Addiction‐related neuroadaptations following chronic nicotine exposure

Wills, Lauren P.; Kenny, Paul J.

doi:10.1111/jnc.15356

Cited by 39 publications

(33 citation statements)

References 310 publications

(403 reference statements)

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“…The first cluster of genes were enriched in pathways related to presynaptic and postsynaptic nicotinic acetylcholine receptors, as marked by the gene CHRNA5. Previous GWAS have identified multiple reproducible variants in the CHRNA5 [31,44], which were attributed to functions in both enhancement and aversion of nicotine intake [45]. We further showed in our study CHRNA5 was highly expressed in all brain tissues and its association with CPD was consistent throughout the brain.…”

Section: Discussionsupporting

confidence: 77%

Meta-Analysis of Transcriptome-Wide Association Studies Across 13 Brain Tissues Identified Novel Clusters of Genes Associated with Nicotine Addiction

Ye¹,

Mo²,

Ke³

et al. 2021

Preprint

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Genome-wide association studies (GWAS) have identified and reproduced thousands of diseases associated loci but many of them are not directly interpretable due to the strong linkage disequilibrium among variants. Transcriptome-wide association studies (TWAS) incorporated expression quantitative trait loci (eQTL) cohorts as reference panel to detect associations with the phenotype at the gene level and were gaining popularity in recent years. For nicotine addiction, several important susceptible genetic variants were identified by GWAS, but TWAS that detected genes associated with nicotine addiction and unveiled the underlying molecular mechanism were still lacking. In this study, we used eQTL data from the Genotype-Tissue Expression (GTEx) consortium as reference panel to conduct tissue specific TWAS on cigarettes per day (CPD) over 13 brain tissues in two large cohorts: UK Biobank (UKBB; N=142,202) and the GWAS &amp; Sequencing Consortium of Alcohol and Nicotine use (GSCAN; N=143,210), and then meta-analyzed the results across tissues while considering the heterogeneity across tissues. We identified three major clusters of genes with different meta-patterns across tissues consistent in both cohorts, including homogenous genes associated with CPD in all brain tissues, partially homogeneous genes associated with CPD in cortex, cerebellum and hippocampus tissues, and lastly the tissue-specific genes associated with CPD in only few specific brain tissues. Downstream enrichment analyses on each gene cluster identified unique biological pathways associated with CPD and provided important biological insights into the regulatory mechanism of nicotine dependence in the brain.

show abstract

Section: Discussionsupporting

confidence: 77%

Meta-Analysis of Transcriptome-Wide Association Studies Across 13 Brain Tissues Identified Novel Clusters of Genes Associated with Nicotine Addiction

Ye¹,

Mo²,

Ke³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…In principle, this approach could also be expanded on to assess neuroadaptations to other drugs of abuse. For example, acute and chronic alterations in neurotransmission and functional connectivity of the mesocorticolimbic circuit have been reported for cocaine ( 69 – 71 ), nicotine ( 72 – 76 ), and alcohol ( 77 – 80 ). The current proposal on how to assess and define neuroadaptations in cannabis users would also call for an international, multi-center research effort in order to include large samples of distinct cannabis user groups, ranging from novice and occasional users at the lowest end of the use frequency spectrum to daily, chronic users at the opposite extreme.…”

Section: Discussionmentioning

confidence: 99%

Cannabis Use and Neuroadaptation: A Call for Δ9-Tetrahydrocannabinol Challenge Studies

et al. 2022

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Currently, the assessment of the neurobehavioral consequences of repeated cannabis use is restricted to studies in which brain function of chronic cannabis users is compared to that of non-cannabis using controls. The assumption of such studies is that changes in brain function of chronic users are caused by repeated and prolonged exposure to acute cannabis intoxication. However, differences in brain function between chronic cannabis users and non-users might also arise from confounding factors such as polydrug use, alcohol use, withdrawal, economic status, or lifestyle conditions. We propose a methodology that highlights the relevance of acute Δ9-tetrahydrocannabinol (THC) dosing studies for a direct assessment of neuroadaptations in chronic cannabis users. The approach includes quantification of neurochemical, receptor, and functional brain network changes in response to an acute cannabis challenge, as well as stratification of cannabis using groups ranging from occasional to cannabis-dependent individuals. The methodology allows for an evaluation of THC induced neuroadaptive and neurocognitive changes across cannabis use history, that can inform neurobiological models on reward driven, compulsive cannabis use.

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“…The first cluster of genes was enriched in pathways related to presynaptic and postsynaptic nicotinic acetylcholine receptors, as marked by the gene CHRNA5 . Previous GWAS have identified multiple reproducible variants in CHRNA5 [ 29 , 31 ], which were attributed to functions in both the enhancement and aversion of nicotine intake [ 42 ]. We further showed in our study that CHRNA5 was highly expressed in all brain tissues, and its association with CPD was consistent throughout the brain.…”

Section: Discussionmentioning

confidence: 99%

Meta-Analysis of Transcriptome-Wide Association Studies across 13 Brain Tissues Identified Novel Clusters of Genes Associated with Nicotine Addiction

et al. 2021

Genes

View full text Add to dashboard Cite

Genome-wide association studies (GWAS) have identified and reproduced thousands of diseases associated loci, but many of them are not directly interpretable due to the strong linkage disequilibrium among variants. Transcriptome-wide association studies (TWAS) incorporated expression quantitative trait loci (eQTL) cohorts as a reference panel to detect associations with the phenotype at the gene level and have been gaining popularity in recent years. For nicotine addiction, several important susceptible genetic variants were identified by GWAS, but TWAS that detected genes associated with nicotine addiction and unveiled the underlying molecular mechanism were still lacking. In this study, we used eQTL data from the Genotype-Tissue Expression (GTEx) consortium as a reference panel to conduct tissue-specific TWAS on cigarettes per day (CPD) over thirteen brain tissues in two large cohorts: UK Biobank (UKBB; number of participants (N) = 142,202) and the GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN; N = 143,210), then meta-analyzing the results across tissues while considering the heterogeneity across tissues. We identified three major clusters of genes with different meta-patterns across tissues consistent in both cohorts, including homogenous genes associated with CPD in all brain tissues; partially homogeneous genes associated with CPD in cortex, cerebellum, and hippocampus tissues; and, lastly, the tissue-specific genes associated with CPD in only a few specific brain tissues. Downstream enrichment analyses on each gene cluster identified unique biological pathways associated with CPD and provided important biological insights into the regulatory mechanism of nicotine dependence in the brain.

show abstract

Addiction‐related neuroadaptations following chronic nicotine exposure

Abstract: This Review article is part of the special issue "Neurochemistry of Reward-Seeking".

Cited by 39 publications

References 310 publications

Meta-Analysis of Transcriptome-Wide Association Studies Across 13 Brain Tissues Identified Novel Clusters of Genes Associated with Nicotine Addiction

Meta-Analysis of Transcriptome-Wide Association Studies Across 13 Brain Tissues Identified Novel Clusters of Genes Associated with Nicotine Addiction

Cannabis Use and Neuroadaptation: A Call for Δ9-Tetrahydrocannabinol Challenge Studies

Meta-Analysis of Transcriptome-Wide Association Studies across 13 Brain Tissues Identified Novel Clusters of Genes Associated with Nicotine Addiction

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