Genetics and Alcoholism: Whats the Connection?

This array was designed for Caucasian and African ancestry, hence the limited number of alcohol metabolism genes. A model of genetic determinism in which different alleles lead to the same phenotype in different individuals, but an individual allele can suffice to produce the phenotype. However, one year later, Joel Gelernter, a professor of genetics and neuroscience at the Yale School of Medicine, along with his team could not find the association between the D2 dopamine receptor gene and AUD, showing a lack How Long Does Heroin Stay in Your System of replicability in the earlier study.

1. 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.
2. 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.
3. Some 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.
4. Now, we enter an exciting time where genetic and environmental studies promise great strides for the understanding of our human genome and real changes in clinical care.

UNDERSTANDING GENE FUNCTION

Foroud and colleagues (2000) also analyzed the combined data set from the initial and replication samples using a more restricted definition of alcoholism as specified in the ICD–10. The region on chromosome 1 provided the strongest evidence for a susceptibility gene in the combined sample. In addition, this new evaluation detected a region on chromosome 8 that was linked with the risk for alcoholism.

Is Alcoholism Hereditary?

Genetic variation in neurobiological pathways, including stress-response systems, may influence vulnerability to the development of permanent neurological changes in response to heavy alcohol use. Likewise, genetic variation may determine increased vulnerability to relapse in response to stressors. This pattern would only be expected if the same risk factors, genetic or environmental, operate across the entire spectrum of alcohol problems, from mild to severe. Critics have argued that genetic research into alcohol dependence and other forms of addiction, including smoking, is not cost-effective from a public health perspective. 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.

The power to examine patterns of inheritance in large populations, and to survey hundreds of thousands of tiny variations in the genomes of each of those individuals, enables investigators to pinpoint specific genes that exert strong or subtle influences on a person’s physiology and his or her resulting risk for disease. Because of the complexity of the risk factors for alcoholism and of the disorder itself, the COGA project was designed to gather extensive data from the participants. Although standard diagnostic systems for alcoholism can reliably determine who needs treatment, the diagnostic criteria used in these systems comprise problems in many domains of functioning. This means that two people with the same diagnosis (e.g., alcohol dependence as defined in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised DSM–III–R of the American Psychiatric Association APA 1987) may have different sets of symptoms, greatly complicating genetic analyses.

After years of family-based linkage studies and case-control candidate gene studies, attention has shifted to large scale genome-wide association studies (GWAS) for the detection of novel common variants (≥ 1%). Exome and whole genome sequencing studies for the detection of rare variants are beginning to emerge. However, it should be borne in mind that no matter how sophisticated genetic techniques might become, further advances in detecting genotype – phenotype associations are hampered by the fact that alcoholism is a heterogeneous phenotype.

Genes Encoding Enzymes Involved in Alcohol Metabolism

Improved understanding of alcohol dependence should therefore help dissect factors involved in the development of related conditions. COGA researchers have also analyzed candidate genes—genes suspected to play a role in the development of alcoholism based on other studies. Some of these candidate genes encode components of various brain chemical systems that allow communication among nerve cells. Two of these genes are the dopamine D2 receptor gene (DRD2) and a serotonin transporter gene (HTT). However, the analyses found no evidence that DRD2 affected the risk for alcoholism (Edenberg et al. 1998a) or that HTT was linked to either alcoholism in general or to a more severe form of alcoholism (Edenberg et al. 1998b). In a meta-analysis, we have jointly analyzed data from all studies already mentioned, except the two outliers.

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). This phenotype is quantitative and heritable, and a low number of drinks consumed in a 24-hour period may reflect a reduced tolerance for high levels of alcohol. An advantage of a quantitative phenotype is that everyone in a study can contribute to the genetic analysis, not just people who meet diagnostic criteria.