Browsing by Subject "Alcohol use disorder (AUD)"
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Item 5. Collaborative Study on the Genetics of Alcoholism: Functional genomics(Wiley, 2023) Gameiro-Ros, Isabel; Popova, Dina; Prytkova, Iya; Pang, Zhiping P.; Liu, Yunlong; Dick, Danielle; Bucholz, Kathleen K.; Agrawal, Arpana; Porjesz, Bernice; Goate, Alison M.; Xuei, Xiaoling; Kamarajan, Chella; COGA Collaborators; Tischfield, Jay A.; Edenberg, Howard J.; Slesinger, Paul A.; Hart, Ronald P.; Medical and Molecular Genetics, School of MedicineAlcohol Use Disorder is a complex genetic disorder, involving genetic, neural, and environmental factors, and their interactions. The Collaborative Study on the Genetics of Alcoholism (COGA) has been investigating these factors and identified putative alcohol use disorder risk genes through genome-wide association studies. In this review, we describe advances made by COGA in elucidating the functional changes induced by alcohol use disorder risk genes using multimodal approaches with human cell lines and brain tissue. These studies involve investigating gene regulation in lymphoblastoid cells from COGA participants and in post-mortem brain tissues. High throughput reporter assays are being used to identify single nucleotide polymorphisms in which alternate alleles differ in driving gene expression. Specific single nucleotide polymorphisms (both coding or noncoding) have been modeled using induced pluripotent stem cells derived from COGA participants to evaluate the effects of genetic variants on transcriptomics, neuronal excitability, synaptic physiology, and the response to ethanol in human neurons from individuals with and without alcohol use disorder. We provide a perspective on future studies, such as using polygenic risk scores and populations of induced pluripotent stem cell-derived neurons to identify signaling pathways related with responses to alcohol. Starting with genes or loci associated with alcohol use disorder, COGA has demonstrated that integration of multimodal data within COGA participants and functional studies can reveal mechanisms linking genomic variants with alcohol use disorder, and potential targets for future treatments.Item Alcohol use disorder is associated with higher risks of Alzheimer's and Parkinson's diseases: A study of US insurance claims data(Wiley, 2022-11-21) Zhang, Pengyue; Edenberg, Howard J.; Nurnberger, John; Lai, Dongbing; Cheng, Feixiong; Liu, Yunlong; Biostatistics, School of Public HealthIntroduction: Alcohol use disorder (AUD) is on the ascendancy in the US older adult population. The association between AUD and adverse brain outcomes remains inconclusive. Method: In a retrospective cohort design using US insurance claim data (2007-2020), 129,182 individuals with AUD were matched with 129,182 controls by age, sex, race, and clinical characteristics. We investigated the association between AUD and adverse brain outcomes using Cox analysis, Kaplan-Meier analysis, and log-rank test. Results: After adjusting for covariates, AUD was associated with a higher risk of Alzheimer's disease (female adjusted hazard ratio [HR] = 1.78, 95% confidence interval [CI]: 1.68-1.90, p < 0.001; male adjusted HR = 1.80, 95% CI: 1.71-1.91, p < 0.001) and a higher risk of Parkinson's disease (female adjusted HR = 1.49, 95% CI: 1.32-1.68, p < 0.001; male adjusted HR = 1.42, 95% CI: 1.32-1.52, p < 0.001) in the overall sample. In separate analyses of Black, White, and Hispanic individuals, those with AUD had higher risk of Alzheimer's disease (adjusted HRs ≥1.58; Ps ≤ 0.001). A significantly elevated risk for Parkinson's disease was found only in the White subpopulation (female adjusted HR = 1.55, 95% CI: 1.36-1.77, p < 0.001; male adjusted HR = 1.45, 95% CI: 1.33-1.57, p < 0.001). Conclusions: AUD is associated with Alzheimer's disease. AUD is associated with Parkinson's disease in White people. Cognitive screening and neurological examination among older adults with AUD hold the promise for early detection of Alzheimer's disease and Parkinson's disease. Highlights: Alcohol use disorder is associated with Alzheimer's disease and dementia. Alcohol use disorder is associated with Parkinson's disease in White people.Item Epidemiology and trends of alcohol use disorder and alcohol-associated liver disease(Wolters Kluwer, 2023-06-02) Lee, Elizabeth; Navadurong, Huttakan; Liangpunsakul, Suthat; Medicine, School of MedicineItem Functional 3’-UTR Variants Identify Regulatory Mechanisms Impacting Alcohol Use Disorder and Related Traits(bioRxiv, 2024-02-05) Chen, Andy B.; Yu, Xuhong; Thapa, Kriti S.; Gao, Hongyu; Reiter, Jill L.; Xuei, Xiaoling; Tsai, Andy P.; Landreth, Gary E.; Lai, Dongbing; Wang, Yue; Foroud, Tatiana M.; Tischfield, Jay A.; Edenberg, Howard J.; Liu, Yunlong; Medical and Molecular Genetics, School of MedicineAlthough genome-wide association studies (GWAS) have identified loci associated with alcohol consumption and alcohol use disorder (AUD), they do not identify which variants are functional. To approach this, we evaluated the impact of variants in 3' untranslated regions (3'-UTRs) of genes in loci associated with substance use and neurological disorders using a massively parallel reporter assay (MPRA) in neuroblastoma and microglia cells. Functionally impactful variants explained a higher proportion of heritability of alcohol traits than non-functional variants. We identified genes whose 3'UTR activities are associated with AUD and alcohol consumption by combining variant effects from MPRA with GWAS results. We examined their effects by evaluating gene expression after CRISPR inhibition of neuronal cells and stratifying brain tissue samples by MPRA-derived 3'-UTR activity. A pathway analysis of differentially expressed genes identified inflammation response pathways. These analyses suggest that variation in response to inflammation contributes to the propensity to increase alcohol consumption.Item Identification of Novel Loci and Cross-Disorder Pleiotropy Through Multi-Ancestry Genome-Wide Analysis of Alcohol Use Disorder in Over One Million Individuals(Research Square, 2023-12-22) Icick, Romain; Shadrin, Alexey; Holen, Børge; Karadag, Naz; Parker, Nadine; O'Connell, Kevin; Frei, Oleksandr; Bahrami, Shahram; Høegh, Margrethe; Lagerberg, Trine; Cheng, Weiqiu; Seibert, Tyler; Djurovic, Srdjan; Dale, Anders; Zhou, Hang; Edenberg, Howard; Gelernter, Joel; Smeland, Olav; Hindley, Guy; Andreassen, Ole; Biochemistry and Molecular Biology, School of MedicineAlcohol use disorder (AUD) is highly heritable and burdensome worldwide. Genome-wide association studies (GWASs) can provide new evidence regarding the aetiology of AUD. We report a multi-ancestry GWASs across diverse ancestries focusing on a narrow AUD phenotype, using novel statistical tools in a total sample of 1,041,450 individuals [102,079 cases; European, 75,583; African, 20,689 (mostly African-American); Hispanic American, 3,449; East Asian, 2,254; South Asian, 104; descent]. Cross-ancestry functional analyses were performed with European and African samples. Thirty-seven genome-wide significant loci were identified, of which seven were novel for AUD and six for other alcohol phenotypes. Loci were mapped to genes enriched for brain regions relevant for AUD (striatum, hypothalamus, and prefrontal cortex) and potential drug targets (GABAergic, dopaminergic and serotonergic neurons). African-specific analysis yielded a unique pattern of immune-related gene sets. Polygenic overlap and positive genetic correlations showed extensive shared genetic architecture between AUD and both mental and general medical phenotypes, suggesting they are not only complications of alcohol use but also share genetic liability with AUD. Leveraging a cross-ancestry approach allowed identification of novel genetic loci for AUD and underscores the value of multi-ancestry genetic studies. These findings advance our understanding of AUD risk and clinically-relevant comorbidities.Item Integrated Single-Cell Multiomic Profiling of Caudate Nucleus Suggests Key Mechanisms in Alcohol Use Disorder(bioRxiv, 2024-08-06) Green, Nick; Gao, Hongyu; Chu, Xiaona; Yuan, Quiyue; McGuire, Patrick; Lai, Dongbing; Jiang, Guanglong; Xuei, Xiaoling; Reiter, Jill; Stevens, Julia; Sutherland, Greg; Goate, Alison; Pang, Zhiping; Slesinger, Paul; Hart, Ronald P.; Tischfield, Jay A.; Agrawal, Arpana; Wang, Yue; Duren, Zhana; Edenberg, Howard J.; Liu, Yunlong; Medical and Molecular Genetics, School of MedicineAlcohol use disorder (AUD) is likely associated with complex transcriptional alterations in addiction-relevant brain regions. We characterize AUD-associated differences in cell type-specific gene expression and chromatin accessibility in the caudate nucleus by conducting a single-nucleus RNA-seq assay and a single-nucleus RNA-seq + ATAC-seq (multiome) assay on caudate tissue from 143 human postmortem brains (74 with AUD). We identified 17 cell types. AUD was associated with a higher proportion of microglia in an activated state and more astrocytes in a reactive state. There was widespread evidence for differentially expressed genes across cell types with the most identified in oligodendrocytes and astrocytes, including genes involved in immune response and synaptic regulation, many of which appeared to be regulated in part by JUND and OLIG2. Microglia-astrocyte communication via interleukin-1 beta, and microglia-astrocyte-oligodendrocyte interaction via transforming growth factor beta 1 were increased in individuals with AUD. Expression quantitative trait loci analysis revealed potential driver genes of AUD, including ADAL, that may protect against AUD in medium spiny neurons and interneurons. This work provides a thorough profile of the effects of AUD in the human brain and identifies several promising genes for further study.Item A Multi-Omic Analysis of the Dorsal Striatum in an Animal Model of Divergent Genetic Risk for Alcohol Use Disorder(Wiley, 2021) Grecco, Gregory G.; Haggerty, David L.; Doud, Emma H.; Fritz, Brandon M.; Yin, Fuqin; Hoffman, Hunter; Mosley, Amber L.; Simpson, Edward; Liu, Yunlong; Baucum, Anthony J., II.; Atwood, Brady K.; Pharmacology and Toxicology, School of MedicineThe development of selectively bred high and low alcohol-preferring mice (HAP and LAP, respectively) has allowed for an assessment of the polygenetic risk for pathological alcohol consumption and phenotypes associated with alcohol use disorder (AUD). Accumulating evidence indicates that the dorsal striatum (DS) is a central node in the neurocircuitry underlying addictive processes. Therefore, knowledge of differential gene, protein, and phosphorylated protein expression in the DS of HAP and LAP mice may foster new insights into how aberrant DS functioning may contribute to AUD-related phenotypes. To begin to elucidate these basal differences, a complementary and integrated analysis of DS tissue from alcohol-naïve male and female HAP and LAP mice was performed using RNA sequencing, quantitative proteomics, and phosphoproteomics. These datasets were subjected to a thorough analysis of gene ontology, pathway enrichment, and hub gene assessment. Analyses identified 2,108, 390, and 521 significant differentially expressed genes, proteins, and phosphopeptides, respectively between the two lines. Network analyses revealed an enrichment in the differential expression of genes, proteins, and phosphorylated proteins connected to cellular organization, cytoskeletal protein binding, and pathways involved in synaptic transmission and functioning. These findings suggest that the selective breeding to generate HAP and LAP mice may lead to a rearrangement of synaptic architecture which could alter DS neurotransmission and plasticity differentially between mouse lines. These rich datasets will serve as an excellent resource to inform future studies on how inherited differences in gene, protein, and phosphorylated protein expression contribute to AUD-related phenotypes.Item Predicting Alcohol-Related Memory Problems in Older Adults: A Machine Learning Study with Multi-Domain Features(MDPI, 2023-05-18) Kamarajan, Chella; Pandey, Ashwini K.; Chorlian, David B.; Meyers, Jacquelyn L.; Kinreich, Sivan; Pandey, Gayathri; Subbie-Saenz de Viteri, Stacey; Zhang, Jian; Kuang, Weipeng; Barr, Peter B.; Aliev, Fazil; Anokhin, Andrey P.; Plawecki, Martin H.; Kuperman, Samuel; Almasy, Laura; Merikangas, Alison; Brislin, Sarah J.; Bauer, Lance; Hesselbrock, Victor; Chan, Grace; Kramer, John; Lai, Dongbing; Hartz, Sarah; Bierut, Laura J.; McCutcheon, Vivia V.; Bucholz, Kathleen K.; Dick, Danielle M.; Schuckit, Marc A.; Edenberg, Howard J.; Porjesz, Bernice; Psychiatry, School of MedicineMemory problems are common among older adults with a history of alcohol use disorder (AUD). Employing a machine learning framework, the current study investigates the use of multi-domain features to classify individuals with and without alcohol-induced memory problems. A group of 94 individuals (ages 50–81 years) with alcohol-induced memory problems (the memory group) were compared with a matched control group who did not have memory problems. The random forests model identified specific features from each domain that contributed to the classification of the memory group vs. the control group (AUC = 88.29%). Specifically, individuals from the memory group manifested a predominant pattern of hyperconnectivity across the default mode network regions except for some connections involving the anterior cingulate cortex, which were predominantly hypoconnected. Other significant contributing features were: (i) polygenic risk scores for AUD, (ii) alcohol consumption and related health consequences during the past five years, such as health problems, past negative experiences, withdrawal symptoms, and the largest number of drinks in a day during the past twelve months, and (iii) elevated neuroticism and increased harm avoidance, and fewer positive “uplift” life events. At the neural systems level, hyperconnectivity across the default mode network regions, including the connections across the hippocampal hub regions, in individuals with memory problems may indicate dysregulation in neural information processing. Overall, the study outlines the importance of utilizing multidomain features, consisting of resting-state brain connectivity data collected ~18 years ago, together with personality, life experiences, polygenic risk, and alcohol consumption and related consequences, to predict the alcohol-related memory problems that arise in later life.Item Repeated Binge Alcohol Drinking Leads to Reductions in Corticostriatal Theta Coherence in Female but not Male Mice(bioRxiv, 2024-03-08) Ardinger, Cherish E.; Lapish, Christopher C.; Linsenbardt, David N.; Psychology, School of ScienceDecreased functional connectivity between the striatum and frontal cortex is observed in individuals with alcohol use disorder (AUD), and predicts the probability of relapse in abstinent individuals with AUD. To further our understanding of how repeated alcohol (ethanol; EtOH) consumption impacts the corticostriatal circuit, extracellular electrophysiological recordings (local field potentials; LFPs) were gathered from the nucleus accumbens (NAc) and prefrontal cortex (PFC) of C57BL/6J mice voluntarily consuming EtOH or water using a 'drinking-in-the-dark' (DID) procedure. Following a three-day acclimation period wherein only water access was provided during DID, mice were given 15 consecutive days of access to EtOH. Each session consisted of a 30-minute baseline period where water was available and was followed immediately by a 2-hour period where sippers containing water were replaced with new sippers containing either unsweetened 20% (v/v) EtOH (days 4-18; DID) or water (days 1-3; acclimation). Our analyses focused primarily on theta coherence during bouts of drinking, as differences in this band are associated with several behavioral markers of AUD. Both sexes displayed decreases in theta coherence during the first day of binge EtOH consumption. However, only females displayed further decreases in theta coherence on the 14th day of EtOH access. No differences in theta coherence were observed between the first and final bout on any EtOH drinking days. These results provide additional support for decreases in the functional coupling of corticostriatal circuits as a consequence of alcohol consumption and suggests that female mice are uniquely vulnerable to these effects following repeated EtOH drinking.Item Subjective Responses to Alcohol in the Development and Maintenance of Alcohol Use Disorder(American Psychiatric Association, 2021) King, Andrea; Vena, Ashley; Hasin, Deborah; deWit, Harriet; O’Connor, Sean J.; Cao, Dingcai; Psychiatry, School of MedicineObjective: Alcohol use disorder (AUD) remains an urgent public health problem. Longitudinal data are needed to clarify the role of acute subjective responses to alcohol in the development and maintenance of excessive drinking and AUD. The authors report on 10 years of repeated examination of acute alcohol responses in the Chicago Social Drinking Project. Methods: Young adult drinkers (N=190) participated in an initial alcohol challenge (0.8 g/kg of alcohol compared with placebo) that was repeated 5 and 10 years later. They were also assessed on drinking behavior and AUD symptoms at numerous intervals across the decade. Retention was high, as 184 of the 185 (99%) nondeceased active participants completed the 10-year follow-up, and 91% (163 of 179) of those eligible for alcohol consumption engaged in repeated laboratory testing during this interval. Results: At the end of the decade, 21% of participants met criteria for past-year AUD. Individuals who reported the greatest alcohol stimulation, liking, and wanting at the initial alcohol challenge were most likely to have developed AUD 10 years later. Further, alcohol-induced stimulation and wanting increased in reexamination testing among those with the highest AUD symptoms as the decade progressed. Conclusions: Initial stimulant and rewarding effects of alcohol predicted heavy alcohol use, and the magnitude of these positive subjective effects increased over a 10-year period in those who developed AUD compared with those who did not develop the disorder. The findings demonstrate systematic changes in subjective responses to alcohol over time, providing an empirical basis for prevention, early intervention, and treatment strategies.