Biology subjects

Palmer, R. H. C.

Publications and source records attributed to Palmer, R. H. C..

5 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↗

bioRxiv2022

Resting-State Network Analysis of Suicide Attempt History in the UK Biobank

BackgroundPrior research has identified altered brain structure and function in individuals at risk for self-directed violence thoughts and behaviors. However, these studies have largely utilized healthy controls and findings have been inconsistent. Thus, this study examined differences in resting-state functional network connectivity among individuals with lifetime suicide attempt(s) versus lifetime self-directed violence thoughts alone. MethodsUsing data from the UK Biobank, this study utilized a series of linear regressions to compare individuals with lifetime suicide attempt(s) (n = 566) versus lifetime self-directed violence thoughts alone (n = 3,447) on within- and between-network resting-state functional connectivity subnetworks. ResultsThere were no significant between-group differences for between-network, within-network, or whole-brain functional connectivity after adjusting for age, sex, ethnicity, and body mass index and performing statistical corrections for multiple comparisons. ConclusionsResting-state network measures may not differentiate between individuals with lifetime suicide attempt(s) and lifetime self-directed violence thoughts alone. Null findings diverge from results reported in smaller neuroimaging studies of suicide risk, but are consistent with null findings in other large-scale studies and meta-analyses. Strengths of the study include its large sample size and stringent control group. Future research on a wider array of imaging, genetic, and psychosocial risk factors can clarify relative contributions of individual and combined variables to suicide risk and inform scientific understanding of ideation-to-action framework.

neuroscience↗

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↗

bioRxiv2019

Cross-Species Integration of Transcriptomic Effects of Tobacco and Nicotine Exposure Helps to Prioritize Genetic Effects on Human Tobacco Consumption

Computational advances have fostered the development of new methods and tools to integrate gene expression and functional evidence into human-genetic association analyses. Integrative functional genomics analysis for altered response to alcohol in mice provided the first evidence that multi-species analysis tools, such as GeneWeaver, can identify or confirm novel alcohol-related loci. The present study describes an integrative framework to investigate how highly-connected genes linked by their association to tobacco-related behaviors, contribute to individual differences in tobacco consumption. Data from individuals of European ancestry in the UKBiobank (N=139,043) were used to examine the relative contribution of orthologs of a set of genes that are transcriptionally co-regulated by tobacco or nicotine exposure in model organism experiments to human tobacco consumption. Multi-component mixed linear models using genotyped and imputed single nucleotide variants indicated that: (1) variation within human orthologs of these genes accounted for 2-5% of the observed heritability (meta h2SNP-Total=0.08 [95% CI: 0.07, 0.09]) of tobacco/nicotine consumption across three independent folds of unrelated individuals (enrichment ranging from 0.85 - 2.98), and (2) variation around (5, 10, 15, 25, and 50 Kb regions) the set of co-transcriptionally regulated genes accounted for 5-36% of the observed SNP-heritability (enrichment ranging from 1.60 - 31.45). Notably, the effects of variants in co-transcriptionally regulated genes were enriched in tobacco GWAS. These findings highlight the advantages of using multiple species evidence to isolate genetic factors to better understand the etiological complexity of tobacco and other nicotine consumption.

genetics↗