Seeking the Connections: Alcoholism and Our Genes

Clinicians are in the earliest stages of using genetic variants to shape treatment decisions for alcoholism, and in the future we expect to have molecular guidelines to help develop such individualized strategies. The first involves focusing the testing on specific genes that are selected on the basis of their physiological roles or their reported involvement in related traits. For example, they led to strong evidence that genes that encode the two main enzymes involved in alcohol metabolism—alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH)—affect risk, which will be discussed in the next section. Some of these studies, particularly the earlier ones, only have assessed a single allele of a candidate gene, whereas in other studies a set of alleles was chosen to provide information on most of the common variations in the gene. Several study designs—including case–control studies, population studies, and family studies—have been used to test whether a specific gene or gene variant affects risk for a disease (for more information, see the article by Foroud and Phillips, pp. 266–272).

THE COGA WEBSITE AS AN INFORMATIONAL PLATFORM

Family, twin, and adoption studies have shown that alcoholism definitely has a genetic component. In 1990, Blum et al. proposed an association between the A1 allele of the DRD2 gene and alcoholism. The DRD2 gene was the first candidate gene that showed promise of an association with alcoholism. To determine whether the same mechanism affects people, the researchers are now examining postmortem tissue samples from the brains of people who is there an alcoholism gene suffered from alcoholism. She said their study opens numerous doors for future research, chasing down possible connections between the alcohol-protective alleles and conditions that have no apparent connection with alcohol consumption. Sanchez-Roige said that such broad, hypothesis-free studies are only possible if researchers have access to very large sets of data.

The Collaborative Study on the Genetics of Alcoholism: Overview

Some of these genes occur in several variants (i.e., alleles1), and the enzymes encoded by these alleles can differ in the rate at which they metabolize ethanol (Table 2) or acetaldehyde or in the levels at which they are produced. These variants have been shown to influence a person’s drinking levels and, consequently, the risk of developing alcohol abuse or dependence (Hurley et al. 2002). Studies have shown that people carrying certain ADH and ALDH alleles are at significantly reduced risk of becoming alcohol dependent. In fact, these associations are the strongest and most widely reproduced associations of any gene with the risk of alcoholism. As will be discussed later in this article, the alleles encoding the different ADH and ALDH variants are unevenly distributed among ethnic groups.

Can a Person Be Born with an Alcohol Use Disorder?

Malic enzyme mediates the conversion of malate to pyruvate, which is accompanied by the production of NADPH. NADPH is a necessary cofactor for the biosynthesis of fatty acids along with acetyl-CoA, generated by the metabolism of ethanol. Pyruvate carboxylase and malic enzyme mediate a cyclic metabolic pathway, which https://ecosoberhouse.com/ via the mitochondrial citrate and pyruvate transporters results in the transport of acetyl-CoA across the mitochondrial membrane and generation of cytosolic NADPH.

Effects of Different ADH Variants on Ethanol Metabolism

• The strongest effects have been found for specific variants of genes that encode two enzymes involved in alcohol metabolism—alcohol dehydrogenase and aldehyde dehydrogenase.
• In a second reaction catalyzed by aldehyde dehydrogenase (ALDH) enzymes, acetaldehyde is oxidized to acetate.
• It is now generally accepted that genetic risk for alcoholism is likely to be due to common variants in numerous genes, each of small effect, however rare variants with large effects might also play a role.
• Scientific American is part of Springer Nature, which owns or has commercial relations with thousands of scientific publications (many of them can be found at /us).

In addition, a fruit fly’s resistance to alcohol appears to be controlled by the same molecular mechanism as humans. The incidence of alcoholism was slightly higher among people who were exposed to alcoholism only through their adoptive families. However, it was dramatically higher among the twins whose biological fathers were alcoholics, regardless of the presence of alcoholism in their adoptive 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. Genetics and family history are the most correlated with risk of AUD; in fact, genetic risk is about half of the problem, while family history is the other half. Certainly, genetics are passed down through families, but family history also includes the environment in which one was raised. Childhood abuse, parental struggles, and mental illness in close family members all contribute to the risk of developing an addiction to drugs or alcohol. 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. Meta-analyses, whichcombine results across a number of studies in order to attain the criticalsample sizes needed, are being developed.

• Gene × environment interaction (G × E) occurs when the effect of exposure to an environmental factor on a person’s health is conditional upon his or her genotype (for review see Caspi & Moffitt 68).
• Variations in the GABRA2 gene, which encodes one of the GABAA receptor subunits, have been found to strongly influence an EEG endophenotype, known as the beta frequency, that appears to play a role in mediating neuronal disinhibition.
• Instead, variations in many, and perhaps hundreds, of genes likely have a small but measurable influence on disease risk that ultimately adds up to a substantial impact.
• In addition to rapid tolerance, flies develop chronic tolerance after prolonged exposure to a low concentration of ethanol 43.
• 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.
• With the advent of microarrays that can measure hundreds of thousands tomillions of single nucleotide polymorphisms (SNPs) across the genome,genome-wide association studies (GWAS) have provided a relatively unbiased wayto identify specific genes that contribute to a phenotype.

Direct Sequencing of Rare Variants

• Blood samples were obtained for genomic data generation and were also immortalized as cell lines in the NIAAA/COGA Sharing repository (see 4. Genetics for details).
• From this perspective the ability to detect gene effects is dependent upon context and timing 65.
• The strongest and most consistent findings for GWAS for AUD are for alcohol metabolizing genes, as in a recent study in an East Asian (Korean) sample of alcoholics in which ALDH2 and ADH1B showed up as GWAS signals with genome-wide significance 68.
• In the COGA sample there was also evidence for linkage to chromosomes 1 and 7, and to chromosome 2 at the location of an opioid receptor gene 96.
• The broader health and social effects of this new type of information may not be seen quickly, but they could be quite profound over time.
• People are also complex and manifest problems with alcohol in diverse ways, especially in the early stages of disease, although cases come to resemble one another clinically in the later stages of illness.

He added that the research could help in identifying youngsters at risk of becoming alcoholics and could lead to early prevention efforts. Researchers at the University of California at San Francisco (UCSF) are using fruit flies to find the genetic causes of alcoholism. According to scientists, drunken drosophila fruit flies behave the same way humans do when they are drunk.

• 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 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.
• The transition to addiction involves multiple neuroadaptations and much of our understanding of these processes has so far been obtained from animal studies.
• This metabolic switch channels excess metabolic energy into the synthesis of fatty acids and contributes to the development of fatty liver syndrome during excessive alcohol consumption.

The knowledge that such genes are likely to be influencing dependence in patients belonging to one of these populations is another tool that can be used to assess the nature of an individual’s problem and to tailor treatment accordingly. The purpose of the Collaborative Study on the Genetics of Alcoholism (COGA) is to advance knowledge about the complex influences of gene and environment on development and progression of alcohol use disorder (AUD). 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. New genetic variants have been identified, refined endophenotypes have been characterized, and functional information Alcoholics Anonymous has begun to emerge on known genetic variants that influence risk for and protection from AUD.