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Network preservation reveals shared and unique biological processes associated with chronic alcohol abuse in NAc and PFC.

ABSTRACT: Chronic alcohol abuse has been linked to the disruption of executive function and allostatic conditioning of reward response dysregulation in the mesocorticolimbic pathway (MCL). Here, we analyzed genome-wide mRNA and miRNA expression from matched cases with alcohol dependence (AD) and controls (n = 35) via gene network analysis to identify unique and shared biological processes dysregulated in the prefrontal cortex (PFC) and nucleus accumbens (NAc). We further investigated potential mRNA/miRNA interactions at the network and individual gene expression levels to identify the neurobiological mechanisms underlying AD in the brain. By using genotyped and imputed SNP data, we identified expression quantitative trait loci (eQTL) uncovering potential genetic regulatory elements for gene networks associated with AD. At a Bonferroni corrected p?0.05, we identified significant mRNA (NAc = 6; PFC = 3) and miRNA (NAc = 3; PFC = 2) AD modules. The gene-set enrichment analyses revealed modules preserved between PFC and NAc to be enriched for immune response processes, whereas genes involved in cellular morphogenesis/localization and cilia-based cell projection were enriched in NAc modules only. At a Bonferroni corrected p?0.05, we identified significant mRNA/miRNA network module correlations (NAc = 6; PFC = 4), which at an individual transcript level implicated miR-449a/b as potential regulators for cellular morphogenesis/localization in NAc. Finally, we identified eQTLs (NAc: mRNA = 37, miRNA = 9; PFC: mRNA = 17, miRNA = 16) which potentially mediate alcohol's effect in a brain region-specific manner. Our study highlights the neurotoxic effects of chronic alcohol abuse as well as brain region specific molecular changes that may impact the development of alcohol addiction.

SUBMITTER: Vornholt E

PROVIDER: S-EPMC7745987 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Network preservation reveals shared and unique biological processes associated with chronic alcohol abuse in NAc and PFC.

Vornholt Eric E Drake John J Mamdani Mohammed M McMichael Gowon G Taylor Zachary N ZN Bacanu Silviu-Alin SA Miles Michael F MF Vladimirov Vladimir I VI

PloS one 20201217 12

Chronic alcohol abuse has been linked to the disruption of executive function and allostatic conditioning of reward response dysregulation in the mesocorticolimbic pathway (MCL). Here, we analyzed genome-wide mRNA and miRNA expression from matched cases with alcohol dependence (AD) and controls (n = 35) via gene network analysis to identify unique and shared biological processes dysregulated in the prefrontal cortex (PFC) and nucleus accumbens (NAc). We further investigated potential mRNA/miRNA ...[more]

PMID: 33332381

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Project description:BackgroundFrench beef producers suffer from the decrease in profitability of their farms mainly because of the continuous increase in feed costs. Selection for feed efficiency in beef cattle represents a relevant solution to face this problem. However, feed efficiency is a complex trait that can be assessed by three major criteria: residual feed intake (RFI), residual gain (RG) and feed efficiency ratio (FE), which involve different genetic determinisms. An analysis that combines phenotype and whole-genome sequence data provides a unique framework for genomic studies. The aim of our study was to identify the gene networks and the biological processes that are responsible for the genetic determinism that is shared between these three feed efficiency criteria.ResultsA population of 1477 French Charolais young bulls was phenotyped for feed intake (FI), average daily gain (ADG) and final weight (FW) to estimate RFI, RG and FE. A subset of 789 young bulls was genotyped on the BovineSNP50 single nucleotide polymorphism (SNP) array and imputed at the sequence level using RUN6 of the 1000 Bull Genomes Project. We conducted a genome-wide association study (GWAS) to estimate the individual effect of 8.5 million SNPs and applied an association weight matrix (AWM) approach to analyse the results, one for each feed efficiency criterion. The results highlighted co-association networks including 626 genes for RFI, 426 for RG and 564 for FE. Enrichment assessment revealed the biological processes that show the strongest association with RFI, RG and FE, i.e. digestive tract (salivary, gastric and mucin secretion) and metabolic processes (cellular and cardiovascular). Energetic functions were more associated with RFI and FE and cardio-vascular and cellular processes with RG. Several hormones such as apelin, glucagon, insulin, aldosterone, the gonadotrophin releasing hormone and the thyroid hormone were also identified, and these should be tested in future studies as candidate biomarkers for feed efficiency.ConclusionsThe combination of network and pathway analyses at the sequence level led to the identification of both common and specific mechanisms that are involved in RFI, RG and FE, and to a better understanding of the genetic determinism underlying these three criteria. The effects of the genes involved in each of the identified processes need to be tested in genomic evaluations to confirm the potential gain in reliability of using functional variants to select animals for feed efficiency.

Dataset Information

Network preservation reveals shared and unique biological processes associated with chronic alcohol abuse in NAc and PFC.

Publications

Network preservation reveals shared and unique biological processes associated with chronic alcohol abuse in NAc and PFC.

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