Genetic Influences on the Development of Alcoholism

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Genetic Influences on the Development of Alcoholism

May 13 2022 | by Author Pathfinder

A standard drink is defined in the US as 12ounces of beer, 5 ounces of wine or 1.5 ounces of spirits, all of which approximate14 g of pure ethanol). The strong effects of binge drinking suggest that merelycalculating an average number of drinks per week is likely to obscure many effectsof alcohol, since it treats 2 standard drinks per day (14 per week) the same as 7drinks on each of two days per week. Biological epistasis results from physical interactions among biomolecules (e.g., DNA, RNA, proteins, enzymes, etc.) and occurs at the cellular level in an individual. Statistical epistasis was first defined by Fisher (1918) as a mathematical phenomenon that occurs at the population level and is realized when there is interindividual variation in DNA sequences. Figure 1 illustrates the conceptual divide between biological and statistical epistasis that is important to understand in order to make biological inferences from statistical results (Moore and Williams 2005).

Candidate Gene Studies

Studies continue to reveal other genes in which variants affect the risk of alcoholism or related traits, including GABRA2, CHRM2, KCNJ6 and AUTS2. As more variants are analysed and studies are combined for meta-analysis to achieve increased sample sizes, an improved picture of the many genes and pathways that affect the risk of alcoholism will be possible. This review describes the genetic approaches and results from the family-based Collaborative Study on the Genetics of Alcoholism (COGA). COGA was designed during the linkage era to identify genes affecting the risk for alcohol use disorder (AUD) and related problems, and was among the first AUD-focused studies to subsequently adopt a genome-wide association (GWAS) approach. COGA’s family-based structure, multimodal assessment with gold-standard clinical and neurophysiological data, and the availability of prospective longitudinal phenotyping continues to provide insights into the =https://ecosoberhouse.com/ etiology of AUD and related disorders. These include investigations of genetic risk and trajectories of substance use and use disorders, phenome-wide association studies of loci of interest, and investigations of pleiotropy, social genomics, genetic nurture, and within-family comparisons.

EARLY RESULTS: CANDIDATE GENE STUDIES

Much additional work is required to narrow the regions and attempt to determine which specific gene or genes play a role in affecting the risk for alcoholism. Therefore, additional markers within these regions of interest were analyzed in the same people. Subsequent analyses that included the additional markers supported the initial findings (Foroud et al. 2000) but did not narrow the chromosomal regions in which genes influencing alcoholism susceptibility are likely to lie.

DNA Regions with Susceptibility Genes

Analyses of these five cohorts were previously published and the detailed QC can be found in ref. 26. Participants with at least one inpatient or two outpatient ICD-9/10 codes for AUD were assigned as AUD cases, while participants with zero ICD codes for AUD were controls. In total, 80,028, 36,330, 10,150, 701 and 107 cases were included in EUR, AFR, LA, EAS and SAS, respectively, and 368,113, 79,100, 28,812, 6,254 and 389 controls were included in EUR, AFR, LA, EAS and SAS, respectively. BOLT-LMM65 was used to correct for relatedness, with age, sex and the first ten PCs as covariates. This article does not contain any studies with human or animal subjects performed by the author. In 2021, more than 46 million people in the United States aged 12 or older had at least one substance use disorder, and only 6.3% had received treatment.

INTRODUCTION: GENETIC ANALYSES IN THE COGA PROJECT

However, it is well known that environmental influences play a strong role in disease development and are presumed causes of low experimental reproducibility (Hamer 2002). For example, it is anticipated that environmental pathogens such as ethanol modulate the effects of susceptibility genetics of alcoholism genes (Caspi and Moffitt 2006). Though useful, model organism proteomic studies cannot necessarily be directly applied to understanding human systems. Human postmortem proteomic studies have been conducted with samples from the brains of alcoholics. Differences in the proteomes of alcoholics with and without liver cirrhosis were detected in three regions of the brain’s cerebellar vermis, when compared with healthy brains. Thiamine deficiency, which is often related to alcoholism, may be responsible for the changes observed in metabolic protein levels in both groups.

Additionally, DRD2, CACNA1C, DPYD, PDE4B, KLB, BRD3, NCAM1, FTO and MAPT were identified as druggable genes.
Interdisciplinary and collaborative work will be necessary to drive the development of tools and standards for interpreting their results in an approach that will be relevant to the understanding of alcoholism and lead to medical applications.
There is evidence that heavy episodic (binge) drinking, which results inexposure of tissues to high levels of alcohol, is particularly harmful81, 87, 88.
The establishment of the NIAAA Data Archive and the Final NIH Data Management and Sharing Policy (NOT-OD ) provide an ecosystem and structure for the sharing of future and past (legacy) data from the COGA studies.
COGA was designed during the linkage era to identify genes affecting the risk for alcohol use disorder (AUD) and related problems, and was among the first AUD-focused studies to subsequently adopt a genome-wide association (GWAS) approach.

It has been suggested that functional studies of unicellular and other simple organisms are key to learning the “rules” governing epistatic interactions and the development of methods that can accurately detail those interactions (Moore and Williams 2005). Because epistasis has been shown to be a ubiquitous principle of biological systems, simple and more controllable subjects than humans provide an analogous venue of study for epistatic interaction. Drosophila has been used for many years to study alterations in ADH and related genes and serves as a highly controllable and alterable system for studying ethanol metabolic genes (Freriksen et al. 1994). The use of Drosophila for such studies is Alcoholics Anonymous controversial, however, because of differences in activity between human and Drosophila ADH (Benach et al. 2005).

Themost common initial approach was linkage analysis, in which markers throughout thegenome were measured to identify chromosomal regions that appeared to segregate withdisease across many families.
The goals of this renewal concept are to continue to integrate and share COGA data and to continue to add data across the lifecycle, specifically in the adolescent and young adult (Prospective Study) and older adult (Lifespan Study) cohorts.
In the study of complex disorders, it has become apparent that quitelarge sample sizes are critical if robust association results are to beidentified which replicate across studies.
Although studies of alcoholism’s etiology have been successful in identifying a few candidate genes for susceptibility, interindividual variation in these genes accounts for only a small proportion of the overall heritability of the disease.
One component of an ERP is a brain wave called P300, which typically occurs 300 milliseconds after a stimulus.

The most robust finding for genetic influences on alcoholism remains with genes encoding ethanol metabolizing enzymes. These genetic variants have a high prevalence in East Asians and protect against the development of alcoholism. It is now appreciated that a whole spectrum of allele frequencies andeffect sizes may play roles, from common variations with small effects throughrare variants of large effect. As whole exome and whole genome sequencingtechnologies come down in cost, they are being applied to identifying rarevariants.

A complete review of all results from genetic, genomic, proteomic, and metabolic studies of alcoholism is beyond the scope of this review. This article focuses on recent literature involving studies of genes selected based on biochemical evidence for their role in disease (i.e., candidate genes) and genome-wide studies, followed by an overview of the interaction among genes (i.e., epistasis) and its current and potential application in the study of alcoholism. This article concludes with a discussion of several methods currently being developed that incorporate a systems approach to genetics and their potential applications for the future study of alcoholism.