Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism.
- Authors
- Kapoor, Manav; Wang, Jen-Chyong; Farris, Sean P; Liu, Yunlong; McClintick, Jeanette; Gupta, Ishaan; Meyers, Jacquelyn L; Bertelsen, Sarah; Chao, Michael; Nurnberger, John; Tischfield, Jay; Harari, Oscar; Zeran, Li; Hesselbrock, Victor; Bauer, Lance; Raj, Towfique; Porjesz, Bernice; Agrawal, Arpana; Foroud, Tatiana; Edenberg, Howard J; Mayfield, R Dayne; Goate, Alison
- Year
- 2019
- Journal
- Translational psychiatry
- PMID
- 30765688
- DOI
- 10.1038/s41398-019-0384-y
- PMCID
- PMC6376002
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 (FDRβ<β0.05) 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.
Top genes, pathways and networks from differential gene expression in DLFPC region from 68 alcoholics and 70 controls.a Volcano plot showing top differentially expressed genes among cases and controls. b The genes passing FDR threshold of 20% were inputted to IPA for pathway enrichment analysis. The figure shows some of the top pathways identified by IPA. P values here are from right tail Fisherβs exact test. c Enrichment analysis of gene ontology βbiological processβ terms. Color depicts the qvalues with red being the strongest evidence of enrichment. d Network analysis on top genes (FDR < =20%) mapped to networks involved in the neurodegenerative disorders and organismal injuries. P value under the gene is the uncorrected p value for differential expression among alcoholics and controls. The nominally significant genes in the UKBB-alc and PGC-SUD GWAS are highlighted with purple border and blue annotation
Trait module correlations with P values for the top 5 modules.WGCNA identified 27 modules, out of which 5 modules showed nominal- moderate statistical significance with any of 4 alcohol-related trait (AUDIT, alcohol consumption (gms/day), duration of drinking (years), DSM4 AD (classification). Thistle2 module also passed the multiple test correction (27 modules, 4 traits; 0.05/31 = 1.6 Γ 10β3)
Enrichment analysis of genes in thistle2 module that are differentially expressed in alcoholics and controls.a More than 50% of genes in calcium signaling pathways were found to be downregulated in the thistle2 module. b Enrichment analysis for GO:BP terms showed downregulation of genes related to response to nicotine and postsynaptic potential. c Nearly 15 genes mapped to network related to amino-acid metabolism with many genes that were involved in G-protein coupled receptor signaling, calcium signaling and opioid signaling pathway. The nominally significant genes in the UKBB-alc and PGC-SUD GWAS are marked with red boundaries (ADCY5 P = 7.07 Γ 10β7 in UKBB-AC, ADCY7, P = 2.2 Γ 10β4 in UKBB-AC), IL12B, P = 1.1 Γ 10β2 in PGC-AD, PIK3C2G, P = 6.8 Γ 10β3 in UKBB-AC, PIK3R4, P = 3.4 Γ 10β2 in PGC-AD, CHRNA6 in UKBB-AC P = 7.60 Γ 10β3, CHRNA2 in PGC-AD P = 1.4 Γ 10β2, MN1 in PGC-AD P = 9.1 Γ 10β3 and HAPLN1 in UKBB-AC P = 1.9 Γ 10β2)
Enrichment analysis of brown4 module genes that were differentially expressed (FDR* < 0.05) among alcoholics and controls.a Pathway analysis showed significant upregulation of genes related immune signaling and metabolism. b Enrichment analysis for GO:BP terms showed enrichment of genes related to inflamatory response. c The genes in the brown4 module mapped to network involved in infectious and respiratory diseases. The genes that were nominally significant in the UKBB-Alc and PGC-SUD GWAS are highlighted with red boundaries
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| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Central amygdala single-nucleus atlas reveals chromatin and gene transcription dynamics in human alcohol use disorder. | Lee CY et al. | β | 2026 | β |
| Cortical reactive microglia activate astrocytes, increasing neurodegeneration in human alcohol use disorder. | Crews FT et al. | β | 2026 | β |
| Disturbances of paraventricular thalamic nucleus neurons in bipolar disorder revealed by single-nucleus analysis. | Nishioka M et al. | β | 2026 | β |
| Integrative Genomics Approach Identifies Glial Transcriptomic Dysregulation and Risk in the Cortex of Individuals With Alcohol Use Disorder. | Warden AS et al. | β | 2026 | β |
| Multimodal profiling of gray matter differences in alcohol use disorder: An integrated SDM-PSI meta-analysis with neuroimaging fusion study. | Long S et al. | β | 2026 | β |
| Alcohol dependence-induced astrocyte immune activation in the nucleus accumbens. | Hashimoto JG et al. | β | 2025 | β |
| Alternative splicing in addiction. | Bhatnagar A et al. | β | 2025 | β |
| A systematic review and meta-analysis on the transcriptomic signatures in alcohol use disorder. | Friske MM et al. | β | 2025 | β |
| Gene expression differences associated with alcohol use disorder in human brain. | Willis C et al. | β | 2025 | β |
| Modeling Brain Gene Expression in Alcohol Use Disorder with Genetic Animal Models. | Hitzemann R et al. | β | 2025 | β |
| Role of glial cells in neurotoxicological effects of alcohol. | Tizabi Y et al. | β | 2025 | β |
| The kynurenine pathway as a potential link between ethanol-induced behavioral alterations and neuroinflammation. | Gil de Biedma-Elduayen L et al. | β | 2025 | β |
| White matter neural substrates in alcohol dependence with genetic risk and their role in pathological reward process. | Wu F et al. | β | 2025 | β |
| Divergent gene expression patterns in alcohol and opioid use disorders lead to consistent alterations in functional networks within the dorsolateral prefrontal cortex. | MacDonald M et al. | β | 2024 | β |
| Effects of repeated alcohol abstinence on within-subject prefrontal cortical gene expression in rhesus macaques. | Hitzemann R et al. | β | 2024 | β |
| IL17RB genetic variants are associated with acamprosate treatment response in patients with alcohol use disorder: A proteomics-informed genomics study. | Ho MF et al. | β | 2024 | β |
| Intragastric administration of short chain fatty acids greatly reduces voluntary ethanol intake in rats. | Quintanilla ME et al. | β | 2024 | β |
| Mutation of novel ethanol-responsive lncRNA Gm41261 impacts ethanol-related behavioral responses in mice. | Plasil SL et al. | β | 2024 | β |
| Neuroimmune Activation and Microglia Reactivity in Female Rats Following Alcohol Dependence. | Melbourne JK et al. | β | 2024 | β |
| Polygenic risk for alcohol use disorder affects cellular responses to ethanol exposure in a human microglial cell model. | Li X et al. | β | 2024 | β |
| Toll-like receptor 7: A novel neuroimmune target to reduce excessive alcohol consumption. | Allard RL et al. | β | 2024 | β |
| 5. Collaborative Study on the Genetics of Alcoholism: Functional genomics. | Gameiro-Ros I et al. | β | 2023 | β |
| Analysis of the brain transcriptome for substance-associated genes: An update on large-scale genome-wide association studies. | Zhao Y et al. | β | 2023 | β |
| Genome- and transcriptome-wide splicing associations with alcohol use disorder. | Huggett SB et al. | β | 2023 | β |
| Investigation of convergent and divergent genetic influences underlying schizophrenia and alcohol use disorder. | Johnson EC et al. | β | 2023 | β |
| Neurotransmission-related gene expression in the frontal pole is altered in subjects with bipolar disorder and schizophrenia. | Medina AM et al. | β | 2023 | β |
| RNA alternative splicing impacts the risk for alcohol use disorder | Liu Y et al. | β | 2023 | β |
| RNA alternative splicing impacts the risk for alcohol use disorder. | Li R et al. | β | 2023 | β |
| The collaborative study on the genetics of alcoholism: Sample and clinical data. | Dick DM et al. | β | 2023 | β |
| The Genetically Informed Neurobiology of Addiction (GINA) model. | Bogdan R et al. | β | 2023 | β |
| Astrocyte ethanol exposure reveals persistent and defined calcium response subtypes and associated gene signatures. | Kim HB et al. | β | 2022 | β |
| Bridge Nodes between Personality Traits and Alcohol-Use Disorder Criteria: The Relevance of Externalizing Traits of Risk Taking, Callousness, and Irresponsibility. | De la Rosa-CΓ‘ceres A et al. | β | 2022 | β |
| Common and distinguishing genetic factors for substance use behavior and disorder: an integrated analysis of genomic and transcriptomic studies from both human and animal studies. | Chang XW et al. | β | 2022 | β |
| DiffBrainNet: Differential analyses add new insights into the response to glucocorticoids at the level of genes, networks and brain regions. | Gerstner N et al. | β | 2022 | β |
| GeneCup: mining PubMed and GWAS catalog for gene-keyword relationships. | Gunturkun MH et al. | β | 2022 | β |
| Genome-wide transcriptomics of the amygdala reveals similar oligodendrocyte-related responses to acute and chronic alcohol drinking in female mice. | Narendra S et al. | β | 2022 | β |
| Hippocampal ceRNA networks from chronic intermittent ethanol vapor-exposed male mice and functional analysis of top-ranked lncRNA genes for ethanol drinking phenotypes. | Plasil SL et al. | β | 2022 | β |
| Integrating human brain proteomic data with genome-wide association study findings identifies novel brain proteins in substance use traits. | Toikumo S et al. | β | 2022 | β |
| Multi-omics signatures of alcohol use disorder in the dorsal and ventral striatum. | Zillich L et al. | β | 2022 | β |
| NLRP3 deficiency decreases alcohol intake controlling anxiety-like behavior via modification of glutamatergic transmission in corticostriatal circuits. | Li Z et al. | β | 2022 | β |
| Proteomics and weighted gene correlated network analysis reveal glutamatergic synapse signaling in diazepam treatment of alcohol withdrawal. | Kong W et al. | β | 2022 | β |
| Research perspectives-Pipelines to human tendon transcriptomics. | Ramos-Mucci L et al. | β | 2022 | β |
| RNA Solutions: Synthesizing Information to Support Transcriptomics (RNASSIST). | Chen YP et al. | β | 2022 | β |
| 10-Dehydrogingerdione ameliorates renal endoplasmic reticulum/oxidative stress and apoptosis in alcoholic nephropathy induced in experimental rats. | Elnagar GM et al. | β | 2021 | β |
| Alcohol use disorder causes global changes in splicing in the human brain. | Van Booven D et al. | β | 2021 | β |
| Candidate pharmacological treatments for substance use disorder and suicide identified by gene co-expression network-based drug repositioning. | Cabrera-Mendoza B et al. | β | 2021 | β |
| Chronic Alcohol Use Induces Molecular Genetic Changes in the Dorsomedial Thalamus of People with Alcohol-Related Disorders. | Hade AC et al. | β | 2021 | β |
| Cortical astrocytes regulate ethanol consumption and intoxication in mice. | Erickson EK et al. | β | 2021 | β |
| Exploration of alcohol use disorder-associated brain miRNA-mRNA regulatory networks. | Lim Y et al. | β | 2021 | β |
| Genetics of substance use disorders: a review. | Deak JD et al. | β | 2021 | β |
| Identifying a novel biological mechanism for alcohol addiction associated with circRNA networks acting as potential miRNA sponges. | Vornholt E et al. | β | 2021 | β |
| Increased transcription of TSPO, HDAC2, and HDAC6 in the amygdala of males with alcohol use disorder. | De Carvalho LM et al. | β | 2021 | β |
| Microglia depletion and alcohol: Transcriptome and behavioral profiles. | Warden AS et al. | β | 2021 | β |
| Multi-omics integration analysis identifies novel genes for alcoholism with potential overlap with neurodegenerative diseases. | Kapoor M et al. | β | 2021 | β |
| Role of cannabinoids in alcohol-induced neuroinflammation. | GarcΓa-Baos A et al. | β | 2021 | β |
| Unveiling the Pathogenesis of Psychiatric Disorders Using Network Models. | Zuo Y et al. | β | 2021 | β |
| An update on the role of common genetic variation underlying substance use disorders. | Johnson EC et al. | β | 2020 | β |
| A Rationale for Allopregnanolone Treatment of Alcohol Use Disorders: Basic and Clinical Studies. | Morrow AL et al. | β | 2020 | β |
| Assessing the Role of Long Noncoding RNA in Nucleus Accumbens in Subjects With Alcohol Dependence. | Drake J et al. | β | 2020 | β |
| Convergent Evidence for Predispositional Effects of Brain Gray Matter Volume on Alcohol Consumption. | Baranger DAA et al. | β | 2020 | β |
| Diverse types of genomic evidence converge on alcohol use disorder risk genes. | Dai Y et al. | β | 2020 | β |
| Genetic Architecture and Molecular Neuropathology of Human Cocaine Addiction. | Huggett SB et al. | β | 2020 | β |
| Microglia Control Escalation of Drinking in Alcohol-Dependent Mice: Genomic and Synaptic Drivers. | Warden AS et al. | β | 2020 | β |
| Mimicking Age-Associated Gadd45Ξ³ Dysregulation Results in Memory Impairments in Young Adult Mice. | Brito DVC et al. | β | 2020 | β |
| New Microglial Mechanisms Revealed in Alcohol Use Disorder: How Does That Translate? | Portis SM et al. | β | 2020 | β |
| Recent advances in genetic studies of alcohol use disorders. | Gupta I et al. | β | 2020 | β |
| Single cell transcriptome profiling of the human alcohol-dependent brain. | Brenner E et al. | β | 2020 | β |
| Transcriptome Analysis of Alcohol Drinking in Non-Dependent and Dependent Mice Following Repeated Cycles of Forced Swim Stress Exposure. | Farris SP et al. | β | 2020 | β |
| Unveiling Sex-Based Differences in the Effects of Alcohol Abuse: A Comprehensive Functional Meta-Analysis of Transcriptomic Studies. | Casanova Ferrer F et al. | β | 2020 | β |
| A Pathway-Based Genomic Approach to Identify Medications: Application to Alcohol Use Disorder. | Ferguson LB et al. | β | 2019 | β |
| Its complicated: The relationship between alcohol and microglia in the search for novel pharmacotherapeutic targets for alcohol use disorders. | Melbourne JK et al. | β | 2019 | β |