Alcohol Use Disorder (AUD) is a chronic, relapsing syndrome diagnosed by a heteroge- neous set of behavioral signs and symptoms. There are no laboratory tests that provide direct objective evidence for diagnosis. Microarray and RNA-Seq technologies enable genome-wide transcriptome profiling at low costs and provide an opportunity to identify bio- markers to facilitate diagnosis, prognosis, and treatment of patients. However, access to brain tissue in living patients is not possible. Blood contains cellular and extracellular RNAs that provide disease-relevant information for some brain diseases. We hypothesized that blood gene expression profiles can be used to diagnose AUD. We profiled brain (prefrontal cortex, amygdala, and hypothalamus) and blood gene expression levels in C57BL/6J mice using RNA-seq one week after chronic intermittent ethanol (CIE) exposure, a mouse model of alcohol dependence. We found a high degree of preservation (rho range: [0.50, 0.67]) between blood and brain transcript levels. There was small overlap between blood and brain DEGs, and considerable overlap of gene networks perturbed after CIE related to cell- cell signaling (e.g., GABA and glutamate receptor signaling), immune responses (e.g., anti- gen presentation), and protein processing / mitochondrial functioning (e.g., ubiquitination, oxidative phosphorylation). Blood gene expression data were used to train classifiers (logis- tic regression, random forest, and partial least squares discriminant analysis), which were highly accurate at predicting alcohol dependence status (maximum AUC: 90.1%). These results suggest that gene expression profiles from peripheral blood samples contain a bio- logical signature of alcohol dependence that can discriminate between CIE and Air subjects.
Authors:
Laura B Ferguson, Amanda J Roberts, R Dayne Mayfield, Robert O Messing
QTL for ethanol withdrawal on Chr13 at D13Ncvs35 (71.29 Mbp , Build 37)
Description:
ethanol withdrawal spans 46.29 - 96.29 Mbp (NCBI Build 37) on Chr13. This interval was obtained by using an interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org).
We investigated the role of microglia in a mouse model of alcohol dependence using a colony stimulating factor 1 receptor inhibitor (PLX5622) to deplete microglia and a chronic intermittent ethanol vapor two-bottle choice drinking procedure. Additionally, we examined anxiety-like behavior during withdrawal. We then analyzed synaptic neuroadaptations in the central nucleus of the amygdala (CeA) and gene expression changes in the medial prefrontal cortex (mPFC) and CeA from the same animals used for behavioral studies.
Microglia depletion and alcohol gene expression logFC
Description:
Alcohol abuse induces changes in microglia morphology and immune function, but whether microglia initiate or simply amplify the harmful effects of alcohol exposure is still a matter of debate. Here, we determine microglia function in acute and voluntary drinking behaviors using a colony-stimulating factor 1 receptor inhibitor (PLX5622). We show that microglia depletion does not alter the sedative or hypnotic effects of acute intoxication. Microglia depletion also does not change the escalation or maintenance of chronic voluntary alcohol consumption. Transcriptomic analysis revealed that although many immune genes have been implicated in alcohol abuse, down regulation of microglia genes does not necessitate changes in alcohol intake. Instead, microglia depletion and chronic alcohol result in compensatory upregulation of alcohol-responsive, reactive astrocyte genes, indicating astrocytes may play a role in regulation of these alcohol behaviors. Taken together, our behavioral and transcriptional data indicate that microglia are not theprimary effector cell responsible for regulation of acute and voluntary alcohol behaviors. Because microglia depletion did not regulate acute or voluntary alcohol behaviors, we hypothesized that these doses were insufficient to activate microglia and recruit them to an effector phenotype. Therefore, we used a model of repeated immune activation using polyinosinic:polycytidylic acid
Alcohol interaction of dependence and MG depletion the medial prefrontal cortex q-value
Description:
We investigated the role of microglia in a mouse model of alcohol dependence using a colony stimulating factor 1 receptor inhibitor (PLX5622) to deplete microglia and a chronic intermittent ethanol vapor two-bottle choice drinking procedure. Additionally, we examined anxiety-like behavior during withdrawal. We then analyzed synaptic neuroadaptations in the central nucleus of the amygdala (CeA) and gene expression changes in the medial prefrontal cortex (mPFC) and CeA from the same animals used for behavioral studies.
Ethanol induced LORR Chr# 2 rs13476399(28144658) with right flanking marker rs3713997(3151175) and left marker rs3679483 (179861211). This was mapped in 300 + (b6x129)F2 mice.
Microglia depletion and alcohol gene expression p-value
Description:
Alcohol abuse induces changes in microglia morphology and immune function, but whether microglia initiate or simply amplify the harmful effects of alcohol exposure is still a matter of debate. Here, we determine microglia function in acute and voluntary drinking behaviors using a colony-stimulating factor 1 receptor inhibitor (PLX5622). We show that microglia depletion does not alter the sedative or hypnotic effects of acute intoxication. Microglia depletion also does not change the escalation or maintenance of chronic voluntary alcohol consumption. Transcriptomic analysis revealed that although many immune genes have been implicated in alcohol abuse, down regulation of microglia genes does not necessitate changes in alcohol intake. Instead, microglia depletion and chronic alcohol result in compensatory upregulation of alcohol-responsive, reactive astrocyte genes, indicating astrocytes may play a role in regulation of these alcohol behaviors. Taken together, our behavioral and transcriptional data indicate that microglia are not theprimary effector cell responsible for regulation of acute and voluntary alcohol behaviors. Because microglia depletion did not regulate acute or voluntary alcohol behaviors, we hypothesized that these doses were insufficient to activate microglia and recruit them to an effector phenotype. Therefore, we used a model of repeated immune activation using polyinosinic:polycytidylic acid
QTL Associated with Bone mineral density. On Chromosome 19 with a LOD score= 12.1, p-value =1.00E-04. From a(n) of QTL Associated with Bone mineral density. On Chromosome 10 with a LOD score= 9.4, p-value =1.00E-04. From a(n) of
Authors:
Koller DL, Alam I, Sun Q, Liu L, Fishburn T, Carr LG, Econs MJ, Foroud T, Turner CH
QTL Associated with Body mass. On Chromosome 10 with a LOD score= 4.38, p-value =0.001. From a(n) "intercross;<b>measurement method</b>: body weight was taken at 18 weeks of age, at the end of the HPA axis function experiment" of
Authors:
Marissal-Arvy N, Heliès JM, Tridon C, Moisan MP, Mormède P
QTL Associated with Cardiac mass. On Chromosome 10 with a LOD score= 4.55, p-value =. From a(n) intercross of
Authors:
Bilusić M, Moreno C, Barreto NE, Tschannen MR, Harris EL, Porteous WK, Thompson CM, Grigor MR, Weder A, Boerwinkle E, Hunt SC, Curb JD, Jacob HJ, Kwitek AE
QTL Associated with Glucose level. On Chromosome 10 with a LOD score= 3.7, p-value =. From a(n) intercross of
Authors:
Nobrega MA, Solberg Woods LC, Fleming S, Jacob HJ
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