Recent Efforts to Dissect the Genetic Basis of Alcohol Use and Abuse.
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ABSTRACT:
SUBMITTER: Sanchez-Roige S
PROVIDER: S-EPMC7071963 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Purpose of reviewAlcohol use disorder (AUD) is a complex genetic disorder with very high heritability. This polygenic disorder not only results in increased morbidity and mortality, it is also a substantial social and economic burden on families and the nation. For past three decades, several genetic studies were conducted to identify genes and pathways associated with AUD. This review aims to summarize past efforts and recent advances in genetic association studies of AUD and related traits.Recent findingsInitial genetic association studies achieved a limted success and suffered from low power due to small sample sizes. AUD is a polygenic trait and data from several thousands individuals was required to identify the genetic factors of small effect sizes. The scenario changed recently with technological advances and significant reduction in cost of the genome wide association analyses (GWAS). This enabled researchers to generate genomic data on mega biobanks and cohorts with access to extensive clinical and non-clinical phenotypes. Public access to data from biobanks and collaborative efforts of researchers lead to identification of several novel loci associated with AUDs and related traits. Efforts are now underway to identify the causal variants under the GWAS loci to identify target genes and biological mechanisms underpining AUDs. Many GWAS variants occur in promoter or enhancer regions of the genes and are involved in regulation of gene expression of causal genes. This, large amounts of "omics" data from projects such as "ENCODE", RoadMap and GTEx is also helping researchers to integrate "multi-omics" data to interpret functional significance of GWAS variants.SummaryWith current review, we aim to present the recent advances in genetic and molecular studies of AUDs. Recent successes in genetic studies of AUDs will definetely motivate researchers and lead to better therapeutic interventions for this complex disorder.
| S-EPMC7748121 | biostudies-literature
Project description:Alcohol is the most commonly abused legal substance and alcoholism is a serious public health problem. It is a leading cause of preventable death in the world. The cellular and molecular mechanisms of alcohol reward and addiction are still not well understood. Emerging evidence indicates that unlike other drugs of abuse, such as nicotine, cocaine, or opioids, alcohol targets numerous channel proteins, receptor molecules, and signaling pathways in the brain. Previously, research has identified brain nicotinic acetylcholine receptors (nAChRs), a heterogeneous family of pentameric ligand-gated cation channels expressed in the mammalian brain, as critical molecular targets for alcohol abuse and dependence. Genetic variations encoding nAChR subunits have been shown to increase the vulnerability to develop alcohol dependence. Here, we review recent insights into the rewarding effects of alcohol, as they pertain to different nAChR subtypes, associated signaling molecules, and pathways that contribute to the molecular mechanisms of alcoholism and/or comorbid brain disorders. Understanding these cellular changes and molecular underpinnings may be useful for the advancement of brain nicotinic-cholinergic mechanisms, and will lead to a better translational and therapeutic outcome for alcoholism and/or comorbid conditions.
| S-EPMC4754113 | biostudies-literature
Project description:Concurrent use of tobacco and alcohol or psychostimulants represents a major public health concern, with use of one substance influencing consumption of the other. Co-abuse of these drugs leads to substantial negative health outcomes, reduced cessation, and high economic costs, but the underlying mechanisms are poorly understood. Epidemiological data suggest that tobacco use during adolescence plays a particularly significant role. Adolescence is a sensitive period of development marked by major neurobiological maturation of brain regions critical for reward processing, learning and memory, and executive function. Nicotine exposure during this time produces a unique and long-lasting vulnerability to subsequent substance use, likely via actions at cholinergic, dopaminergic, and serotonergic systems. In this review, we discuss recent clinical and preclinical data examining the genetic factors and mechanisms underlying co-use of nicotine and alcohol or cocaine and amphetamines. We evaluate the critical role of nicotinic acetylcholine receptors throughout, and emphasize the dearth of preclinical studies assessing concurrent drug exposure. We stress important age and sex differences in drug responses, and highlight a brief, low-dose nicotine exposure paradigm that may better model early use of tobacco products. The escalating use of e-cigarettes among youth necessitates a closer look at the consequences of early adolescent nicotine exposure on subsequent alcohol and drug abuse.
| S-EPMC5493323 | biostudies-literature
Project description:From the early 1990s to the middle of the last decade, the search for genes influencing osteoporosis proved difficult with few successes. However, over the last 5 years this has begun to change with the introduction of genome-wide association (GWA) studies. In this short period of time, GWA studies have significantly accelerated the pace of gene discovery, leading to the identification of nearly 100 independent associations for osteoporosis-related traits. However, GWA does not specifically pinpoint causal genes or provide functional context for associations. Thus, there is a need for approaches that provide systems-level insight on how associated variants influence cellular function, downstream gene networks, and ultimately disease. In this review we discuss the emerging field of "systems genetics" and how it is being used in combination with and independent of GWA to improve our understanding of the molecular mechanisms involved in bone fragility.
| S-EPMC3422742 | biostudies-literature
Project description:Consumption of ethanol has detrimental effects on gastric organs such as the intestine. To demonstrate the deleterious effect of alcohol, we sacrificed isobaric feeding or ethanol feeding mice and sorted the dendritic cells from their intestine organ. The dendritic cells were analyzed by a small-scale global proteomics approach. We achieved to obtain the biological signatures in the alcohol abuse mice group using bioinformatics analysis.
2024-06-16 | PXD033700 | Pride
Project description:An estimated 15-50% of the population experiences pain at any given time, at great personal and societal cost. Pain is the most common reason patients seek medical attention, and there is a high degree of individual variability in reporting the incidence and severity of symptoms. Research suggests that pain sensitivity and risk for chronic pain are complex heritable traits of polygenic origin. Animal studies and candidate gene testing in humans have provided some progress in understanding the heritability of pain, but the application of the genome-wide association methodology offers a new tool for further elucidating the genetic contributions to normal pain responding and pain in clinical populations. Although the determination of the genetics of pain is still in its infancy, it is clear that a number of genes play a critical role in determining pain sensitivity or susceptibility to chronic pain. This review presents an update of the most recent findings that associate genetic variation with variability in pain and an overview of the candidate genes with the highest translational potential.
| S-EPMC3821734 | biostudies-literature
Project description:ObjectivesAlcohol abuse and addiction are big current problems of the developed world having multivariate causality and multiple effects. Alcohol abuse in young people is a matter of central importance due to its wide range long lasting effects, especially so in Greece where the problem has only recently started growing. The Hellenic Navy is interested in the complications of alcohol abuse in training conscripts. Because young conscripts will be placed in demanding positions, but also because in Greece the military service is obligatory and represents an important period for the socialization of young men.MethodsIn the present study, levels of alcohol use and abuse were measured in a sample of 650 male training conscripts of the Hellenic Navy. The tools used are: (a) two questionnaires measuring frequency and quantity of alcohol consumption and psychosocial variables, (b) the CAGE test, which is a questionnaire measuring hidden alcoholism.Results38,1% conscripts were characterized problematic drinkers according the adolescents criteria. Additional psychological complications were related to alcohol use. Using the stricter criterion for adults (plus psychological complications) 8.9% were found to be problematic drinkers. The use of CAGE questionnaire which is measuring hidden alcoholism, identified 16% of the total sample as hidden alcoholics.DiscussionThe findings regarding unregular levels of alcohol use and abuse are presented as well as their relation to psychosocial complications and to demographic characteristics. The results are discussed in the light of Creek and international bibliography.
| S-EPMC1698475 | biostudies-literature
Project description:Genetic variation was first shown to be important in systemic lupus erythematosus (SLE or lupus) in the 1970s with associations in the human leukocyte antigen region. Almost four decades later, and with the help of increasingly powerful genetic approaches, more than 25 genes are now known to contribute to the mechanisms that predispose individuals to lupus. Over half of these loci have been discovered in the past 2 years, underscoring the extraordinary success of genome-wide association approaches in SLE. Well-established risk factors include alleles in the major histocompatibility complex region (multiple genes), IRF5, ITGAM, STAT4, BLK, BANK1, PDCD1, PTPN22, TNFSF4, TNFAIP3, SPP1, some of the Fcgamma receptors, and deficiencies in several complement components, including C1q, C4 and C2. As reviewed here, many susceptibility genes fall into key pathways that are consistent with previous studies implicating immune complexes, host immune signal transduction and interferon pathways in the pathogenesis of SLE. Other loci have no known function or apparent immunological role and have the potential to reveal novel disease mechanisms. Certainly, as our understanding of the genetic etiology of SLE continues to mature, important new opportunities will emerge for developing more effective diagnostic and clinical management tools for this complex autoimmune disease.
| S-EPMC3144759 | biostudies-literature
Project description:Many identified genetic risk factors for systemic lupus erythematosus (SLE) contribute to the function of the immune system, which has expanded our understanding of disease pathogenesis. We outline the genetic variants in recently identified SLE-associated loci, the immunological pathways affected by these gene products and the disease manifestations linked to these loci. Pathways potentially influenced by SLE risk variants include: apoptosis, DNA degradation and clearance of cellular debris; antigen presentation; type I interferon, Toll-like receptor and nuclear factor kappa κB activation; defective clearance of immune complexes containing nuclear antigens; B and T-cell function and signalling; and monocyte and neutrophil function and signalling. These identified SLE susceptibility loci are predominantly common variants that have been confirmed among multiple ancestries, suggesting shared mechanisms in disease aetiology. Ongoing genetic studies continue the investigation of specific functional variants, and their potential consequences on immune dysregulation, enhancing our understanding of links between genotypes and specific disease manifestations. The next generation of sequencing explores the identification of causal rare variants that may contribute robust genetic effects to developing SLE. Novel insights coming from genetic studies of SLE provide the opportunity to elucidate pathogenic mechanisms as well as contribute to the development of innovative therapeutic targets for this complex disease.
| S-EPMC3780983 | biostudies-literature
Project description:Rheumatoid arthritis (RA) is the most common inflammatory arthritis and exhibits genetic overlap with other autoimmune and inflammatory disorders. Although predominant associations with the HLA-DRB1 locus have been known for decades, recent data have revealed additional insight into the likely causative variants within HLA-DRB1 as well as within other HLA loci that contribute to disease risk. In addition, more than 100 common variants in non-HLA loci have been implicated in disease susceptibility. Genetic factors are involved not only in the development of RA, but also with various disease subphenotypes, including production and circulating levels of autoantibodies and joint destruction. The major current challenge is to integrate these new data into a precise understanding of disease pathogenesis, including the critical cell types and molecular networks involved as well as interactions with environmental factors. We predict that delineating the functional effects of genetic variants is likely to drive new diagnostic and therapeutic approaches to the disease.
| S-EPMC6727201 | biostudies-literature