The Genetics of Alcohol Metabolism: Role of Alcohol Dehydrogenase and Aldehyde Dehydrogenase Variants

Examples of genes that have been shown to influence vulnerability to alcoholism and related phenotypes are also discussed. Genes may interact with specific toxic environments, such as abuse or neglect, to result in problems for some gene carriers but not for others. Nobody gets to be alcohol-dependent without making some poor choices, but clearly some people are more sensitive to alcohol than others in the same set of circumstances, and scientists are working to identify the sources of that vulnerability. The previous COGA studies have provided critical information to better understand the genetic and biological underpinnings of AUD. However, there is a need for a framework to unify the findings and provide the data to the community for additional analysis and discovery.

Variations in the ALDH1A1 Gene

One way around this has been the use of intermediate phenotypes, including electrophysiological and imaging, that reflect mediating factors in behavior and are likely to be influenced by variation at fewer genes. In recent years there have been attempts at empirical classification of alcoholics into clinically relevant and potentially genetically distinct subgroups based on the large National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) 2 that will be discussed later. Finally, the diagnostic criteria for the alcoholism phenotype (now called alcohol use disorder (AUD)) have just been radically revised in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 3. The aim of this review is to highlight some recent studies in human research that are of particular interest and not to provide exhaustive coverage of the literature.

Table 1. Criteria for alcohol use disorders.

• For example, it is much easier to collect individual cases (i.e., people with alcoholism) and control subjects (i.e., nonalcoholic people) or samples of the general population than it is to recruit family samples.
• Previous twin, adoption and family studies had indicated that alcohol problems are strongly heritable–indeed, more than 50 percent of the overall risk for alcoholism is attributable to inherited factors, which makes family groups a powerful resource for tracking specific traits and linking them to the relevant genes.
• As more genes are linked to the development of alcohol dependence, these insights will be used to improve tools for gauging an individual’s risk for developing alcoholism and identifying those with alcohol problems who may respond better to specific treatments.
• The current hope is that with very large sample sizes, GWAS will provide novel information about genetic underpinnings of alcoholism, including gene pathways that are altered in disease.
• Acetate is conjugated to coenzyme A and the resulting acetyl-CoA can be metabolized in the Krebs cycle, or utilized for the synthesis of fatty acids.

Some Halfway house researchers have hypothesized that there may be large panels of rare functional variants, each of large effect, that predict risk for alcoholism with different variants occurring in different people. It is becoming increasingly easy, and the costs are rapidly decreasing, to detect rare variants using next-generation sequencing. Sequencing is rapidly becoming the key tool for characterization of the genetic basis of human diseases 84.

• Carriers of the low activity variant of MAOA–LPR display hyperactivation of the hippocampus and amygdala during the retrieval of negatively valenced emotional material but not during the retrieval of neutral material 82.
• First and perhaps foremost, most studies ofalcohol-related phenotypes have been small – hundreds or a few thousandsamples.
• While there is overlap between alcohol use disorder and alcohol consumption, the researchers did further analysis and found a “distinct genetic architecture” differentiating alcohol abuse from alcohol consumption.
• Finally, genome-wide analyses of transcripts and chromatin remodeling promise an increase in our understanding of the genome function and of the mechanisms through which gene and environment cause diseases.
• The GI tract is exposed to very high levels of alcohol as it passes throughthe mouth, esophagus, stomach and intestinal tract, and most ethanol passes throughthe liver before entering the circulation.
• Such isolated populations, and large families within them, are likely to confer the advantage of reduced genetic heterogeneity.

The Neurobiology of Addiction: Dopamine Reward Circuitry and Interacting Stress Response Systems

Complex epigenetic mechanisms that regulate gene activity without altering DNA code have been shown to produce long-lasting changes in gene expression essential to development and cellular differentiation and to adaptation to environmental changes. These mechanisms, that include DNA methylation, post-translational covalent modifications of histones, nucleosome sliding and nucleosome and histone substitution, cause modifications of chromatin conformation which, in turn, regulate gene expression (for review see Tsankova et al. 123). For example, the amount of DNA methylation in promoter regions correlates with gene inactivation. Chromatin remodeling can be studied at the single locus level; however, methods such as the chromatin immunoprecipitation in combination with DNA sequencing (ChIP-seq) allow for high-resolution genome-wide analysis. Alpha synuclein (SNCA) is a gene that maps to a QTL for alcohol preference, and expression of alpha synuclein is increased in different brain areas in rats displaying alcohol preference 126. Recently, an increase in alpha synuclein promoter DNA methylation has been found in patients with https://ecosoberhouse.com/ alcoholism 127, and genetic variation within the human SNCA gene has been linked to alcohol craving 128.

• Alcoholism has a substantial heritability yet the detection of specific genetic influences has largely proved elusive.
• As the project enters its late third decade of scientific exploration, we approach our contributions to the study of AUD with optimism.
• Living in a household where you’re regularly exposed to parental alcohol use can also increase your chances of AUD, regardless of your genetic predisposition.
• Hugo Bellen, a geneticist at Baylor College of Medicine in Houston, Texas, said the study “lays the foundation for a genetic approach to dissecting the acute, and possibly the chronic, effects” of alcohol in people.
• For instance, some claim that it would make more sense to direct resources toward reducing the use of potentially addictive substances across the board than to identify–and potentially stigmatize–the individuals who would be most affected by such reductions.

Genes contributing to the risk of alcohol dependence

Multiple and complementary approaches will be required to piece together the mosaic of causation. People who meet criteria for dependence often have multiple cases is there an alcoholism gene of alcoholism in their families. 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.