk features. In fact, clinical, epidemiological, and genetic studies have revealed similar phenotypic characteristics between BPD and MDD [3, 6], and there are also overlapping risk genes, such as CACNA1C [7], CREB1 [8], and AS3MT [9-11]. It is thus proposed that genetic analyses of these two illnesses could uncover important genes underlying the symptoms observed in both diseases.…”

Section: Introductionmentioning

confidence: 99%

“…We then collected the published data of 15,318 cases and 91,990 controls worldwide and conducted a meta-analysis to further verify the replication results. In addition, considering the substantial genetic overlap between BPD and MDD [6, 29], we also examined rs1064395 in two MDD GWAS samples.…”

Section: Introductionmentioning

confidence: 99%

Further Evidence of an Association between NCAN rs1064395 and Bipolar Disorder

Wang

Liu

et al. 2018

Complex Psychiatry

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Genome-wide association studies suggest that rs1064395 in the neurocan gene (NCAN) is a potential risk factor for bipolar disorder (BPD), and further replication analyses in larger independent samples are needed. We herein analyzed rs1064395 in a Han Chinese sample of 1,146 BPD cases and 2,031 controls, followed by a meta-analysis of BPD samples from worldwide populations including a total of 15,318 cases and 91,990 controls. The meta-analysis found that rs1064395 showed a genome-wide significant association with BPD (p = 4.92 × 10^–9, OR = 1.126 for the A allele), although it did not reach the significance level in the Han Chinese sample (p = 0.415, OR = 1.070 for the A allele). We also examined the association between the single nucleotide polymorphisms and major depressive disorder (MDD) given the presumed genetic overlap between BPD and MDD, and rs1064395 was also associated with MDD (p = 0.0068, OR = 1.067 for the A allele) in a meta-analysis of 14,543 cases and 14,856 controls. Our data provide further evidence for the involvement of NCAN in the genetic susceptibility to BPD and also implicate its broader role in major mood disorders.

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Molecular and Genetic Characterization of Depression: Overlap with Other Psychiatric Disorders and Aging

Cited by 58 publications

References 45 publications

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

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

<b><i>VRK2</i></b>, a Candidate Gene for Psychiatric and Neurological Disorders

Further Evidence of an Association between <b><i>NCAN</i></b> rs1064395 and Bipolar Disorder

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