The FKBP5 Gene Affects Alcohol Drinking in Knockout Mice and Is Implicated in Alcohol Drinking in Humans

Qiu, Bin; Luczak, Susan E.; Wall, Tamara L.; Kirchhoff, Aaron M.; Xu, Yuxue; Eng, Mimy Y.; Stewart, Robert B.; Shou, Weinian; Boehm, Stephen L.; Chester, Julia A.; Yong, Weidong; Liang, Tiebing

doi:10.3390/ijms17081271

Cited by 28 publications

(35 citation statements)

References 73 publications

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“…The present study identified 129 genes (FDR < 0.05) that were differentially expressed in alcohol dependent subjects (Supplementary table 1). FKBP5, a well studied gene that is asoociated with alcohol use [28][29][30][31] , showed increased expression in the PFC of alcohol dependent subjects in our differential gene expression analysis (l 2 FC 0.27; P = 4.57 x 10 -7 ). Other studies have also shown that FKBP5 plays a role in alcohol drinking behaviors in rodents 28,29 and humans 32 .…”

Section: Discussionmentioning

confidence: 70%

“…Other studies have also shown that FKBP5 plays a role in alcohol drinking behaviors in rodents 28,29 and humans 32 . FKBP5 encodes FK506-binding protein 5, a glucocorticoid receptor (GR)-binding protein implicated in various psychiatric disorders and alcohol withdrawal severity 30 . Qiu and colleagues 30 reported that Fkbp5 KO mice exhibited increased alcohol consumption compared with wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

“…FKBP5 encodes FK506-binding protein 5, a glucocorticoid receptor (GR)-binding protein implicated in various psychiatric disorders and alcohol withdrawal severity 30 . Qiu and colleagues 30 reported that Fkbp5 KO mice exhibited increased alcohol consumption compared with wild-type mice. Another study has shown that the absence of Fkbp5 enhances sensitivity to alcohol withdrawal in mice 33 .…”

Section: Discussionmentioning

confidence: 99%

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Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism

Kapoor

Wang

Farris

et al. 2018

Preprint

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Alcohol exposure triggers changes in gene expression and biological pathways in human brain.We explored alterations in gene expression in the Pre-Frontal Cortex (PFC) of 65 alcoholics and 73 controls of European descent, and identified 129 genes that showed altered expression (FDR < 0.05) in subjects with alcohol dependence. Differentially expressed genes were enriched for pathways related to interferon signaling and Growth Arrest and DNA Damage-inducible 45 (GADD45) signaling. A coexpression module (thistle2) identified by weighted gene co-expression network analysis (WGCNA) was significantly correlated with alcohol dependence, alcohol consumption, and AUDIT scores. Genes in the thistle2 module were enriched with genes related to calcium signaling pathways and showed significant downregulation of these pathways, as well as enrichment for biological processes related to nicotine response and opioid signaling. A second module (brown4) showed significant upregulation of pathways related to immune signaling.Expression quantitative trait loci (eQTLs) for genes in the brown4 module were also enriched for genetic associations with alcohol dependence and alcohol consumption in large genome-wide studies included in the Psychiatric Genetic Consortium and the UK Biobank's alcohol consumption dataset. By leveraging multi-omics data, this transcriptome analysis has identified genes and biological pathways that could provide insight for identifying therapeutic targets for alcohol dependence.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism

Kapoor

Wang

Farris

et al. 2018

Preprint

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“…Another study investigating the association between polymorphisms in NR3C1 and suicide attempts in 597 affective disorder patients reports no difference between groups with and without a history of suicide attempts (71). Recent studies show SNPs in FKBP5 and NR3C1 to be associated with alcohol drinking and crucial for alcohol abuse interventions (72, 73). …”

Section: Genetic Risk Constellationmentioning

confidence: 99%

Neuroendocrinology of a Male-Specific Pattern for Depression Linked to Alcohol Use Disorder and Suicidal Behavior

et al. 2017

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Epidemiological studies show low rates of diagnosed depression in men compared to women. At the same time, high rates of alcohol use disorders (AUDs) and completed suicide are found among men. These data suggest that a male-specific pattern for depression may exist that is linked to AUDs and suicidal behavior. To date, no underlying neuroendocrine model for this specific pattern of male depression has been suggested. In this paper, we integrate findings related to this specific pattern of depression with underlying steroid secretion patterns, polymorphisms, and methylation profiles of key genes in order to detail an original neuroendocrine model of male-specific depression. Low circulating levels of sex steroids seem to increase the vulnerability for male depression, while concomitant high levels of glucocorticoids further intensify this vulnerability. Interactions of hypothalamus–pituitary–gonadal (HPG) and hypothalamus–pituitary–adrenocortical (HPA) axis-related hormones seem to be highly relevant for a male-specific pattern of depression linked to AUDs and suicidal behavior. Moreover, genetic variants and the epigenetic profiles of the androgen receptor gene, well-known depression related genes, and HPA axis-related genes were shown to further interact with men’s steroid secretion and thus may further contribute to the proposed male-specific pattern for depression. This mini-review points out the multilevel interactions between the HPG and HPA axis for a male-specific pattern of depression linked to AUDs and suicidal behavior. An integration of multilevel interactions within the three-hit concept of vulnerability and resilience concludes the review.

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“…Among these, the strongest interaction effect was observed for FKBP5 and rs9394312. Several studies have implicated FKBP5 in the severity of alcohol withdrawal (72), alcohol drinking patterns in rodents (73), problematic drinking (74), as well as direct regulation of FKBP5 expression and phosphorylation by acute ethanol in mouse prefrontal cortex (75;76).…”

Section: Discussionmentioning

confidence: 99%

Assessing the role of long-noncoding RNA in nucleus accumbens in subjects with alcohol dependence

McMichael

Drake

Vornholt

et al. 2019

Preprint

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Recently, long noncoding RNA (lncRNA) were implicated in the etiology of alcohol dependence (AD). As lncRNA provide another layer of complexity to the transcriptome, assessing their expression in the brain is the first critical step towards understanding lncRNA functions in AD. To that end, we profiled the expression of lncRNA and protein coding genes (PCG) in nucleus accumbens (NAc) from 41 subjects with AD and 41 controls. At false discovery rate (FDR) of 5%, we identified 69 and 309 differentially expressed lncRNA and PCG genes, respectively. Using co-expression network analyses, we identified three lncRNA and five PCG modules significantly correlated with AD at Bonferroni adj. p≤0.05. To better understand lncRNA functions, we integrated the lncRNA and PCG hubs from the significant AD modules; at FDR of 5%, we identified 3 151 positive and 2 255 negative correlations supporting the functional role of lncRNA in the development of AD. Gene enrichment analysis revealed that PCG significantly correlated with lncRNA are, among others, enriched for neuronal and immune related processes. To highlight the mechanisms, by which genetic variants contribute to AD, we integrated lncRNA and PCG hubs with genome-wide SNP data. At FDR≤0.3, we identified 276 expression quantitative trait loci (eQTL), affecting the expression of 20 and 256 lncRNA and PCG hubs, respectively. Our study is the first to profile lncRNA expression in nucleus accumbens in a large postmortem alcohol brain sample and our results may provide novel insights into the regulation of the brain transcriptome across disease.

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The FKBP5 Gene Affects Alcohol Drinking in Knockout Mice and Is Implicated in Alcohol Drinking in Humans

Cited by 28 publications

References 73 publications

Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism

Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism

Neuroendocrinology of a Male-Specific Pattern for Depression Linked to Alcohol Use Disorder and Suicidal Behavior

Assessing the role of long-noncoding RNA in nucleus accumbens in subjects with alcohol dependence

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