Alcohol use disorder is a pattern of alcohol use that involves problems controlling your drinking, being preoccupied with alcohol or continuing to use alcohol even when it causes problems. This disorder also involves having to drink more to get the same effect or having withdrawal symptoms when you rapidly decrease or stop drinking. That doesn’t mean you’ll absolutely develop AUD if you have a family member living with the condition.
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- In addition, different strategies such as candidate gene analyses and genome-wide association studies have been used.
- Majority of genomic data for large alcohol consumption and AUD meta-analysis was either from UKBiobank or from Million Veterans Project.
- The accompanying review (3. Brain Function) covers the available brain function data and resulting findings in detail.
These findings are important for researchers because of similar overlap with other addictive behavior, said lead researcher Prof. Abraham Palmer. Quantitative traits are characteristics that are distributed along a continuum across a population, such as height. “Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine,” Sanchez-Roige noted.
Genes Contributing to the Development of Alcoholism: An Overview
A meta-analysis noted that chronic alcohol consumption reduces serum testosterone by an average of 4.86 nmol/L compared to abstainers. Additionally, alcohol disrupts lipid and carbohydrate metabolism, impairing fatty acid oxidation, gluconeogenesis, and mitochondrial homeostasis, which results in liver fat accumulation and glucose intolerance. This metabolic dysregulation also promotes inflammatory cascades, oxidative damage, and epigenetic changes that may underlie alcohol-related metabolic syndrome. Chronic alcohol intake leads to significant liver dysfunction through several mechanisms, including excess acetaldehyde production, oxidative stress, impaired lipid metabolism, and apoptosis. The risks of smoking were first widely publicized by the Surgeon General’s Report of 1964, and the combination of that medical information and social pressure has reduced the prevalence of smoking over the subsequent decades. An individual’s awareness of personal is alcoholism a genetic disease genetic medical risks may similarly change his or her choices.
Strategies for Identifying Genes Associated With Alcoholism Risk
“We know now that it was only a first step of a very long road of complex genetics,” said Renato Polimanti, a colleague of Gelernter at the Yale School of Medicine. In contrast to Angier’s conclusion that AUD is decided by the environment, scientists have since found multiple genetic players. A review of studies from 2020, which looked at a genome-wide analysis of more than 435,000 people, found 29 different genetic variants that increased the risk of problematic drinking. According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), a person’s genetic makeup accounts for roughly half of their risk for developing an AUD.
The genes with the clearest contribution to the risk for alcoholism andalcohol consumption are alcohol dehydrogenase 1B (ADH1B) andaldehyde dehydrogenase 2 (ALDH2; mitochondrial aldehydedehydrogenase), two genes central to the metabolism of alcohol (Figure 1)20. Alcohol is metabolized primarily in the liver, although thereis some metabolism in the upper GI tract and stomach. The first step in ethanolmetabolism is oxidation to acetaldehyde, catalyzed primarily by ADHs; there are 7closely related ADHs clustered on chromosome 4 (reviewed in20). The second step is metabolism of theacetaldehyde to acetate by ALDHs; again, there are many aldehyde dehydrogenases,among which ALDH2 has the largest impact on alcohol consumption20. In conclusion, the review highlights the negative effects of chronic alcohol consumption on metabolism and testicular function, including hormonal disruption, impaired spermatogenesis, and reduced sperm quality. In the present review, researchers explored the effect of alcohol consumption on men’s reproductive health and gonadal axis, focusing on the complex physiological and pathological mechanisms of alcohol metabolism and its interactions with other lifestyle factors, such as diet and physical activity.
BEHAVIORAL AND CLINICAL DATA
Although studies in recent years have identified a plethora of genes that may play a role in determining risk of alcoholism, much work remains to be done. A failure to replicate the initial findings may not always disprove the association but may result from differences in the genetic background of the study participants, the environment, or the study design (e.g., differences in the definition of alcohol dependence). Beyond replication, the exploration of which specific aspects of the alcoholism phenotype each involved gene affects and which other diseases or traits may be influenced by it is essential. Moreover, it will be equally important to determine the potential underlying mechanisms through functional studies, including the use of animal models, particularly those in which candidate genes or alleles are introduced into the organism (i.e., knocked-in).
DATA AVAILABILITY STATEMENT
The AUDIT, a 10-item, self-reported test was developed by the World Health Organization as a screen for hazardous and harmful drinking and can be used as a total (AUDIT-T), AUDIT-Consumption (AUDIT-C) and AUDIT-Problems (AUDIT-P) sub-scores. This finding suggests that variants of a gene or genes within this region reduced the risk of becoming alcoholic. ADH alleles are known to affect the risk for alcoholism; however, the known protective alleles occur at high frequency in Asian populations but are rare in the Caucasian population that makes up most of the COGA sample (Edenberg 2000). Therefore, these analyses may have identified a new protective ADH allele or another protective gene located nearby. The number of unaffected sibling pairs genotyped in the replication sample was too small to analyze. Another phenotype that may reflect a protective influence against alcoholism is the maximum number of drinks a person has consumed in a 24-hour period (MAXDRINKS).
Genetics of alcohol-associated diseases
- Extensive study of the alcoholmetabolizing genes has demonstrated their important role in disease risk.
- From its inception, COGA has generated and utilized extensive arrays of genotypic and phenotypic data from families densely affected by AUD and from comparison families to identify genes and understand their role in susceptibility to (or protection from) developing AUD and related phenotypes.
- The class I ADH enzymes encoded by the ADH1A, ADH1B and ADH1C genes contribute about 70% of the total ethanol oxidizing capacity, and the class II enzyme encoded by ADH4 contributes about 30% 19.
- This article briefly reviews these strategies and summarizes some of the results already obtained in the ongoing COGA study.
- Overview of COGA participants across data modalitiesa including the Semi‐Structured Assessment for the Genetics of Alcoholism (SSAGA), genome‐wide association study (GWAS) and electroencephalography (EEG) data.
Binge drinkingis generally defined as a man consuming 5 standard drinks within 2 hours; women are typically smaller and have a lower percentage of body water, so 4 standarddrinks can reach similar alcohol levels. 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. Acute alcohol intake can lower testosterone levels by depleting NAD+, suppressing gonadotropins, and disrupting steroidogenesis while altering the hypothalamic-pituitary-gonadal (HPG) axis. The tendency to become dependent on alcohol has long been known to run in families, which for some only added to the social stigma attached to this complicated condition. But to scientists, that apparent heritability suggested that some genetic component underlying vulnerability to alcohol problems was being transmitted from generation to generation.
Genetics and alcoholism
As yet, no GABRA2 functional variant has been detected to explain the yin yang haplotype (or tag SNP) associations with alcoholism-related phenotypes. HapMap data and other studies 52 reveal moderate long distance linkage disequilibrium across GABRA2 and the closely adjacent gene GABRG1 raising the possibility that the functional locus is in GABRG1. The results of several studies suggest that there are likely to be independent, complex contributions to alcoholism vulnerability from both linked genes 52–54.
One component of an ERP is a brain wave called P300, which typically occurs 300 milliseconds after a stimulus. Previous studies had found that a reduced amplitude of the P300 wave is a heritable phenotype that correlates with alcohol dependence and other psychiatric disorders (Porjesz et al. 1998). The genetic analyses of the COGA participants identified four regions, on chromosomes 2, 5, 6, and 13, that appear to contain genes affecting the amplitude of the P300 (Begleiter et al. 1998). Analyses of 987 people from 105 families in the initial sample provided evidence that regions on 3 chromosomes contained genes that increase the risk for alcoholism (Reich et al. 1998). The strongest evidence was for regions on chromosomes 1 and 7, with more modest evidence for a region on chromosome 2. The DNA regions identified through these analyses were broad, as is typical for studies of complex genetic diseases, and therefore are likely to contain numerous genes.
