Single nuclei transcriptomics in human and non-human primate striatum in opioid use disorder

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 31, 2024

Abstract In brain, the striatum is a heterogenous region involved in reward and goal-directed behaviors. Striatal dysfunction linked to psychiatric disorders, including opioid use disorder (OUD). subregions are divided based on neuroanatomy, each with unique roles OUD. OUD, dorsal altered processing, formation of habits, development negative affect during withdrawal. Using single nuclei RNA-sequencing, we identified both canonical (e.g., dopamine receptor subtype) less abundant cell populations interneurons) human striatum. Pathways related neurodegeneration, interferon response, DNA damage were significantly enriched striatal neurons individuals markers also elevated opioid-exposed rhesus macaques. Sex-specific molecular differences glial subtypes associated chronic stress found particularly female individuals. Together, describe different types identify type-specific alterations

Language: Английский

---

Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects in brain regions associated with addiction

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(10), P. 1279 - 1287

Published: Sept. 28, 2022

Language: Английский

---

Utility of Candidate Genes From an Algorithm Designed to Predict Genetic Risk for Opioid Use Disorder

JAMA Network Open, Journal Year: 2025, Volume and Issue: 8(1), P. e2453913 - e2453913

Published: Jan. 9, 2025

Importance Recently, the US Food and Drug Administration gave premarketing approval to an algorithm based on its purported ability identify individuals at genetic risk for opioid use disorder (OUD). However, clinical utility of candidate variants included in has not been independently demonstrated. Objective To assess 15 from intended predict OUD risk. Design, Setting, Participants This case-control study examined association with using electronic health record data December 20, 1992, September 30, 2022. Electronic data, including pharmacy records, were accrued participants Million Veteran Program across exposure (n = 452 664). Cases identified International Classification Diseases, Ninth Revision , or Tenth diagnostic codes, controls no diagnosis. Exposures Number alleles present variants. Main Outcome Measures Performance identifying assessed via logistic regression machine learning models. Results A total 664 (including 33 669 OUD) had a mean (SD) age 61.15 (13.37) years, 90.46% male; sample was ancestrally diverse (with genetically inferred European, African, admixed American ancestries). Using Nagelkerke R 2 collectively, genes accounted 0.40% variation In comparison, sex alone 3.27% variation. The ensemble learning. model as predictive factors correctly classified 52.83% (95% CI, 52.07%-53.59%) independent testing sample. Conclusions Relevance this suggest that approved do meet reasonable standards efficacy Given algorithm’s limited accuracy, care would lead high rates both false-positive false-negative findings. More clinically useful models are needed developing OUD.

Language: Английский

---

Multi-ancestral genome-wide association study of clinically defined nicotine dependence reveals strong genetic correlations with other substance use disorders and health-related traits.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

ABSTRACT Genetic research on nicotine dependence has utilized multiple assessments that are in weak agreement. We conducted a genome-wide association study of defined using the Diagnostic and Statistical Manual Mental Disorders (DSM-NicDep) 61,861 individuals (47,884 European ancestry, 10,231 African 3,746 East Asian ancestry) compared results to other nicotine-related phenotypes. replicated well-known at CHRNA5 locus (lead SNP: rs147144681, p =1.27E-11 ancestry; lead SNP = rs2036527, 6.49e-13 cross-ancestry analysis). DSM-NicDep showed strong positive genetic correlations with cannabis use disorder, opioid problematic alcohol use, lung cancer, material deprivation, several psychiatric disorders, negative respiratory function educational attainment. A polygenic score predicted DSM-5 tobacco disorder 6 11 individual diagnostic criteria, but none Fagerström Test for Nicotine Dependence (FTND) items, independent NESARC-III sample. In genomic structural equation models, loaded more strongly previously identified factor general addiction liability than did “problematic use” (a combination cigarettes per day by FTND). Finally, was genetically correlated GWAS as electronic health records, suggesting combining wide availability EHR data nuanced criterion-level analyses DSM may produce new insights into genetics this disorder.

Language: Английский

---

The Genetically Informed Neurobiology of Addiction (GINA) model

Nature reviews. Neuroscience, Journal Year: 2022, Volume and Issue: 24(1), P. 40 - 57

Published: Nov. 29, 2022

Language: Английский

---

Profiling neuronal methylome and hydroxymethylome of opioid use disorder in the human orbitofrontal cortex

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 28, 2023

Abstract Opioid use disorder (OUD) is influenced by genetic and environmental factors. While recent research suggests epigenetic disturbances in OUD, this mostly limited to DNA methylation (5mC). hydroxymethylation (5hmC) has been widely understudied. We conducted a multi-omics profiling of OUD male cohort, integrating neuronal-specific 5mC 5hmC as well gene expression profiles from human postmortem orbitofrontal cortex (OUD = 12; non-OUD 26). Single locus methylomic analysis co-methylation showed higher number OUD-associated genes networks for compared 5mC; these were enriched GPCR, Wnt, neurogenesis, opioid signaling. marks also correlation with patterns GWAS psychiatric traits. Drug interaction revealed interactions opioid-related drugs, some used treatments. Our findings suggest an important role reveal loci epigenetically dysregulated OFC neurons individuals OUD.

Language: Английский

---

Examining the shared etiology of psychopathology with genome-wide association studies

Physiological Reviews, Journal Year: 2023, Volume and Issue: 103(2), P. 1645 - 1665

Published: Jan. 12, 2023

Genome-wide association studies (GWASs) have ushered in a new era of reproducible discovery psychiatric genetics. The field has now identified hundreds common genetic variants that are associated with mental disorders, and many them influence more than one disorder. By advancing the understanding causal biology underlying psychopathology, GWAS results poised to inform development novel therapeutics, stratification at-risk patients, perhaps even revision top-down classification systems psychiatry. Here, we provide concise review findings an emphasis on elucidated shared etiology summarizing insights at three levels analysis: 1) genome-wide architecture; 2) networks, pathways, gene sets; 3) individual variants/genes. Three themes emerge from these efforts. First, all phenotypes heritable, highly polygenic, influenced by pleiotropic incomplete penetrance. Second, highlight broad etiological roles neuronal biology, system-wide effects over localized effects, early neurodevelopment as critical period. Third, loci robustly multiple forms psychopathology harbor genes involved synaptic structure function. Finally, conclude our discussing implications hold for psychiatry, well expected challenges future directions next stage

Language: Английский

---

Genetic and non-genetic predictors of risk for opioid dependence

Psychological Medicine, Journal Year: 2024, Volume and Issue: 54(8), P. 1779 - 1786

Published: Feb. 6, 2024

Abstract Background Elucidation of the interaction biological and psychosocial/environmental factors on opioid dependence (OD) risk can inform our understanding etiology OD. We examined role in moderating polygenic for use disorder (OUD). Methods Data from 1958 European ancestry adults who participated Yale-Penn 3 study were analyzed. Polygenic scores (PRS) based a large-scale multi-trait analysis genome-wide association studies (MTAG) OUD. Results A total 420 (21.1%) individuals had lifetime diagnosis OUD PRS positively associated with OD (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.21–1.66). Household income education strongest correlates Among higher PRS, those level lower odds (OR 0.92, CI 0.85–0.98); posttraumatic stress (PTSD) more likely to have relative without PTSD 1.56, 1.04–2.35). Conclusions suggest an interplay between genetics psychosocial environment contributing risk. While alone do not yet useful clinical predictive utility, may help enhance prediction. These findings could targeted policy interventions address this public health crisis.

Language: Английский

---

The single-cell opioid responses in the context of HIV (SCORCH) consortium

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(12), P. 3950 - 3961

Published: June 15, 2024

Substance use disorders (SUD) and drug addiction are major threats to public health, impacting not only the millions of individuals struggling with SUD, but also surrounding families communities. One seminal challenges in treating studying human populations is high prevalence co-morbid conditions, including an increased risk contracting a immunodeficiency virus (HIV) infection. Of ~15 million people who inject drugs globally, 17% persons HIV. Conversely, HIV factor for SUD because chronic pain syndromes, often encountered HIV, can lead opioid medications that turn increase addiction. We hypothesize exert shared effects on brain cell types, adaptations related neuroplasticity, neurodegeneration, neuroinflammation. Basic research needed refine our understanding these affected types adaptations. Studying context at single-cell level represents compelling strategy understand reciprocal interactions among both made feasible by availability large, extensively-phenotyped tissue collections have been amassed Neuro-HIV community. In addition, sophisticated animal models developed conditions provide means precisely evaluate specific exposures stages disease. propose genomics uniquely powerful technology characterize brain, integrating data from cohorts models. formed Single-Cell Opioid Responses Context (SCORCH) consortium carry out this strategy.

Language: Английский

---

CpH methylome analysis in human cortical neurons identifies novel gene pathways and drug targets for opioid use disorder

Frontiers in Psychiatry, Journal Year: 2023, Volume and Issue: 13

Published: Jan. 19, 2023

Introduction DNA methylation (DNAm), an epigenetic mechanism, has been associated with opioid use disorder (OUD) in preclinical and human studies. However, most of the studies have focused on DNAm at CpG sites. non-CpG sites (mCpHs, where H indicates A, T, or C) recently shown to a role gene regulation be highly abundant neurons. its OUD is unknown. This work aims evaluate mCpHs postmortem orbital frontal cortex (OFC) context OUD. Methods A total 38 Postmortem OFC samples were obtained from VA Brain Bank (OUD = 12; Control 26). assessed using reduced representation oxidative bisulfite sequencing neuronal nuclei. Differential analysis was performed “methylkit” R package. Age, ancestry, interval, PTSD, smoking status included as covariates. Significant set q -value < 0.05. Gene Ontology (GO) KEGG enrichment analyses for annotated genes all differential mCpH loci String, ShinyGO, amiGO software. Further, analyzed Drug interaction database (DGIdb). Results 2,352 differentially methylated genome-wide significant identified OUD, mapping 2,081 genes. GO showed nervous system development ( p 2.32E-19). axon guidance glutamatergic synapse (FDR 9E-4–2.1E-2). found 3,420 interactions between drugs, identifying 15 opioid-related including lofexidine tizanidine, both previously used treatment OUD-related symptoms. Conclusion Our findings suggest cortical neurons reveal important biological pathways drug targets disorder.

Language: Английский

---