Genetic Architecture and Molecular Neuropathology of Human Cocaine Addiction

Huggett, Spencer B.; Stallings, Michael C.

doi:10.1523/jneurosci.2879-19.2020

Cited by 42 publications

(27 citation statements)

References 86 publications

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“…Thus far, there has been one GWS variant identified: rs2629540, located in the FAM53B gene (Gelernter et al, 2014 a ). Huggett and Stallings ( 2020 a , b ) applied a gene-wise test to these data and identified four significant genes: C1QL2 , STK38 , and KCTD20 in European Americans ( N = 3176), and NDUFB9 in African Americans ( N = 3370). A meta-analysis of CocUD (all European-ancestry; N cases = 2085, N controls = 4293) identified an association with HIST1H2BD in a gene-based test (Cabana-Domínguez, Shivalikanjli, Fernàndez-Castillo, & Cormand, 2019 ).…”

Section: Genetics Of Sudsmentioning

confidence: 99%

Genetics of substance use disorders: a review

Deak

Johnson

2021

Psychol. Med.

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Substance use disorders (SUDs) are prevalent and result in an array of negative consequences. They are influenced by genetic factors (h2 = ~50%). Recent years have brought substantial progress in our understanding of the genetic etiology of SUDs and related traits. The present review covers the current state of the field for SUD genetics, including the epidemiology and genetic epidemiology of SUDs, findings from the first-generation of SUD genome-wide association studies (GWAS), cautions about translating GWAS findings to clinical settings, and suggested prioritizations for the next wave of SUD genetics efforts. Recent advances in SUD genetics have been facilitated by the assembly of large GWAS samples, and the development of state-of-the-art methods modeling the aggregate effect of genome-wide variation. These advances have confirmed that SUDs are highly polygenic with many variants across the genome conferring risk, the vast majority of which are of small effect. Downstream analyses have enabled finer resolution of the genetic architecture of SUDs and revealed insights into their genetic relationship with other psychiatric disorders. Recent efforts have also prioritized a closer examination of GWAS findings that have suggested non-uniform genetic influences across measures of substance use (e.g. consumption) and problematic use (e.g. SUD). Additional highlights from recent SUD GWAS include the robust confirmation of loci in alcohol metabolizing genes (e.g. ADH1B and ALDH2) affecting alcohol-related traits, and loci within the CHRNA5-CHRNA3-CHRNB4 gene cluster influencing nicotine-related traits. Similar successes are expected for cannabis, opioid, and cocaine use disorders as sample sizes approach those assembled for alcohol and nicotine.

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Section: Genetics Of Sudsmentioning

confidence: 99%

Genetics of substance use disorders: a review

Deak

Johnson

2021

Psychol. Med.

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“…In the IVSA paradigm, several circadian genes (Per1/2/3, Cry1/2) and IEGs ( Egr1 , Jun ) were altered by cocaine [ 32 – 34 ]. C1ql2 was also upregulated following IVSA, which is associated with human cocaine addiction using GWAS [ 35 ]. IVSA cocaine also increased expression of Cartpt and decreased expression of Mef2a , both genes previously studied in cocaine action [ 15 , 22 ].…”

Section: Resultsmentioning

confidence: 99%

Cocaine induces paradigm-specific changes to the transcriptome within the ventral tegmental area

Campbell

Chen

Beardwood

et al. 2021

Neuropsychopharmacol.

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During the initial stages of drug use, cocaine-induced neuroadaptations within the ventral tegmental area (VTA) are critical for drug-associated cue learning and drug reinforcement processes. These neuroadaptations occur, in part, from alterations to the transcriptome. Although cocaine-induced transcriptional mechanisms within the VTA have been examined, various regimens and paradigms have been employed to examine candidate target genes. In order to identify key genes and biological processes regulating cocaine-induced processes, we employed genome-wide RNA-sequencing to analyze transcriptional profiles within the VTA from male mice that underwent one of four commonly used paradigms: acute home cage injections of cocaine, chronic home cage injections of cocaine, cocaine-conditioning, or intravenous-self administration of cocaine. We found that cocaine alters distinct sets of VTA genes within each exposure paradigm. Using behavioral measures from cocaine self-administering mice, we also found several genes whose expression patterns corelate with cocaine intake. In addition to overall gene expression levels, we identified several predicted upstream regulators of cocaine-induced transcription shared across all paradigms. Although distinct gene sets were altered across cocaine exposure paradigms, we found, from Gene Ontology (GO) term analysis, that biological processes important for energy regulation and synaptic plasticity were affected across all cocaine paradigms. Coexpression analysis also identified gene networks that are altered by cocaine. These data indicate that cocaine alters networks enriched with glial cell markers of the VTA that are involved in gene regulation and synaptic processes. Our analyses demonstrate that transcriptional changes within the VTA depend on the route, dose and context of cocaine exposure, and highlight several biological processes affected by cocaine. Overall, these findings provide a unique resource of gene expression data for future studies examining novel cocaine gene targets that regulate drug-associated behaviors.

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“…From the conserved VTA and hippocampus gene networks, we observed nine common hub genes that may modulate brain function in multiple regions. Notably, over half of these genes ( Calm3 , Aldoc , Clstn1 , Eef1a1 and Slc1a2 ) were also hub genes in a PFC gene network associated with human CUD that was enriched for analogous KEGG pathways 44 . It is possible that common hub genes recruit similar biological systems relevant to cocaine addiction across various brain regions.…”

Section: Discussionmentioning

confidence: 99%

Do gene expression findings from mouse models of cocaine use recapitulate human cocaine use disorder in reward circuitry?

Huggett

Bubier

Chesler

et al. 2020

Genes Brain and Behavior

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Animal models of drug use have investigated possible mechanisms governing human substance use traits for over 100 years. Most cross‐species research on drug use/addiction examines behavioral overlap, but studies assessing neuromolecular (e.g. RNA) correspondence are lacking. Our study utilized transcriptome‐wide data from the hippocampus and ventral tegmental area (VTA)/midbrain from a total of 35 human males with cocaine use disorder/controls and 49 male C57BL/6J cocaine/saline administering/exposed mice. We hypothesized differential expressed genes and systems of co‐expressed genes (gene networks) would show appreciable overlap across mouse cocaine self‐administration and human cocaine use disorder. We found modest, but significant relationships between differentially expressed genes associated with cocaine self‐administration (short access) and cocaine use disorder within reward circuitry. Differentially expressed genes underlying models of acute cocaine exposure (cocaine), context re‐exposure and cocaine + context re‐exposure were not consistently associated with human CUD across brain regions. Investigating systems of co‐expressed genes, we found several validated gene networks with weak to moderate conservation between cocaine/saline self‐administering mice and disordered cocaine users/controls. The most conserved hippocampal and VTA gene networks demonstrated substantial overlap (2029 common genes) and included both novel and previously implicated targets for cocaine use/addiction. Lastly, we conducted (expression‐based) phenome‐wide association studies of the nine common hub genes across conserved gene networks. Common hub genes were associated with dopamine/serotonin function, cocaine self‐administration and other relevant mouse traits. Overall, our study pinpointed and characterized conserved brain‐related RNA patterns across mouse cocaine self‐administration and human cocaine use disorder. We offer recommendations for future research and add to the dialogue surrounding pre‐clinical animal research for human disease.

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Genetic Architecture and Molecular Neuropathology of Human Cocaine Addiction

Cited by 42 publications

References 86 publications

Genetics of substance use disorders: a review

Genetics of substance use disorders: a review

Cocaine induces paradigm-specific changes to the transcriptome within the ventral tegmental area

Do gene expression findings from mouse models of cocaine use recapitulate human cocaine use disorder in reward circuitry?

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