Genetic pathways regulating the longitudinal acquisition of cocaine self-administration in a panel of inbred and recombinant inbred mice

Ah, Khan; Bagley, Jared R.; LaPierre, Nathan; Gonzalez-Figueroa, Carlos; Spencer, Tadeo C.; Choudhury, Mudra; Xiao, Xinshu; Eskin, Eleazar; Jentsch, James David; Smith, Desmond J.

doi:10.1016/j.celrep.2023.112856

Cited by 3 publications

(2 citation statements)

References 114 publications

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“…Four of these CpGs also had consistent estimates of the reverse effects of current smoking on DNAm (identified by the column “g1_nominal” in Supplementary Table S4 ): cg25612391 ( SLC25A42 ), cg05424060 ( GNAI1 ), cg10590964 (near KIAA2012 ), and cg05877788 ( TP53I13 ). Furthermore, prior pre-clinical and clinical studies have implicated 14 of the 17 mapped genes, including three with potential bidirectional effects, in behavioral or neurological traits, such as alcohol dependence ( OSBPL5 ) 28 , cocaine use ( SLCO5A1 ) 29 , anxiety ( CCDC92 ) 30 , depression ( GNAI1 ) 31 , encephalomyopathy and brain stress response ( SLC25A42 ) 32 , 33 , and dementia or Alzheimer’s disease pathology ( SIAH3 , SRM , TP53I13 ) 34 – 36 .…”

Section: Resultsmentioning

confidence: 99%

Twin-based Mendelian Randomization Analyses Highlight Smoking’s Effects on Blood DNA Methylation, with Putative Reverse Causation

Singh,

Dolan,

Lapato

et al. 2024

Preprint

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Epigenome-wide association studies (EWAS) aim to identify differentially methylated loci associated with complex traits and disorders. EWAS of cigarette smoking shows some of the most widespread DNA methylation (DNAm) associations in blood. However, traditional EWAS cannot differentiate between causation and confounding, leading to ambiguity in etiological interpretations. Here, we apply an integrated approach combining Mendelian Randomization and twin-based Direction-of-Causation analyses (MR-DoC) to examine causality underlying smoking-associated blood DNAm changes in the Netherlands Twin Register (N=2577). Evidence across models suggests that current smoking’s causal effects on DNAm likely drive many of the previous EWAS findings, implicating functional pathways relevant to several adverse health outcomes of smoking, including hemopoiesis, cell- and neuro-development, and immune regulation. Additionally, we find evidence of potential reverse causal influences at some DNAm sites, with 17 of these sites enriched for gene regulatory functional elements in the brain. The top three sites with evidence of DNAm’s effects on smoking annotate to genes involved in G protein-coupled receptor signaling (GNG7,RGS3) and innate immune response (SLC15A4), elucidating potential biological risk factors for smoking. This study highlights the utility of integrating genotypic and DNAm measures in twin cohorts to clarify the causal relationships between health behaviors and blood DNAm.

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Section: Resultsmentioning

confidence: 99%

Twin-based Mendelian Randomization Analyses Highlight Smoking’s Effects on Blood DNA Methylation, with Putative Reverse Causation

Singh,

Dolan,

Lapato

et al. 2024

Preprint

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“…2E, F ) were surprising, considering that this factor is arguably the most important one influencing statistical power [ 154 – 156 ]. Accordingly, a more rigorous analysis of power, and larger sample sizes [ 157 ], will lead in future work to better reproducibility, and should be enforced, especially when studying rodent outbred strains, or humans, who display higher inter-individual variability [ 158 , 159 ]. In humans, similar to what has been observed for GWAS [ 160 ], functional genomic studies of OUD are expected to evolve in the next decade towards collaborative efforts involving multiple labs (e.g.…”

Section: Discussionmentioning

confidence: 99%

Functional genomic mechanisms of opioid action and opioid use disorder: a systematic review of animal models and human studies

Falconnier,

Caparros-Roissard,

Decraene

et al. 2023

Mol Psychiatry

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In the past two decades, over-prescription of opioids for pain management has driven a steep increase in opioid use disorder (OUD) and death by overdose, exerting a dramatic toll on western countries. OUD is a chronic relapsing disease associated with a lifetime struggle to control drug consumption, suggesting that opioids trigger long-lasting brain adaptations, notably through functional genomic and epigenomic mechanisms. Current understanding of these processes, however, remain scarce, and have not been previously reviewed systematically. To do so, the goal of the present work was to synthesize current knowledge on genome-wide transcriptomic and epigenetic mechanisms of opioid action, in primate and rodent species. Using a prospectively registered methodology, comprehensive literature searches were completed in PubMed, Embase, and Web of Science. Of the 2709 articles identified, 73 met our inclusion criteria and were considered for qualitative analysis. Focusing on the 5 most studied nervous system structures (nucleus accumbens, frontal cortex, whole striatum, dorsal striatum, spinal cord; 44 articles), we also conducted a quantitative analysis of differentially expressed genes, in an effort to identify a putative core transcriptional signature of opioids. Only one gene, Cdkn1a, was consistently identified in eleven studies, and globally, our results unveil surprisingly low consistency across published work, even when considering most recent single-cell approaches. Analysis of sources of variability detected significant contributions from species, brain structure, duration of opioid exposure, strain, time-point of analysis, and batch effects, but not type of opioid. To go beyond those limitations, we leveraged threshold-free methods to illustrate how genome-wide comparisons may generate new findings and hypotheses. Finally, we discuss current methodological development in the field, and their implication for future research and, ultimately, better care.

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Functional genomic mechanisms of opioid action and opioid use disorder: a systematic review of animal models and human studies

Falconnier

Caparros-Roissard

Decraene

et al. 2022

Preprint

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In the past two decades, over-prescription of opioids for pain management has driven a steep increase in opioid use disorder (OUD) and death by overdose, exerting a dramatic toll on western countries. OUD is a chronic relapsing disease associated with a lifetime struggle to control drug consumption, suggesting that opioids trigger long-lasting brain adaptations, notably through functional genomic and epigenomic mechanisms. Current understanding of these processes, however, remain scarce, and have not been previously reviewed systematically. To do so, the goal of the present work was to synthesize current knowledge on genome-wide transcriptomic and epigenetic mechanisms of opioid action, in primate and rodent species. Using a prospectively registered methodology, comprehensive literature searches were completed in PubMed, Embase, and Web of Science. Of the 2705 articles identified, 69 met our inclusion criteria and were considered for qualitative analysis. Focusing on the 5 most studied nervous system structures (nucleus accumbens, frontal cortex, whole striatum, dorsal striatum, spinal cord; 44 articles), we also conducted a quantitative analysis of differentially expressed genes, in an effort to identify a putative core transcriptional signature of opioids. Only one gene, Cdkn1a, was replicated in six studies and, globally, our results unveil surprisingly low consistency across published work, even when considering most recent single-cell approaches. Analysis of putative sources for this poor reproducibility suggest contributions from species, brain structures, duration of opioid exposure, as well as batch effects. To go beyond those limitations, we leveraged threshold-free methods to illustrate how genome-wide comparisons may generate new findings and hypotheses. Finally, we discuss current methodological development in the field, and their implication for future research and, ultimately, better care.

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Genetic pathways regulating the longitudinal acquisition of cocaine self-administration in a panel of inbred and recombinant inbred mice

Cited by 3 publications

References 114 publications

Twin-based Mendelian Randomization Analyses Highlight Smoking’s Effects on Blood DNA Methylation, with Putative Reverse Causation

Twin-based Mendelian Randomization Analyses Highlight Smoking’s Effects on Blood DNA Methylation, with Putative Reverse Causation

Functional genomic mechanisms of opioid action and opioid use disorder: a systematic review of animal models and human studies

Functional genomic mechanisms of opioid action and opioid use disorder: a systematic review of animal models and human studies

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