Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism.
Manav KapoorJen-Chyong WangSean P FarrisYunlong LiuJeanette N McClintickIshaan GuptaJacquelyn L MeyersSarah BertelsenMichael ChaoJohn NurnbergerJay TischfieldOscar HarariLi ZeranVictor HesselbrockLance BauerTowfique RajBernice PorjeszArpana AgrawalTatiana ForoudHoward J EdenbergR Dayne MayfieldAlison Mary GoatePublished in: Translational psychiatry (2019)
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.
Keyphrases
- alcohol consumption
- genome wide
- dna methylation
- gene expression
- copy number
- network analysis
- poor prognosis
- genome wide identification
- dna damage
- signaling pathway
- functional connectivity
- bioinformatics analysis
- cell proliferation
- computed tomography
- single cell
- mass spectrometry
- electronic health record
- resting state
- oxidative stress
- high resolution
- cross sectional
- pain management
- transcription factor
- rna seq
- blood brain barrier
- brain injury
- multiple sclerosis
- dendritic cells
- pi k akt
- dna repair
- long non coding rna
- epithelial mesenchymal transition
- white matter
- contrast enhanced
- endoplasmic reticulum stress
- working memory
- cell cycle