Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism
Open accessPublished version of a preprint
Abstract
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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TL;DR
This study integrated RNA-seq from postmortem prefrontal cortex with GWAS/eQTL data to identify genes and co-expression networks associated with alcohol dependence. It reports 129 differentially expressed genes at FDR < 0.05 and two alcohol-related modules, thistle2 and brown4, implicating calcium, interferon, GADD45, and immune signaling.
Key findings
- In prefrontal cortex from 65 alcohol-dependent subjects and 73 controls of European descent, 827 genes were differentially expressed at 25% FDR, 298 at 10% FDR, and 129 at 5% FDR. TRPC3 showed lower expression in alcohol-dependent subjects (FC 0.82; p = 4.6 × 10−9), while KFM19 showed higher expression (FC 1.24; p = 5.7 × 10−9).
- Differentially expressed genes were enriched for interferon signaling, GADD45 signaling, and other immune-related pathways; Gene Ontology analysis mapped many genes to blood coagulation and fluid transport.
- WGCNA identified 27 modules. The thistle2 module (72 genes) was negatively correlated with alcohol dependence (−0.28, P = 9.0 × 10−4), alcohol consumption (−0.22, P = 9.0 × 10−3), and AUDIT score (−0.25, P = 3.0 × 10−3), and showed downregulated calcium signaling, nicotine response, and opioid signaling. The brown4 module (795 genes) was positively correlated with alcohol dependence (0.18, P = 4.0 × 10−2) and enriched for immune signaling and GADD45 signaling.
- eQTLs for brown4 genes were enriched for GWAS signals in PGC-AD (P = 4.20 × 10−3) and TAG-CPD (P = 4.81 × 10−3), while thistle2 eQTLs were depleted for PGC-AD (P = 1.50 × 10−2) and UKBB-AC (P = 1.30 × 10−2) signals.
Methods
- Postmortem superior frontal gyrus (Brodmann area 8; PFC) samples were obtained from the New South Wales Tissue Resource Centre; alcohol dependence was confirmed by DSM-IV criteria. RNA was extracted, samples with RIN < 5.5 were removed, and sequencing was performed at two sites (60 samples at WCAAR, 83 at Mount Sinai).
- Reads were aligned to hg19 with STAR, quantified with featureCounts using Gencode Release 19, and filtered to 18,463 genes with at least 1 CPM in at least 50% of individuals. Differential expression used DESeq2 with the model: gene expression ~ DSM4 alcohol classification + sex + age + PMI + RIN + batch.
- Co-expression networks were built with WGCNA (minimum module size = 100, soft power = 14), and module-trait correlations used Spearman’s rank correlation. Pathway and ontology analyses used IPA and clusterProfiler. GWAS enrichment used eQTLs from 461 ROS/MAP postmortem brains and summary statistics from PGC-AD, UKBB-AC, and TAG-CPD, with permutation testing and MAGMA/FUMA gene-based analysis.
Limitations
- The paper states that the variance explained by individual differentially expressed genes was very small (0.15–1%), that human postmortem tissue with DSM4 alcohol dependence phenotype was limited, and that the thistle2 module’s small size (N = 72 genes) may explain its under-enrichment for GWAS signals.
- The paper states that no correction for cell-type heterogeneity was performed because digital deconvolution showed no significant differences in neuron, astrocyte, or microglia percentages between alcoholics and controls.
- Evident from the text: the sample size is inconsistent between the abstract/methods (65 alcoholics, 73 controls) and the Fig. 1 caption (68 alcoholics, 70 controls); the design is cross-sectional postmortem and cannot establish causality; and validation was in rodent datasets rather than an independent human cohort.
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Claims the paper makes
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- Findingown data
In the prefrontal cortex of 65 alcoholics and 73 controls of European descent, 129 genes showed altered expression at FDR < 0.05.
“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.”
- Also stated in: § Differential expression analysis · plain
“Analysis of PFC tissue derived from 65 alcoholics and 73 controls identified 827 differentially expressed genes at 25% FDR, 298 genes at 10% FDR and 129 genes at 5% FDR (Fig. 1a, Supplemental Table 1; protein coding genes only).”
Quote in the paperSubstantial claim - Also stated in: § Differential expression analysis · plain
- Findingown data
Genes in the thistle2 module were enriched for biological processes related to nicotine response.
“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.”
- Also stated in: § Identification of gene co-expression networks and modules · plain
“Gene-ontology enrichment analysis using the clusterpProfiler showed significant enrichment for biological processes involved in “response to nicotine” and “excitatory postsynaptic potential” (Fig. 3b).”
Quote in the paperNot a substantial claim - Also stated in: § Identification of gene co-expression networks and modules · plain
- Findingown data
Differentially expressed genes in the prefrontal cortex of alcoholics were enriched for interferon signaling and GADD45 signaling pathways.
“Differentially expressed genes were enriched for pathways related to interferon signaling and Growth Arrest and DNA Damage-inducible 45 (GADD45) signaling.”
- Also stated in: § Differential expression analysis · plain
“IPA analysis of the differentially expressed genes (FDR < 25%) showed significant enrichment for pathways involved in interferon signaling, GADD45 signaling, and other immune-related pathways (Fig. 1b).”
Quote in the paperSubstantial claim - Also stated in: § Differential expression analysis · plain
- Findingown data
Genes in the thistle2 module were enriched for opioid signaling.
“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.”
- Also stated in: § Identification of gene co-expression networks and modules · plain
“Differentially expressed genes in the thistle2 module mapped to networks involved in G-protein coupled receptor signaling, calcium signaling, and opioid signaling (Fig. 3c).”
Quote in the paperNot a substantial claim - Also stated in: § Identification of gene co-expression networks and modules · plain
- Findingown data
After correcting for batch, age, and RNA integrity number, hierarchical clustering of expression data from nearly 18,000 genes generated 27 different modules.
“After correcting for the effects of batch, age, and RIN, the hierarchical clustering of expression data from nearly 18,000 genes generated 27 different modules (Supplementary Figure 1).”
Quote in the paperSubstantial claim
- Findingown data
The brown4 module was enriched for GWAS association in the TAG-CPD dataset.
“The brown4 module was also enriched for GWAS association in the TAG-CPD dataset.”
Quote in the paperSubstantial claim - Findingown data
GWAS enrichment analysis of significant eQTLs (P ≤ 5 × 10−8) for genes in the top 5 modules showed enrichment for SNPs associated with AD in PGC-AD and alcohol consumption in UKBB-AC datasets.
“GWAS enrichment analysis of significant eQTLs (P ≤ 5 × 10−8) for all genes in the top 5 modules (ranked by P value in module-trait correlation analysis), showed evidence of enrichment for SNPs associated with AD (GWAS p ≤ 0.05) in PGC-AD and alcohol consumption in UKBB-AC datasets (Table 2).”
Quote in the paperSubstantial claim - Findingown data
The brown4 module (containing 795 genes) was positively correlated with alcohol dependence, AUDIT, alcohol consumption and duration of alcohol use.
“The brown4 module (containing of 795 genes) was positively correlated with AD, AUDIT, alcohol consumption and duration of alcohol use.”
Quote in the paperSubstantial claim - Findingown data
Genes in the thistle2 module were enriched for biological processes involved in excitatory postsynaptic potential.
“Gene-ontology enrichment analysis using the clusterpProfiler showed significant enrichment for biological processes involved in “response to nicotine” and “excitatory postsynaptic potential” (Fig. 3b).”
Quote in the paperNot a substantial claim - Findingown data
After removing the effects of covariates, alcohol-related phenotypes explained the largest proportion of the remaining variation in gene expression.
“After removing the effects of these covariates, alcohol-related phenotypes explained the largest proportion of the remaining variation in gene expression (Supplementry Figure 1B).”
Quote in the paperSubstantial claim - Findingown data
Genes in the thistle2 module were significantly depleted for GWAS signals in the PGC-AD and UKBB-AC GWAS analyses.
“Surprisingly, genes in the thistle2 modules were significantly depleted for GWAS signals in the PGC-AD and UKBB-AC GWAS analyses.”
Quote in the paperNot a substantial claim - Findingown data
Other genes that were significantly upregulated in the prefrontal cortex of alcoholics mapped to networks involved in infectious and respiratory diseases.
“Other genes that were also significantly upregulated in the PFC of alcoholics mapped to networks involved in infectious and respiratory diseases.”
Quote in the paperNot a substantial claim - Findingown data
TRPC3 was the top differentially expressed gene, with significantly lower expression in alcohol-dependent subjects (FC 0.82; p = 4.6 × 10−9).
“Transient Receptor Potential Cation Channel Subfamily C Member 3 (TRPC3) was the top differentially expressed gene with significantly lower expression in alcohol-dependent subjects (FC 0.82; p = 4.6 × 10−9)”
Quote in the paperNot a substantial claim - Findingown data
Differentially expressed genes in the thistle2 module mapped to networks involved in G-protein coupled receptor signaling, calcium signaling, and opioid signaling.
“Differentially expressed genes in the thistle2 module mapped to networks involved in G-protein coupled receptor signaling, calcium signaling, and opioid signaling (Fig. 3c).”
Quote in the paperNot a substantial claim - Findingown data
Network analysis in IPA mapped the significant genes to networks involved in neurodegenerative disorders and organismal injury.
“The network analysis in IPA mapped the significant genes to networks involved in neurodegenerative disorders and organismal injury.”
Quote in the paperNot a substantial claim - Findingown data
The present study identified 129 genes (FDR < 0.05) that were differentially expressed in alcohol-dependent subjects.
“The present study identified 129 genes (FDR < 0.05) that were differentially expressed in alcohol-dependent subjects (Supplementary table 1).”
Quote in the paperSubstantial claim - Findingown data
Expression quantitative trait loci for genes in the brown4 module were enriched for genetic associations with alcohol dependence and alcohol consumption in large genome-wide studies from the Psychiatric Genetic Consortium and the UK Biobank alcohol consumption dataset.
“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.”
Quote in the paperSubstantial claim - Findingown data
Several genes in the thistle2 module were significantly downregulated in the prefrontal cortex of alcohol-dependent subjects.
“Several genes in the thistle2 module that were significantly downregulated in the PFC of alcohol-dependent subjects.”
Quote in the paperSubstantial claim - Findingown data
The thistle2 module did not show enrichment of GWAS association.
“The thistle2 module did not show enrichment of GWAS association.”
Quote in the paperNot a substantial claim - Findingown data
Kinesin Family Member 19 showed significantly higher expression in alcohol-dependent subjects (FC 1.24; p = 5.7 × 10−9).
“Kinesin Family Member 19 (KFM19) showed significantly higher expression in alcohol-dependent subjects (FC 1.24; p = 5.7 × 10−9).”
Quote in the paperNot a substantial claim - Findingown data
FKBP5 showed increased expression in the PFC of alcohol-dependent subjects in the differential gene expression analysis (l2FC 0.27; P = 4.57 × 10−7).
“FKBP5, a well studied gene that is asoociated with alcohol use28–31, showed increased expression in the PFC of alcohol-dependent subjects in our differential gene expression analysis (l2FC 0.27; P = 4.57 × 10−7).”
Quote in the paperNot a substantial claim - Findingown data
Several differentially expressed genes in the thistle2 module, including CHRNA6, CHRNA2, MN1 and HAPLN1, showed some evidence of genetic contribution towards alcohol consumption or dependence.
“Cholinergic Receptor Nicotinic Alpha subunits 6 and 2 (CHRNA6 UKBB-AC P = 7.60 × 10−3; CHRNA2 PGC-AD P = 1.4 × 10−2), Meningioma 1 (MN1, PGC-AD P = 9.1 × 10−3) and Hyaluronan And Proteoglycan Link Protein 1 (HAPLN1, UKBB-AC P = 1.9 × 10−2) are some exmples where differntialy expressed genes in thistle 2 module also showed some evidence of genetic contribution towards alcohol consumption or depend”
Quote in the paperSubstantial claim - Findingown data
Several genes in the network were also nominally significant (p < 0.05) in the PGC-AD and UKBB-AC GWAS.
“Several genes that were part of this network were also nominally significant (p < 0.05) in the PGC-AD and UKBB-AC GWAS (Fig. 1d).”
Quote in the paperNot a substantial claim - Findingown data
Trait-module correlation analyses identified five modules that were significantly correlated to at least one alcohol-related trait.
“Trait-module correlation analyses identified five modules that were significantly correlated to at least one alcohol-related trait (Fig. 2).”
Quote in the paperSubstantial claim - Findingown data
The brown4 module showed significant upregulation of pathways related to immune signaling.
“A second module (brown4) showed significant upregulation of pathways related to immune signaling.”
- Also stated in: § Identification of gene co-expression networks and modules · plain
“Pathway analysis for differentially expressed genes in the brown4 module showed significant enrichment for Growth Arrest and DNA Damage (GADD45) signaling and for biological processes related to the inflammatory response (Fig. 4).”
Quote in the paperSubstantial claim - Also stated in: § Identification of gene co-expression networks and modules · plain
- Findingown data
Some differentially expressed genes in this network were statistically significant in gene-based tests (RASD1, UKBB-AC, P = 1.64 × 10−5 and ARID5A, UKBB-AC, P = 1.4 × 10−3).
“Some of the differentially expressed genes in this network were also statistical significant in the gene-based tests (RASD1, UKBB-AC, P = 1.64 × 10−5 and ARID5A, UKBB-AC, P 1.4 × 10−3).”
Quote in the paperNot a substantial claim - Findingown data
eQTLs for genes in the brown4 module (N = 726 genes) were significantly enriched for GWAS signals (P = 4.2 × 10−3) in the PGC-AD GWAS.
“eQTLs for genes in the brown4 module (N = 726 genes) were significantly enriched for GWAS signals (P = 4.2 × 10−3) in the PGC-AD GWAS.”
Quote in the paperSubstantial claim - Findingown data
The variance explained by individual differentially expressed genes was very small (0.15-1%).
“Although we identified several genes that were differentially expressed in the PFC of alcohol-dependent subjects, the variance explained by individual genes was very small (0.15–1%).”
Quote in the paperSubstantial claim - Findingown data
The hub genes identified in the present analysis were significantly enriched for association signals in rodents.
“The hub genes identified in present analysis were found to be significant enriched for association signals in the rodents.”
Quote in the paperSubstantial claim - Findingown data
Many genes in the thistle2 module mapped to networks involved in opioid signaling and nicotine response.
“Many genes in the thistle2 module mapped to networks involved in opioid signaling and nicotine response, highlighting the importance of this module in addiction-related traits.”
Quote in the paperNot a substantial claim - Findingown data
Many differentially expressed genes in this network are involved in nervous system development and function.
“Many differentially expressed genes in this network are involved in nervous system development and function.”
Quote in the paperNot a substantial claim - Findingown data
The gene co-expression network analysis identified networks of genes altered in alcohol-dependent subjects.
“The gene co-expression network analysis also identified networks of genes altered in alcohol-dependent subjects.”
Quote in the paperSubstantial claim - Findingown data
Enrichment analysis of nominally significant GWAS variants that were also eQTLs for genes in the thistle2 module showed significant under-enrichment in the two-tail Fisher test.
“Enrichment analysis of nominally significant GWAS variants (p < 0.05) that were also eQTLs (p < 5 × 10−8) for genes in the thistle2 module showed significant under enrichment in the two-tail Fisher test (Table 2).”
Quote in the paperNot a substantial claim - Findingown data
Pathway analysis showed that all genes that overlapped with genes involved in calcium signaling were significantly downregulated.
“Pathway analysis showed that all genes that overlapped with genes involved in calcium signaling were significantly downregulated (Fig. 3a).”
Quote in the paperSubstantial claim - Findingown data
In the calcium signaling network, a few genes that were not part of the thistle2 module but were essential to create network connections were also significant (3.4 × 10−2 ≤ P ≥ 4.8 × 10−2) in gene-based tests.
“In the calcium signaling network (Fig. 3c), a few genes that were not part of the thistle2 module, but were essential to create network connections, were also found to be significant (3.4 × 10−2 ≤ P ≥ 4.8 × 10−2) in the gene-based tests (circled in red; Fig. 4c).”
Quote in the paperNot a substantial claim - Findingown data
The brown4 module showed a positive correlation (0.18, P = 4.0 × 10−2) with alcohol dependence in trait-module correlation analysis.
“Trait-module correlation analysis for the thistle2 module showed a significant negative correlation with alcohol dependence (−0.28, P = 9.0 × 10−4), alcohol consumption (−0.22, P = 9.0 × 10−3), and AUDIT score (−0.25, P = 3.0 × 10−3), while the brown4 module showed a positive correlation (0.18, P = 4.0 × 10−2) with alcohol dependence (Fig. 2; Table 2).”
- Also stated in: § Discussion · plain
“Interestingly this module was also positively correlated with alcohol dependence (0.18, P = 4.0 × 10−2) in trait-module correlation analysis.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
The brown4 module was enriched in immune response and infectious diseases.
“Another module that correlated with alcohol dependence, brown4, was also enriched in immune response and infectious diseases, providing additional evidence for the role of the neuroimmune system in the etiology of alcohol dependence.”
Quote in the paperSubstantial claim - Findingown data
Genes showing significant differences in expression between alcohol-dependent subjects and controls were enriched in pathways related to interferon and GADD45 signaling.
“Genes showing significant differences in expression between alcohol-dependent subjects and controls were enriched in pathways related to interferon and GADD45 signaling (Fig. 1b).”
Quote in the paperSubstantial claim - Findingown data
Some differentially expressed genes were significant in gene-based tests performed in UKBB-AC and PGC-AD datasets using MAGMA (CHRNA6, CHRNA2, MN1 and HAPLN1).
“Although some of the differntialy expressed genes were significant in the gene-based tests performed in UKBB-AC and PGC-AD datasets using MAGMA (CHRNA6, CHRNA2, MN1 and HAPLN1).”
Quote in the paperNot a substantial claim - Findingown data
Genes in the thistle2 module were significantly downregulated in the PFC from alcoholics.
“Genes in the thistle2 module were significantly downregulated in the PFC from alcoholics.”
Quote in the paperSubstantial claim - Findingown data
The salmon4 module was associated with the total number of drinking years (−0.24, P = 4.0 × 10−3), independent of the age of the subjects.
“The salmon4 module was associated with the total number of drinking years (−0.24, P = 4.0 × 10−3), independent of the age of the subjects.”
Quote in the paperNot a substantial claim - Findingown data
Differentially expressed genes (FDR < 25%) mapped to networks associated with neurodegenerative disorders and organismal injury.
“Differentially expressed genes (FDR < 25%) also mapped to networks associated with neurodegenerative disorders and organismal injury (Fig. 1d).”
Quote in the paperNot a substantial claim - Premisecitation
Transcriptomes from complex tissues such as human brain may be organized into networks of co-expressed genes that better reflect the biological functions and organization of the tissue.
“Transcriptomes from complex tissues, such as human brain, may be organized into networks of co-expressed genes that better reflect the biological functions and organization of the tissue7–14.”
Quote in the paperSubstantial claim0 of 8 sources checked- cites [7] McClintick, J. N. et al. Stress-response pathways are altered in the hippocampus of chronic. Alcohol. Alcohol Fayettev. N. 47, 505–515 (2013). source
Not checked in the free run.
- cites [8] Mamdani, M. et al. Integrating mRNA and miRNA weighted gene co-expression networks with eqtls in the nucleus accumbens of subjects with alcohol dependence. PLoS ONE 10, e0137671 (2015). source
Not checked in the free run.
- cites [9] Farris, S. P., Arasappan, D., Hunicke-Smith, S., Harris, R. A. & Mayfield, R. D. Transcriptome organization for chronic alcohol abuse in human brain. Mol. Psychiatry 20, 1438–1447 (2015). source
Not checked in the free run.
- cites [10] Oldham, M. C. et al. Functional organization of the transcriptome in human brain. Nat. Neurosci. 11, 1271–1282 (2008). source
Not checked in the free run.
- cites [11] Flatscher-Bader, T. & Wilce, P. A. Chronic smoking and alcoholism change expression of selective genes in the human prefrontal cortex. Alcohol. Clin. Exp. Res. 30, 908–915 (2006). source
Not checked in the free run.
- cites [12] Mayfield, J., Ferguson, L. & Harris, R. A. Neuroimmune signaling: a key component of alcohol abuse. Curr. Opin. Neurobiol. 23, 513–520 (2013). source
Not checked in the free run.
- cites [13] Farris, S. P. & Mayfield, R. D. RNA-Seq reveals novel transcriptional reorganization in human alcoholic brain. Int. Rev. Neurobiol. 116, 275–300 (2014). source
Not checked in the free run.
- cites [14] Hermann, D. et al. Low μ-opioid receptor status in alcohol dependence identified by combined positron emission tomography and post-mortem brainanalysis. Neuropsychopharmacology 42, 606–614 (2017). source
Not checked in the free run.
- Study design and conductown data
Postmortem interval was significantly lower for alcohol-dependent subjects than for controls.
“Postmortem interval (PMI) was significantly lower for the alcohol-dependent subjects.”
Quote in the paperNot a substantial claim - Study design and conductown data
The thistle2 module passed multiple test correction (27 modules, 4 traits; 0.05/31 = 1.6 × 10−3).
“Thistle2 module also passed the multiple test correction (27 modules, 4 traits; 0.05/31 = 1.6 × 10−3)”
Quote in the paperSubstantial claim - Premisecitation
Alcohol exposure triggers changes in gene expression and biological pathways in human brain.
“Alcohol exposure triggers changes in gene expression and biological pathways in human brain.”
- Also stated in: § Introduction · plain
“Alcohol crosses the blood brain barrier and triggers changes in the central nervous system4, including transcriptional changes in many different regions of the brain5–9.”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [4] Alfonso-Loeches, S. & Guerri, C. Molecular and behavioral aspects of the actions of alcohol on the adult and developing brain. Crit. Rev. Clin. Lab. Sci. 48, 19–47 (2011). source
Not checked in the free run.
- cites [5] Fan, L. et al. Increased expression of mitochondrial genes in human alcoholic brain revealed by differential display. Alcohol. Clin. Exp. Res. 23, 408–413 (1999). source
Not checked in the free run.
- cites [6] Mayfield, R. D., Harris, R. A. & Schuckit, M. A. Genetic factors influencing alcohol dependence. Br. J. Pharmacol. 154, 275–287 (2008). source
Not checked in the free run.
- cites [7] McClintick, J. N. et al. Stress-response pathways are altered in the hippocampus of chronic. Alcohol. Alcohol Fayettev. N. 47, 505–515 (2013). source
Not checked in the free run.
- cites [8] Mamdani, M. et al. Integrating mRNA and miRNA weighted gene co-expression networks with eqtls in the nucleus accumbens of subjects with alcohol dependence. PLoS ONE 10, e0137671 (2015). source
Not checked in the free run.
- cites [9] Farris, S. P., Arasappan, D., Hunicke-Smith, S., Harris, R. A. & Mayfield, R. D. Transcriptome organization for chronic alcohol abuse in human brain. Mol. Psychiatry 20, 1438–1447 (2015). source
Not checked in the free run.
- Also stated in: § Introduction · plain
- Study design and conductown data
The thistle2 depletion finding was confirmed by permutation analysis.
“This finding was confirmed by permutation analysis.”
Quote in the paperNot a substantial claim - Study design and conductcitation
Digital deconvolution showed no significant differences in the percentage of neurons, astrocytes and microglia in the prefrontal cortex of alcoholics and controls.
“Digital deconvolution showed no significant differences in the percentage of neurons, astrocytes and microglia in the PFC of alcoholics and controls (Supplementary Figure 3)21; therefore we did not perform any correction for cell-type heterogeneity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Li, Z. et al. Genetic variants associated with Alzheimer’s disease confer different cerebral cortex cell-type population structure. Genome Med. 10, 43 (2018). source
Not checked in the free run.
- Interpretationown data
The study's analysis provides systems-level evidence of genetic networks within the prefrontal cortex that contribute to the pathophysiology of alcohol drinking behavior in humans.
“Our analysis provides systems-level evidence of genetic networks within the PFC that contribute to the pathophysiology of alcohol drinking behavior in humans.”
Quote in the paperSubstantial claim - Interpretationown data
The enrichment of brown4 in immune response and infectious diseases provides additional evidence for the role of the neuroimmune system in the etiology of alcohol dependence.
“Another module that correlated with alcohol dependence, brown4, was also enriched in immune response and infectious diseases, providing additional evidence for the role of the neuroimmune system in the etiology of alcohol dependence.”
Quote in the paperSubstantial claim - Study design and conductown data
The thistle2 under-enrichment remained significant even after 100,000 permutations.
“The under-enrichment remained significant even after 100,000 permutations.”
Quote in the paperNot a substantial claim - Interpretationown data
This systematic exploration of transcriptomic organization in the PFC from alcoholics provides further support for the role of the neuroimmune system in alcohol dependence.
“This systematic exploration of transcriptomic organization in the PFC from alcoholics provides further support for the role of the neuroimmune system in alcohol dependence.”
Quote in the paperSubstantial claim - Premisecitation
mRNA expression studies in human brain showed significant changes in expression of genes related to immune or inflammatory responses in hippocampus and nucleus accumbens.
“Furthermore, mRNA expression studies in human brain showed significant changes in expression of genes related to immune or inflammatory responses in hippocampus7 and nucleus accumbens8.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [7] McClintick, J. N. et al. Stress-response pathways are altered in the hippocampus of chronic. Alcohol. Alcohol Fayettev. N. 47, 505–515 (2013). source
Not checked in the free run.
- cites [8] Mamdani, M. et al. Integrating mRNA and miRNA weighted gene co-expression networks with eqtls in the nucleus accumbens of subjects with alcohol dependence. PLoS ONE 10, e0137671 (2015). source
Not checked in the free run.
- Interpretationcitation
The paper's pathway analysis results are consistent with earlier findings showing induction of innate immune genes by stress and drug abuse.
“Our pathway analysis results are consistent with earlier findings showing induction of innate immune genes by stress and drug abuse35.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Crews, F. T., Zou, J. & Qin, L. Induction of innate immune genes in brain create the neurobiology of addiction. Brain Behav. Immun. 25, S4–S12 (2011). source
Not checked in the free run.
- Interpretationown data
The rodent enrichment observation adds to the validity of hub genes in the identified modules.
“This observation adds to the validity of hub genes in the identified modules.”
Quote in the paperSubstantial claim- Rests on an assumption: Rodent RNA-expression datasets can validate findings about human alcohol dependence.
- Interpretationown data
Genes that have altered expression due to alcohol exposure interact with risk genes (GWAS) to increase an individual's risk of becoming dependent on alcohol.
“As mentioned in the discussion we identified that genes that have altered expression due to alcohol exposure interact with risk genes (GWAS) to increase an individual’s risk of becoming dependent on alcohol.”
Quote in the paperSubstantial claim - Interpretationown data
The findings suggest possible gene-environment (alcohol exposure) interactions in the etiology of alcohol dependence.
“This suggests possible gene–environment (alcohol exposure) interactions in the etiology of alcohol dependence.”
Quote in the paperSubstantial claim
- May combine two claims. 13
- The quote only partly states this claim. 1
- Classified as probably not a substantial claim. 15
May combine two claims.
Findingown dataThe thistle2 coexpression module was significantly negatively correlated with alcohol dependence, alcohol consumption, and AUDIT scores.
“A coexpression module (thistle2) identified by weighted gene co-expression network analysis (WGCNA) was significantly correlated with alcohol dependence, alcohol consumption, and AUDIT scores.”
- Also stated in: § Identification of gene co-expression networks and modules · plain
“Of these five modules, the thistle2 module (containing 72 genes), was negatively correlated with alcohol dependence and other alcohol-related traits.”
Quote in the paperSubstantial claim- Also stated in: § Identification of gene co-expression networks and modules · plain
May combine two claims.
Findingown dataGenes in the thistle2 module were enriched for calcium signaling pathways and these pathways were significantly downregulated.
“Pathway enrichment analysis of the thistle2 module showed a significant downregulation of pathways related to calcium signaling (Fig. 3a).”
- Also stated in: § Abstract · plain
“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.”
Quote in the paperSubstantial claim- Also stated in: § Abstract · plain
The quote only partly states this claim.
Findingown dataGene-ontology enrichment analysis mapped a large proportion of differentially expressed genes to biological processes involved in blood coagulation and fluid transport.
“Gene-ontology enrichment analysis using clusteProfiler mapped a large proportion of genes to biological processes involved in blood coagulation and fluid transport (Fig. 1c).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataPathway analysis for differentially expressed genes in the brown4 module showed significant enrichment for GADD45 signaling and for biological processes related to the inflammatory response.
“Pathway analysis for differentially expressed genes in the brown4 module showed significant enrichment for Growth Arrest and DNA Damage (GADD45) signaling and for biological processes related to the inflammatory response (Fig. 4).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataTrait-module correlation analysis showed the thistle2 module had a significant negative correlation with alcohol dependence (−0.28, P = 9.0 × 10−4), alcohol consumption (−0.22, P = 9.0 × 10−3), and AUDIT score (−0.25, P = 3.0 × 10−3).
“Trait-module correlation analysis for the thistle2 module showed a significant negative correlation with alcohol dependence (−0.28, P = 9.0 × 10−4), alcohol consumption (−0.22, P = 9.0 × 10−3), and AUDIT score (−0.25, P = 3.0 × 10−3), while the brown4 module showed a positive correlation (0.18, P = 4.0 × 10−2) with alcohol dependence (Fig. 2; Table 2).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe differentially expressed FKBP5 gene was part of the brown module but was not identified as a hub gene according to intra-modular connectivity.
“The differentially expressed FKBP5 gene was also part of the brown module, but it was not identified as hub gene according to intra-modular connectivity (supplementary table 2).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe mean age of alcohol-dependent subjects (55.65 years) was not significantly different from that of control subjects (54.96 years).
“The mean age of AD subjects was 55.65 years and was not significantly different from the age of control subjects (54.96) (Table 1).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe transcriptional effects of long-term alcohol consumption are associated with pathways involved in the neuro-immune system, neurotoxicity, and changes in neuroplasticity.
“The transcriptional effects of long-term alcohol consumption are associated with pathways involved in the neuro-immune system, neurotoxicity, and changes in neuroplasticity6,7,9.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [6] Mayfield, R. D., Harris, R. A. & Schuckit, M. A. Genetic factors influencing alcohol dependence. Br. J. Pharmacol. 154, 275–287 (2008). source
Not checked in the free run.
- cites [7] McClintick, J. N. et al. Stress-response pathways are altered in the hippocampus of chronic. Alcohol. Alcohol Fayettev. N. 47, 505–515 (2013). source
Not checked in the free run.
- cites [9] Farris, S. P., Arasappan, D., Hunicke-Smith, S., Harris, R. A. & Mayfield, R. D. Transcriptome organization for chronic alcohol abuse in human brain. Mol. Psychiatry 20, 1438–1447 (2015). source
Not checked in the free run.
May combine two claims.
Study design and conductown dataThere was no significant difference in the distribution of RNA integrity number and brain pH between cases and controls.
“There was no significant difference in distribution of RIN and brain pH between cases and controls (Table 1).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationApplication of bioinformatics techniques such as weighted gene co-expression network analysis has uncovered networks associated with alcohol dependence.
“Application of bioinformatics techniques, such as weighted gene co-expression network analysis (WGCNA)15, has uncovered networks associated with alcohol dependence8,9.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [8] Mamdani, M. et al. Integrating mRNA and miRNA weighted gene co-expression networks with eqtls in the nucleus accumbens of subjects with alcohol dependence. PLoS ONE 10, e0137671 (2015). source
Not checked in the free run.
- cites [9] Farris, S. P., Arasappan, D., Hunicke-Smith, S., Harris, R. A. & Mayfield, R. D. Transcriptome organization for chronic alcohol abuse in human brain. Mol. Psychiatry 20, 1438–1447 (2015). source
Not checked in the free run.
- cites [15] Langfelder, P. & Horvath, S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinforma. 9, 559 (2008). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn individuals with alcohol dependence, there is a complex interplay between genetic background, environmental factors, and history of alcohol exposure.
“In individuals with alcohol dependence, there is a complex interplay between genetic background, environmental factors, and history of alcohol exposure3.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3] Contet, C. Gene expression under the influence: transcriptional profiling of ethanol in thebrain. Curr. Psychopharmacol. 1, 301–314 (2012). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationFKBP5 encodes FK506-binding protein 5, a glucocorticoid receptor (GR)-binding protein implicated in various psychiatric disorders and alcohol withdrawal severity.
“FKBP5 encodes FK506-binding protein 5, a glucocorticoid receptor (GR)-binding protein implicated in various psychiatric disorders and alcohol withdrawal severity30.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Qiu, B. et al. The FKBP5 gene affects alcohol drinking in knockout mice and is implicated in alcohol drinking in humans. Int. J. Mol. Sci. 17. https://doi.org/10.3390/ijms17081271 (2016). source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductnone givenThe analysis used the voom function in the Limma package to account for the effect of sequencing batch, RNA integrity number, age, sex and postmortem interval on gene expression.
“We used the voom function in the Limma package (https://www.bioconductor.org/packages/devel/bioc/vignettes/limma/) to account for the effect of sequencing batch, RIN, age, sex and PMI on gene expression.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFKBP5 plays a role in alcohol drinking behaviors in rodents and humans.
“Other studies have also shown that FKBP5 plays a role in alcohol drinking behaviors in rodents28,29 and humans32.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [28] Kerns, R. T. et al. Ethanol-responsive brain region expression networks: implications for behavioral responses to acute ethanol in DBA/2J versus C57BL/6J Mice. J. Neurosci. 25, 2255–2266 (2005). source
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- cites [29] Treadwell, J. A. & Singh, S. M. Microarray analysis of mouse brain gene expression following acute ethanol treatment. Neurochem. Res. 29, 357–369 (2004). source
Not checked in the free run.
- cites [32] Xie, P. et al. Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder. Neuropsychopharmacol. Publ. Am. Coll. Neuropsychopharmacol. 35, 1684–1692 (2010). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationInterferons are cytokines with antiviral, antiproliferative, and immunomodulatory effects, and the interferon pathway plays a critical role in human innate and adaptive immune responses.
“Interferons are cytokines that have antiviral, antiproliferative, and immunomodulatory effects and the interferon pathway plays a critical role in human innate and adaptive immune responses34.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [34] Platanias, L. C. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat. Rev. Immunol. 5, 375–386 (2005). source
Not checked in the free run.
May combine two claims.
PremisecitationNeuroinflammation associated with chronic alcohol exposure and withdrawal may be attributed to microglial activation and is associated with the neuropathology of chronic alcohol exposure.
“The neuroinflammation associated with chronic alcohol exposure and withdrawal may be attributed to microglial activation and is associated with the neuropathology of chronic alcohol exposure36.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Kalinin, S. et al. Transcriptome analysis of alcohol-treated microglia reveals downregulation of beta amyloid phagocytosis. J. Neuroinflamm. 15, 141 (2018). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFkbp5 KO mice exhibited increased alcohol consumption compared with wild-type mice.
“Qiu and colleagues30 reported that Fkbp5 KO mice exhibited increased alcohol consumption compared with wild-type mice.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Qiu, B. et al. The FKBP5 gene affects alcohol drinking in knockout mice and is implicated in alcohol drinking in humans. Int. J. Mol. Sci. 17. https://doi.org/10.3390/ijms17081271 (2016). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAcute ethanol exposure inhibits Ca2+ currents induced by PKC-dependent phosphorylation of mGluR5 in neurons.
“Acute ethanol exposure has been shown to inhibit Ca2+ currents induced by PKC-dependent phosphorylation of mGluR5 in neurons42.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] Netzeband, J. G. & Gruol, D. L. Modulatory effects of acute ethanol on metabotropic glutamate responses in cultured Purkinje neurons. Brain Res. 688, 105–113 (1995). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationStudies using a co-expression network approach showed that alcohol dependence is shaped, in part, by persistent alterations in networks of co-expressed genes that collectively mediate excessive drinking and other alcohol-dependent phenotypes.
“Studies that used a co-expression network approach also showed that alcohol dependence is shaped, in part, by persistent alterations in networks of co-expressed genes that collectively mediate excessive drinking and other alcohol-dependent phenotypes8,9.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [8] Mamdani, M. et al. Integrating mRNA and miRNA weighted gene co-expression networks with eqtls in the nucleus accumbens of subjects with alcohol dependence. PLoS ONE 10, e0137671 (2015). source
Not checked in the free run.
- cites [9] Farris, S. P., Arasappan, D., Hunicke-Smith, S., Harris, R. A. & Mayfield, R. D. Transcriptome organization for chronic alcohol abuse in human brain. Mol. Psychiatry 20, 1438–1447 (2015). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEthanol has a significant inhibitory effect on the influx of Ca2+ through L-type voltage-gated Ca2+ channels in PC12 cell cultures.
“Early studies in PC12 cell cultures also showed that ethanol has a significant inhibitory effect on the influx of Ca2+ through L-type voltage-gated Ca2+ channels43.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [43] Mullikin-Kilpatrick, D., Mehta, N. D., Hildebrandt, J. D. & Treistman, S. N. Gi is involved in ethanol inhibition of L-type calcium channels in undifferentiated but not differentiated PC-12 cells. Mol. Pharmacol. 47, 997–1005 (1995).
Not checked in the free run.
May combine two claims.
InterpretationcitationThe differential expression observed in this study is smaller than that reported in earlier differential expression studies of alcoholism, but it is consistent with differential expression studies of larger sample size.
“The differential expression observed here is smaller than that reported in earlier differential expression studies of alcoholism, but it is consistent with differential expression studies of larger sample size37.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Fromer, M. et al. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat. Neurosci. 19, 1442–1453 (2016). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAlcohol exposure modulates Ca2+ signaling between astrocytes and neurons, and Ca2+ acts as a second messenger that controls multiple processes in immune cells, including chemotaxis and secretion of pro- and anti-inflammatory cytokines.
“Alcohol exposure also modulates Ca2+ signaling between astrocytes and neurons44 (Warden et al.), and Ca2+ acts as a second messenger that controls multiple processes in immune cells, including chemotaxis and secretion of pro- and anti-inflammatory cytokines.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [44] Warden, A., Erickson, E., Robinson, G., Harris, R. A. & Mayfield, R. D. The neuroimmune transcriptome and alcohol dependence: potential for targeted therapies. Pharmacogenomics 17, 2081–2096 (2016). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe absence of Fkbp5 enhances sensitivity to alcohol withdrawal in mice.
“Another study has shown that the absence of Fkbp5 enhances sensitivity to alcohol withdrawal in mice33.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Huang, M.-C. et al. FKBP5 moderates alcohol withdrawal severity: human genetic association and functional validation in knockout mice. Neuropsychopharmacology 39, 2029–2038 (2014). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe polygenicity of AD has been observed by GWAS of alcoholism and other complex behavioral/psychiatric disorders, and the effect size for each individual genetic variant is very small.
“The polygenicity of AD has also been observed by the GWAS of alcoholism and other complex behavioral/psychiatric disorders22,38–41, and it was demonstrated that effect size for each individual genetic variant is very small.”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [22] Walters, R. K. et al. Trans-ancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders. Nat. Neurosci. 21, 1656–1669 (2018). source
Not checked in the free run.
- cites [38] Agrawal, A. & Bierut, L. J. Identifying genetic variation for alcohol dependence. Alcohol Res Curr. Rev. 34, 274–281 (2012).
Not checked in the free run.
- cites [39] Edenberg, H. J. & Foroud, T. The genetics of alcoholism: identifying specific genes through family studies. Addict. Biol. 11, 386–396 (2006). source
Not checked in the free run.
- cites [40] Gelernter, J. et al. Genome-wide association study of alcohol dependence:significant findings in African- and European-Americans including novel risk loci. Mol. Psychiatry 19, 41–49 (2014). source
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- cites [41] Kapoor, M. et al. Genome-wide polygenic scores for age at onset of alcohol dependence and association with alcohol-related measures. Transl. Psychiatry 6, e761 (2016). source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe paper's analyses provide further evidence that alcohol exposure alters Ca2+ signaling in the brains of alcoholics and could potentially alter communication between neurons and brain immune cells.
“Our analyses provide further evidence that alcohol exposure alters Ca2+ signaling in the brains of alcoholics and could potentially alter communication between neurons and brain immune cells.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Past studies of alcohol dependence transcriptomes were performed on small numbers of alcohol-dependent cases, limiting the statistical power to detect small changes in alcohol-induced gene expression.
“However, past studies were performed on small numbers of AD cases, thus limiting the statistical power to detect small changes in alcohol-induced gene expression.”
The paper relies on this without support.
Human post-mortem tissue with DSM4 alcohol dependence phenotype is limited in availability.
“Because of limited availability of human post-mortem tissue with DSM4 alcohol dependence phenotype, we tried to look for validation in rodent RNA-expression datasets (Supplementary methods; supplementary table 2).”
The paper relies on this without support.
Rodent RNA-expression datasets can validate findings about human alcohol dependence.
“Because of limited availability of human post-mortem tissue with DSM4 alcohol dependence phenotype, we tried to look for validation in rodent RNA-expression datasets (Supplementary methods; supplementary table 2).”
“The hub genes identified in present analysis were found to be significant enriched for association signals in the rodents. This observation adds to the validity of hub genes in the identified modules.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Bulk and scRNA-seq studies often exclude non-coding RNAs from their analyses.
“Bulk and scRNA-seq studies often exclude non-coding RNAs from their analyses (3,8,35) .”
From Single cell transcriptome profiling of the human alcohol-dependent brain (2020) · cites this paper as [3]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Multiple-test correction uses the wrong number of tests
MajorThe stated 27 modules and 4 traits imply 108 module-trait tests, not 31. A 0.05/108 threshold is approximately 4.63 × 10−4, so the reported thistle2 AD P value of 9.00E-04 would not pass that correction.
Reported 31 · recomputed 108
“Thistle2 module also passed the multiple test correction (27 modules, 4 traits; 0.05/31 = 1.6 × 10−3)”
Claimed brown4 UK Biobank enrichment conflicts with Table 2
MajorThe abstract claims brown4 eQTL enrichment for alcohol consumption associations in UK Biobank, but Table 2 reports a UKBB-AC enrichment P value of 0.228 for brown4.
“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.”
“| Brown4 | 0.18 | 4.00E-02 | 0.14 | 1.00E-01 | 0.12 | 1.00E-01 | 4.20E-03b | 2.28E-01b | 4.81E-03b |”
Figure 1 reports different case and control counts
MajorThe results describe 65 alcoholics and 73 controls, whereas the Figure 1 caption describes 68 alcoholics and 70 controls.
“Figure: Fig. 1 Top genes, pathways and networks from differential gene expression in DLFPC region from 68 alcoholics and 70 controls.”
“Analysis of PFC tissue derived from 65 alcoholics and 73 controls identified 827 differentially expressed genes”
PMI direction is reversed
MinorThe text says PMI was lower in alcohol-dependent subjects, but Table 1 reports a higher mean for them: 33.66 versus 26.63 hours.
“Postmortem interval (PMI) was significantly lower for the alcohol-dependent subjects.”
“| Mean PMI (SD) (hrs) | 33.66 (15.59)* | 26.63 (13.25) |”
Brown4 gene count differs between sections
MinorThe results assign 795 genes to brown4, while the discussion gives its size as 726 genes.
“The brown4 module (containing of 795 genes) was positively correlated with AD, AUDIT, alcohol consumption and duration of alcohol use.”
“eQTLs for genes in the brown4 module (N = 726 genes) were significantly enriched for GWAS signals”
Figure 1 gives a different FDR cutoff for pathway analysis
MinorThe results say the IPA pathway analysis used genes at FDR < 25%, but the Figure 1 caption says genes passing a 20% FDR threshold were input to IPA.
“IPA analysis of the differentially expressed genes (FDR < 25%) showed significant enrichment for pathways involved in interferon signaling, GADD45 signaling, and other immune-related pathways (Fig. 1b).”
“b The genes passing FDR threshold of 20% were inputted to IPA for pathway enrichment analysis.”
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Role of glial cells in neurotoxicological effects of alcohol
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- Authors
- Kapoor, M., Wang, J.-C., Farris, S. P., Liu, Y., McClintick, J., Gupta, I., Meyers, J. L., Bertelsen, S., Chao, M., Nurnberger, J., Tischfield, J., Harari, O., Zeran, L., Hesselbrock, V., Bauer, L., Raj, T., Porjesz, B., Agrawal, A., Foroud, T., Edenberg, H. J., Mayfield, R. D., & Goate, A.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- The University of Texas at Austin (US)
- Indiana University Indianapolis (US)
- Indian Institute of Science Education and Research, Bhopal (IN)
- State University of New York (US)
- Rutgers, The State University of New Jersey (US)
- Washington University in St. Louis (US)
- University of Connecticut (US)
- Corresponding author
- Kapoor, Manav
- Goate, Alison
- ORCID
- Venue
- Translational Psychiatry
- Published
- 2019-02-14
- Volume
- 9
- Issue
- 1
- Pages
- 89-89
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC6376002
- OpenAlex
- W2905361881
- Semantic Scholar
- 9a5e48dedcf9b87f012c4336af5fa9870e9e862e
- Cited by
- 92
- References
- 44
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 11 · 2023: 12 · 2022: 14 · 2021: 11 · 2020: 16 · 2019: 6
- FWCI
- 8.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- SUNY Digital Repository Support (State University of New York System) (submittedVersion, cc-by-nc-nd)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
- Purdue University Indianapolis (Indiana University) (submittedVersion, cc-by-nc-nd)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Alcohol Abuse and Alcoholism (R21 AA026388 01A1, U01 AA020926, R01 AA012404, 5U24AA025479-02, U10AA008401)
- Topics
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- alcoholism, prefrontal cortex, gene expression, differentially expressed genes, interferon signaling, calcium signaling, opioid signaling, immune signaling, expression quantitative trait loci, alcohol consumption, auditing, therapeutic target
- MeSH terms
- Adult, Aged, Alcohol Drinking, Ethanol, Alcoholism, Autopsy, Female, Gene Expression Regulation, Humans, Male, Middle Aged, New South Wales, Case-Control Studies, Prefrontal Cortex, Gene Expression Profiling, Quantitative Trait Loci, Gene Regulatory Networks, Genome-Wide Association Study, Transcriptome
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