Genetic variant of <i>AKT1</i> and <i>AKTIP</i> associated with late‐onset depression in a Brazilian population

Pereira, Patrícia A.; Bicalho, Maria Aparecida Camargos; Moraes, Edgar Nunes de; Malloy-Diniz, Leandro Fernandes; Bozzi, Isadora Cristine Reis Sguizzato; Nicolato, Rodrigo; Valadão, Daniela Rosa; Miranda, Débora Marques de; Romano-Silva, Marco Aurélio

doi:10.1002/gps.4018

Cited by 23 publications

(12 citation statements)

References 39 publications

(42 reference statements)

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“…Genetic polymorphism in SLC29A2 showed suggestive association in candidate-gene studies ( p -value < 0.05) with depression and depression with fatigue phenotypes in men 109 , as well with childhood trauma score within MDD cases 110 . Genetic polymorphism in AKT1 was associated with severity of depression, anxiety symptoms and suicide attempts in patients with MDD from a Chinese Han population 111 , with late-onset depression in a Brazilian population 112 , and antidepressant treatment response in patients with depressive disorder in a Caucasian population 113 . Differential methylation of AKT1 in blood was associated with clinical post-traumatic stress disorder in combat veterans 114 , and in post-mortem brain of schizophrenia patients compared to unaffected controls 115 , while changes in its expression level in blood were positively correlated with improvement of depression symptoms among bipolar disorder patients treated with lithium 116 .…”

Section: Discussionmentioning

confidence: 99%

Epigenome-wide association study of depression symptomatology in elderly monozygotic twins

et al. 2019

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Depression is a severe and debilitating mental disorder diagnosed by evaluation of affective, cognitive and physical depression symptoms. Severity of these symptoms strongly impacts individual’s quality of life and is influenced by a combination of genetic and environmental factors. One of the molecular mechanisms allowing for an interplay between these factors is DNA methylation, an epigenetic modification playing a pivotal role in regulation of brain functioning across lifespan. The aim of this study was to investigate if there are DNA methylation signatures associated with depression symptomatology in order to identify molecular mechanisms contributing to pathophysiology of depression. We performed an epigenome-wide association study (EWAS) of continuous depression symptomatology score measured in a cohort of 724 monozygotic Danish twins (346 males, 378 females). Through EWAS analyses adjusted for sex, age, flow-cytometry based blood cell composition, and twin relatedness structure in the data we identified depression symptomatology score to be associated with blood DNA methylation levels in promoter regions of neuropsin ( KLK8 , p -value = 4.7 × 10 −7 ) and DAZ associated protein 2 ( DAZAP2 , p -value = 3.13 × 10 −8 ) genes. Other top associated probes were located in gene bodies of MAD1L1 ( p -value = 5.16 × 10 −6 ), SLC29A2 ( p -value = 6.15 × 10 −6 ) and AKT1 ( p -value = 4.47 × 10 −6 ), all genes associated before with development of depression. Additionally, the following three measures (a) DNAmAge (calculated with Horvath and Hannum epigenetic clock estimators) adjusted for chronological age, (b) difference between DNAmAge and chronological age, and (c) DNAmAge acceleration were not associated with depression symptomatology score in our cohort. In conclusion, our data suggests that depression symptomatology score is associated with DNA methylation levels of genes implicated in response to stress, depressive-like behaviors, and recurrent depression in patients, but not with global DNA methylation changes across the genome.

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Section: Discussionmentioning

confidence: 99%

Epigenome-wide association study of depression symptomatology in elderly monozygotic twins

et al. 2019

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“…Atypical antipsychotics also promote AKT activity (Alimohamad et al, 2005;Li et al, 2007). In other disorders, AKT has been implicated by postmortem brain tissue from suicide victims showing decreased AKT activity (Hsiung et al, 2003), genetic studies associating AKT1 SNPs with BD (Karege et al, 2010;Karege et al, 2012) and depression (Ellsworth et al, 2013;Pereira et al, 2014), and pharmacological studies showing that lithium, used widely to treat schizophrenia and BP (Chalecka-Franaszek and Chuang, 1999;De Sarno et al, 2002;Beaulieu et al, 2004;Beaulieu et al, 2008;Nciri et al, 2013), and the antidepressant ketamine (Park et al, 2014) induce AKT signaling. Altogether, these studies suggest AKT is a key factor in the manifestation of psychiatric disorders and a key mechanism of action by current treatments.…”

Section: Human and Animal Studies Linking Akt To Psychiatric Disordersmentioning

confidence: 99%

Isoform-specific roles for AKT in affective behavior, spatial memory, and extinction related to psychiatric disorders

Wong

Levenga

LaPlante

et al. 2020

eLife

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AKT is implicated in neurological disorders. AKT has three isoforms, AKT1/AKT2/AKT3, with brain cell type-specific expression that may differentially influence behavior. Therefore, we examined single Akt isoform, conditional brain-specific Akt1, and double Akt1/3 mutant mice in behaviors relevant to neuropsychiatric disorders. Because sex is a determinant of these disorders but poorly understood, sex was an experimental variable in our design. Our studies revealed AKT isoform- and sex-specific effects on anxiety, spatial and contextual memory, and fear extinction. In Akt1 mutant males, viral-mediated AKT1 restoration in the prefrontal cortex rescued extinction phenotypes. We identified a novel role for AKT2 and overlapping roles for AKT1 and AKT3 in long-term memory. Finally, we found that sex-specific behavior effects were not mediated by AKT expression or activation differences between sexes. These results highlight sex as a biological variable and isoform- or cell type-specific AKT signaling as potential targets for improving treatment of neuropsychiatric disorders.

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“…It is in the monopolistic position between modules in the network and more suitable as a therapeutic target. AKT1, a downstream enzyme that has been implicated in the pathogenesis of serotonin-related disorders, facilitates growth factor-mediated cell survival and block apoptosis through the regulation of its downstream effector (GSK-3) in depressants [22][23]. Thus, the regulation of AKT1 activity by ginseng (kaempferol) inhibit and alleviate depression by a variety of ways.…”

Section: Discussionmentioning

confidence: 99%

Network pharmacology-based active compounds and pharmacological mechanisms of ginseng for depression in post-COVID-19

Wang

et al. 2020

Preprint

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Abstract Introduction: The novel coronavirus disease 2019 (COVID-19) is in the midst of worldwide panic. Sudden onset of an immediate life-threatening illness, quarantine and unemployment caused by epidemic are all contributors to depression. Ginseng has been reported to be an effective and safe clinical treatment on both immune-regulation and anti-depression. However, the mechanism of its anti-depression effect has not been fully characterized. In order to provide theoretical guidance for further clinical application in post-pandemic, we investigated active compounds and pharmacological mechanisms of ginseng to exert anti-depressant activity using network pharmacology, and discussed the active ingredients with immune-regulation and anti-depression.Methods: Information on compounds in ginseng was obtained from public databases, and genes related to depression were gathered using the GeneCards database. Networks of ginseng-associated targets and depression-related genes were constructed through STRING database. Potential targets and pathway enrichment analysis related to the therapeutic efficacy of ginseng for depression were identified using Cytoscape and Database for Annotation, Visualization and Integrated Discovery (DAVID). Results: Network pharmacological analysis of ginseng in treatment of depression identified 16 active ingredients, 47 potential targets, 32 GO terms, and 8 target gene-regulated major pathways. Among them, kaempferol, beta-sitosterol, stigmasterol, fumarine and frutinone A are bioactive compounds and key chemicals. Core genes in PPI network were AKT1, CASP3, NOS3, TNF, and PPARG. Enrichment results revealed that ginseng could regulate multiple aspects of depression through neuroactive ligand-receptor interaction, HIF-1 signaling pathway, and Serotonergic synapse. More importantly, we found that frutinone A and kaempferol are key ingredients in ginseng with dual activities of immune-regulation and anti-depression. Conclusions: We discovered that the therapeutic activities of ginseng for depression mainly involve neurotransmitters, neurotrophic factors, neurogenesis, HPA axis and inflammatory response. Pharmacological network analysis can help to explain the potential effects of ginseng for treating depression, indicating that ginseng is a preferable herb clinically for immune-regulation and anti-depression in post-pandemic.

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Genetic variant of AKT1 and AKTIP associated with late‐onset depression in a Brazilian population

Abstract: This study is the first one to establish the association of the AKT1/AKTIP genes and LOD, and further studies are necessary to clarify the functional role of these proteins.

Cited by 23 publications

References 39 publications

Epigenome-wide association study of depression symptomatology in elderly monozygotic twins

Epigenome-wide association study of depression symptomatology in elderly monozygotic twins

Isoform-specific roles for AKT in affective behavior, spatial memory, and extinction related to psychiatric disorders

Network pharmacology-based active compounds and pharmacological mechanisms of ginseng for depression in post-COVID-19

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