Biology subjects

Huggett, S. B.

Publications and source records attributed to Huggett, S. B..

4 recordsLinked to original sources

bioRxiv2024

Bulk and Single-cell Transcriptomic Brain Data Identify Overlapping Processes and Cell-types with Human AUD and Mammalian Models of Alcohol Use

This study explores the neurobiological underpinnings of alcohol use disorder (AUD) by integrating bulk and single-cell transcriptomic data from humans, primates, and mice across three brain regions associated with addiction (i.e., prefrontal cortex (PFC), nucleus accumbens (NAc), and central amygdala (CeA)). We compared AUD RNA expression and cell-type abundance from 92 human brain to data from 53 primates and 90 mice engaged in diverse alcohol use paradigms. The findings revealed significant and reproducible correlations between human AUD and mammalian models of alcohol use that vary by tissue, species, and behavioral paradigm. The strongest correlations occurred between primate and mouse models of binge drinking (i.e., high drinking in the dark). Certain primate models demonstrated that the brain RNA correlations with human alcohol use disorder (AUD) were approximately 40% as strong as the correlations observed within human samples themselves. By integrating single-cell transcriptomic data, this study observed decreased oligodendrocyte proportions in the PFC and NAc of human AUD with similar trends in animal models. Gene co-expression network analyses revealed conserved systems associated with human AUD and animal models of heavy/binge alcohol consumption. Gene co-expression networks were enriched for pathways related to inflammation, myelination, and synaptic plasticity and the genes within them accounted for [~]20% of the heritability in human alcohol consumption. Identified hub genes were associated with relevant traits (e.g., impulsivity, motivation) in humans and mice. This study sheds light on conserved biological entities underlying AUD and chronic alcohol use, providing insights into the cellular, genetic, and neuromolecular basis across species.

genetics↗

bioRxiv2021

Genome- and Transcriptome-wide Splicing Associations with Problematic Alcohol Use and Alcohol Use Disorder

Genetic mechanisms of alternative mRNA splicing have been shown in the brain for a variety of neuropsychiatric traits, but not substance use disorders. Our study used RNA-sequencing data on alcohol use disorder (AUD) in the brains reward circuitry (n=56; ages 40-73; 100% Caucasian; four brain regions) and genome-wide association data on problematic alcohol use (n=435,563, ages 22-90; 100% European-American) to investigate potential genetic links with alcohol-related alternative mRNA splicing. Polygenic scores of problematic alcohol use predicted alternative mRNA brain splicing associated with AUD, which depended on brain region. Across brain regions, we found 714 differentially spliced genes in various putative addiction genes and other novel gene targets. We found 6,463 splicing quantitative trait loci (sQTLs) that were associated with the AUD differentially spliced genes. sQTLs were enriched in loose chromatin genomic regions and downstream gene targets. Additionally, the heritability of problematic alcohol use was significantly enriched for DNA variants in and around differentially spliced genes associated with AUD. Our study also performed splicing transcriptome-wide association studies (TWASs) of problematic alcohol use and other drug use traits that unveiled individual genes for follow-up and robust splicing correlations across SUDs. Finally, we show that differentially spliced genes associated showed significant overlap in primate models of chronic alcohol consumption at the gene-level in similar brain regions. Altogether, our study illuminates substantial genetic contributions of alternative mRNA splicing in relation to problematic alcohol use and AUD.

genomics↗

bioRxiv2021

Genes identified in rodent studies of alcohol intake are enriched for heritability of human substance use

BackgroundRodent paradigms and human genome-wide association studies (GWASs) on drug use have the potential to provide biological insight into the pathophysiology of addiction. MethodsUsing GeneWeaver, we created rodent alcohol and nicotine gene-sets derived from 19 gene expression studies on alcohol and nicotine outcomes. We partitioned the SNP-heritability of these gene-sets using four large human GWASs: 1) alcoholic drinks per week, 2) problematic alcohol use, 3) cigarettes per day and 4) smoking cessation. We benchmarked our findings with curated human alcoholism and nicotine addiction gene-sets and performed specificity analyses using other rodent gene-sets (e.g., locomotor behavior) and other human GWASs (e.g., height). ResultsThe rodent alcohol gene-set was enriched for heritability of drinks per week, cigarettes per day, and smoking cessation, but not problematic alcohol use. However, the rodent nicotine gene-set was not significantly associated with any of these traits. Both rodent gene-sets showed enrichment for several non-substance use GWASs, and the extent of this relationship tended to increase as a function of trait heritability. In general, larger gene-sets demonstrated more significant enrichment. Finally, when evaluating human traits with similar heritabilities, both rodent gene-sets showed greater enrichment for substance use traits. ConclusionOur results suggest that rodent gene expression studies can help to identify genes that capture heritability of substance use traits in humans, yet the specificity to human substance use was less than expected due to various factors such as the genetic architecture of a trait. We outline various limitations, interpretations and considerations for future research.

genetics↗

bioRxiv2020

Meso-limbic Gene Expression Findings from Mouse Cocaine Self-Administration Recapitulate Human Cocaine Use Disorder

Animal models of drug use have been employed for over 100 years to facilitate the identification of mechanisms governing human substance use and addiction. Most cross-species research on drug use/addiction examines behavioral overlap, but studies assessing neuro-molecular 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 that individual genes (differential expression) and systems of co-expressed genes (gene networks) would demonstrate appreciable overlap across mouse cocaine self-administration and human cocaine use disorder. We found modest, but significant associations between differentially expressed genes associated with cocaine self-administration (short access) and cocaine use disorder within meso-limbic circuitry, but non-robust associations with mouse models of acute cocaine exposure, (cocaine) context re-exposure and cocaine + context re-exposure. Investigating systems of co-expressed genes, we also 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 (2,029 common genes) and included novel and previously implicated targets of cocaine use/addiction. Lastly, we conducted expression-based phenome-wide association studies of the nine common hub genes across conserved gene networks and found that they were associated with dopamine/serotonin function, cocaine self-administration and other relevant mouse traits. Overall, our study identified and characterized homologous transcriptional effects between mouse models of cocaine self-administration and human cocaine use disorder that may serve as a benchmark for future research.

bioinformatics↗