The Molecular Basis of Alcohol Use Disorder (AUD). Genetics, Epigenetics, and Nutrition in AUD: An Amazing Triangle.
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ABSTRACT:
SUBMITTER: Siomek-Gorecka A
PROVIDER: S-EPMC8072802 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Noncoding SNP variants in KCNJ6 have been linked with increased risk of alcohol use disorder (AUD) and the endophenotype EEG frontal theta event related oscillation (ERO) power. We prepared iPSC from subjects with contrasting diagnosis of AUD and KCNJ6 variants (AF, affected) or unaffected with reference KCNJ6 (UN). Induced neurons cultures were prepared from each iPSC line and harvested for RNAseq analysis. In these bulk RNAseq analyses, we do not identify meaningful differences by KCNJ6 haplotype, we we can validate expression of the long (18kb) 3'UTR from the KCNJ6 gene, and identify several additional SNPs linked with the original three. Additional studies used single cell RNAseq to isolate differentiated neurons from iN cultures and analysis of these samples found differences in neuron process formation and synaptic function, which were validated with morphometrics, immunocytochemistry, and electrophysiology.
2022-10-07 | GSE196491 | GEO
Project description:BackgroundPrimary care provider skills such as screening, longitudinal monitoring, and medication management are generalizable to prescribing alcohol use disorder (AUD) pharmacotherapy. The association between primary care engagement (i.e., longitudinal utilization of primary care services) and prescribing of AUD pharmacotherapy is unknown.MethodsWe examined a 5-year (2010-2014) retrospective cohort of patients with AUD, 18 years and older, at an urban academic medical center in the Bronx, NY, USA. Our main exposure was level of primary care engagement (no primary care, limited primary care, and engaged with primary care) and our outcome was any AUD pharmacotherapy prescription within 2 years of AUD diagnosis. Using multivariable logistic regression, we examined the association between primary care engagement and pharmacotherapy prescribing, accounting for demographic and clinical factors.ResultsOf 21,159 adults (28.9% female) with AUD, 2.1% (n = 449) were prescribed pharmacotherapy. After adjusting for confounders, the probability of receiving an AUD pharmacotherapy prescription for patients with no primary care was 1.61% (95% CI 1.39, 1.84). The probability of AUD pharmacotherapy prescribing was 2.56% (95% CI 2.06, 3.06) for patients with limited primary care and 2.89% (95% CI 2.44, 3.34%) for patients engaged with primary care.ConclusionsThe percentage of AUD patients prescribed AUD pharmacotherapy was low; however, primary care engagement was associated with a higher, but modest, probability of receiving a prescription. Efforts to increase primary care engagement among patients with AUD may translate into increased AUD pharmacotherapy prescribing; however, strategies to increase prescribing across health care settings are needed.
| S-EPMC6492411 | biostudies-literature
Project description:Alcohol use disorder (AUD) represents a significant and ongoing public health concern with 12-month prevalence estimates of ?5.6%. Quantitative genetic studies suggest a heritability of approximately 50% for AUD, and as a result, significant efforts have been made to identify specific variation within the genome related to the etiology of AUD. Given the limited number of replicable findings that have emerged from genome-wide linkage and candidate gene association studies, more recent efforts have focused on the use of genome-wide association studies (GWAS). These studies have suggested that hundreds of variants across the genome, most of small effect (R2?<?0.002), contribute to the genetic etiology of AUD. The present review describes the initial, though limited, successes of GWAS to identify loci related to risk for AUD as well as other etiologically relevant traits (e.g. alcohol consumption). In addition, 'Post-GWAS' approaches that rely on GWAS data to estimate the heritability and co-heritability of traits, test causal relations between traits, and aid in gene discovery are described. Together, the described research findings illustrate the importance of molecular genetic research on AUD as we seek to better understand the mechanisms through which genetic variation leads to increased risk for AUD.
| S-EPMC6368900 | biostudies-literature
Project description:Alcohol Use Disorder (AUD) is a chronic psychiatric illness characterized by harmful drinking patterns leading to negative emotional, physical, and social ramifications. While the underlying pathophysiology of AUD is poorly understood, there is substantial evidence for a genetic component; however, identification of universal genetic risk variants for AUD has been difficult. Recent efforts in the search for AUD susceptibility genes will be reviewed in this article.In this review, we provide an overview of genetic studies on AUD, including twin studies, linkage studies, candidate gene studies, and genome-wide association studies (GWAS).Several potential genetic susceptibility factors for AUD have been identified, but the genes of alcohol metabolism, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), have been found to be protective against the development of AUD. GWAS have also identified a heterogeneous list of SNPs associated with AUD and alcohol-related phenotypes, emphasizing the complexity and heterogeneity of the disorder. In addition, many of these findings have small effect sizes when compared to alcohol metabolism genes, and biological relevance is often unknown.Although studies spanning multiple approaches have suggested a genetic basis for AUD, identification of the genetic risk variants has been challenging. Some promising results are emerging from GWAS studies; however, larger sample sizes are needed to improve GWAS results and resolution. As the field of genetics is rapidly developing, whole genome sequencing could soon become the new standard of interrogation of the genes and neurobiological pathways which contribute to the complex phenotype of AUD.This review examines the genetic underpinnings of Alcohol Use Disorder (AUD), with an emphasis on GWAS approaches for identifying genetic risk variants. The most promising results associated with AUD and alcohol-related phenotypes have included SNPs of the alcohol metabolism genes ADH and ALDH.
| S-EPMC5004749 | biostudies-literature
Project description:Alcohol use disorder (AUD) is a major contributor to morbidity and mortality worldwide. Although there is a heritable component, the etiology of AUD is complex and can involve environmental exposures like trauma and can be associated with many different patterns of alcohol consumption. Epigenetic modifications, which can mediate the influence of genetic variants and environmental variables on gene expression, have emerged as an important area of AUD research. Over the past decade, the number of studies investigating AUD and DNA methylation, a form of epigenetic modification, has grown rapidly. Yet we are still far from understanding how DNA methylation contributes to or reflects aspects of AUD. In this paper, we reviewed studies of DNA methylation and AUD and discussed how the field has evolved. We found that global DNA and candidate DNA methylation studies did not produce replicable results. To assess whether findings of epigenome-wide association studies (EWAS) were replicated, we aggregated significant findings across studies and identified 184 genes and 15 gene ontological pathways that were differentially methylated in at least two studies and four genes and three gene ontological pathways that were differentially methylated in three studies. These genes and pathways repeatedly found enrichment of immune processes, which is in line with recent developments suggesting that the immune system may be altered in AUD. Finally, we assess the current limitations of studies of DNA methylation and AUD and make recommendations on how to design future studies to resolve outstanding questions.
| S-EPMC8596445 | biostudies-literature
Project description:Alcohol use disorder (AUD) affects millions of people and costs nearly 250 billion dollars annually. Few effective FDA-approved treatments exist, and more are needed. AUDs have a strong heritability, but only a few genes have been identified with a large effect size on disease phenotype. Genomewide association studies (GWASs) have identified common variants with low effect sizes, most of which are in noncoding regions of the genome. Animal models frequently fail to recapitulate key molecular features of neuropsychiatric disease due to the polygenic nature of the disease, partial conservation of coding regions, and significant disparity in noncoding regions. By contrast, human induced pluripotent stem cells (hiPSCs) derived from patients provide a powerful platform for evaluating genes identified by GWAS and modeling complex interactions in the human genome. hiPSCs can be differentiated into a wide variety of human cells, including neurons, glia, and hepatic cells, which are compatible with numerous functional assays and genome editing techniques. In this review, we focus on current applications and future directions of patient hiPSC-derived central nervous system cells for modeling AUDs in addition to highlighting successful applications of hiPSCs in polygenic neuropsychiatric diseases.
| S-EPMC6120805 | biostudies-literature
Project description:Prenatal alcohol exposure produces a multitude of detrimental alcohol-induced defects in children collectively known as fetal alcohol spectrum disorder (FASD). Children with FASD often exhibit delayed or abnormal mental, neural, and physical growth. Socioeconomic status, race, genetics, parity, gravidity, age, smoking, and alcohol consumption patterns are all factors that may influence FASD. Optimal maternal nutritional status is of utmost importance for proper fetal development, yet is often altered with alcohol consumption. It is critical to determine a means to resolve and reduce the physical and neurological malformations that develop in the fetus as a result of prenatal alcohol exposure. Because there is a lack of information on the role of nutrients and prenatal nutrition interventions for FASD, the focus of this review is to provide an overview of nutrients (vitamin A, docosahexaenoic acid, folic acid, zinc, choline, vitamin E, and selenium) that may prevent or alleviate the development of FASD. Results from various nutrient supplementation studies in animal models and FASD-related research conducted in humans provide insight into the plausibility of prenatal nutrition interventions for FASD. Further research is necessary to confirm positive results, to determine optimal amounts of nutrients needed in supplementation, and to investigate the collective effects of multiple-nutrient supplementation.
| S-EPMC4224205 | biostudies-other
Project description:BackgroundFollowing a finding of alcohol use among children aged 5-8 years old in Mbale, Uganda, this project investigates the magnitude of alcohol and substance use among children ged 6-13 years old and related household, community, school, health system and clinical factors.MethodsThe project includes four larger work packages (WPs). WP1 comprises management, WP2 and 3 include the scientific components and WP4 includes integration of results, dissemination, policy and implementation advice. This protocol presents the planned research work in WP 2 and 3. WP2 comprises the adaptation and validation of the alcohol use screening tool Car-Relax-Alone-Forget-Family and Friends-Trouble (CRAFFT) to the age group and setting. WP3 comprises four substudies (SS). SS1 is a cross-sectional community household survey with an estimated sample size of 3500 children aged 6-13 years and their caregivers. We apply cluster sampling and systematic sampling within the clusters. Data collection includes a structured questionnaire for caregiver and child, measuring social and demographic factors, mental health status, alcohol and substance use, nutrition history and anthropometry. Urine samples from children will be collected to measure ethyl glucuronide (EtG), a biological marker of alcohol intake. Further, facilitators, barriers and response mechanisms in the health system (SS2) and the school system (SS3) is explored with surveys and qualitative assessments. SS4 includes qualitative interviews with children. Analysis will apply descriptive statistics for the primary outcome of establishing the magnitude of alcohol drinking and substance use, and associated factors will be assessed using appropriate regression models. The substudies will be analysed independently, as well as inform each other through mixed methods strategies at the stages of design, analysis, and dissemination.Ethics and disseminationData protection and ethical approvals have been obtained in Uganda and Norway, and referral procedures developed. Dissemination comprises peer-reviewed, open access research papers, policy recommendations and intersectoral dialogues.Trial registration numberClinicaltrials.gov 29.10.2020 (NCT04743024).
| S-EPMC8322685 | biostudies-literature
Project description:Alcohol use disorder (AUD) affects transcriptomic, epigenetic and proteomic expression in several organs including the brain. Multi-omic analyses of the brain from individuals with AUD to date lack a comprehensive analysis of protein alterations in the multiple brain regions that underlie neuroadaptations occurring in AUD. We performed quantitative proteomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of human post-mortem tissue from brain regions that play a key role in the development and maintenance of AUD: amygdala (AMG), hippocampus (HIPP), hypothalamus (HYP), nucleus accumbens (NAc), prefrontal cortex (PFC) and ventral tegmental area (VTA). Brain tissues analyzed were from individuals with AUD (n = 11) and matched controls (n = 16).
2023-10-24 | PXD040884 | Pride
Project description:Alcohol use disorder (AUD) is a life-threatening disease characterized by compulsive drinking, cognitive deficits, and social impairment that continue despite negative consequences, which are driven by dysfunction of cortical areas, such as the orbitofrontal cortex (OFC), that normally balances decisions related to reward and risk. In this study, proteomics and machine learning analysis of post-mortem OFC brain samples collected from individuals with AUD revealed dysregulation of presynaptic (e.g., AP2A1) and mitochondrial proteins that predicted the occurrence and severity of AUD. Alcohol-sensitive OFC proteins also mapped to abnormal social behaviors and interactions. Validation using reverse genetics, we found that prefrontal Ap2a1 regulates alcohol drinking in genetically diverse mouse strains. Furthermore, we demonstrated sexual dimorphism in human OFC proteins that regulate extracellular matrix structure and signaling. Together, these findings highlight the impact of excessive alcohol consumption on the human OFC proteome and identify important cross-species cortical mechanisms underlying AUD.
2023-10-09 | PXD041727 | Pride