Through our collaborative gene‐brain‐behavior paradigm, we aspire to address both the causes and consequences of heavy alcohol use and AUD, which still contributes annually to 3 million preventable deaths globally. Alcohol use disorder, and other substance use disorders are often misunderstood and stigmatized. The concept that there are both genetic and environmental contributions to risk for AUD and its outcomes can be difficult to explain. Polygenic risk can also be challenging to communicate, and can lead to unrealistic expectations of what genomic medicine can do for the treatment and prevention of AUD. These were developed in collaboration with digital communication specialists and include https://ecosoberhouse.com/ short videos, text descriptions, interactive graphical elements, and key take‐aways, and can be found at cogastudy.org. An accompanying blog provides an overview of new findings with an eye towards public communication.
Linkage Studies
- Reassuringly, many COGA findings have been replicated in other samples (e.g., References 76, 77, 78, 79).
- Several genes that were expressed differentially in the two strains as well as several ethanol-regulated genes were found within brain regions that are involved in reward, including the nucleus accumbens, pre-frontal cortex and ventral tegmental area.
- Moreover, the impact of any one gene variation depends both on the individual’s genetic background (i.e., other genetic variations the person carries) and on the environment.
An increasing number of genes not related to ethanol metabolism also affect risk (Edenberg and Foroud 2006). Moreover, the contribution of any gene(s) to risk is modulated by other genes as well as by social and environmental factors. COGA’s asset is its family‐based longitudinal design that supports an intensive clinical, behavioral, genetic, genomic and brain function data collection. As the project enters its late third decade of scientific exploration, we approach our contributions to the study of AUD with optimism. Our science aims to identify pathways to enduring remission and processes that can be modified to minimize the deleterious impact of AUD across the lifespan.
From model organisms to human genetics
Although it is clearly known that genetic heroin addiction factors play a role in alcoholism, identification of the specific genes involved has proved challenging. Major determinants of complexity are likely to include genetic heterogeneity (see Glossary at the end of this paper), heterogeneity at the level of neurobiological vulnerability, polygenicity, phenocopies, gene × environment interaction and incomplete penetrance. Consequently, several genetic loci that moderate vulnerability to alcoholism have been identified. At the phenotype level, major progress has been made through the use of intermediate phenotypes. As mentioned, alcoholism is a multi-factorial disease and several genes, each of small effect, as well as environmental variables, are likely to be involved. As will be discussed, in some instances common functional alleles of small effect have been identified, and in other cases uncommon alleles of strong effect are also known.
Gene Structure and Gene Expression in Higher Organisms
Blood tests on subjects displaying this effect showed increased levels of acetaldehyde, a breakdown product of alcohol, which resulted in an uncomfortable sensation of warmth in the skin, palpitations and weakness. By the 1980s investigators traced the reaction to an enzyme involved in alcohol metabolism, aldehyde dehydrogenase, and eventually to the gene that encodes it, ALDH1. The enzyme breaks down acetaldehyde, but slight variations in the gene’s DNA code in these subjects caused the enzyme to work more slowly. When these individuals ingested alcohol, the acetaldehyde–which may be toxic in high doses–was building up in their bodies. Scientists have learned through studies of identical and non-identical twins that alcohol use disorder is heritable, with genetic factors accounting for about half of the risk of alcohol dependence. Part of the challenge has been to gather a study that is large enough to detect a genetic signal, said Palmer.
Associated Data
A non-exhaustive list of convergent findings across studies includes a region on chromosome 4q, that contains the alcohol dehydrogenase (ADH) gene cluster 96,97,99,100, and a chromosome 4p region near the centromere containing a γ-aminobutyric acid receptor (GABAA) gene cluster 96,99. 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. A region on chromosome 1 was linked to alcoholism and affective disorder in the COGA data set 102, supporting further the existence of a genetic overlap between alcoholism and internalizing disorders.
- Studies arerevealing other genes in which variants impact risk for alcoholism or relatedtraits, including GABRA2, CHRM2,KCNJ6, and AUTS2.
- The ADH risk variants may contribute to the development of alcoholism directly by promoting heavy drinking, whereas the GABRA2 variants predispose a person to conduct problems, which are themselves a risk factor for alcoholism.
- 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.
- There is also value, however, in supporting individual self-knowledge as it pertains to susceptibility so that people can make informed choices for themselves and in shaping a culture that regards this as a positive goal.
Whole Genome Association studies represent a unique opportunity to identify alcohol-related loci in hypothesis-free fashion. Finally, genome-wide analyses of transcripts and chromatin remodeling promise an increase in our understanding of the genome function is there an alcoholism gene and of the mechanisms through which gene and environment cause diseases. Alcoholism has a substantial heritability yet the detection of specific genetic influences has largely proved elusive.
- In addition, different strategies such as candidate gene analyses and genome-wide association studies have been used.
- 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.
- Consequently, several genetic loci that moderate vulnerability to alcoholism have been identified.
- Such comorbidity between disorders can indicate the existence of etiological factors that are shared (co-causation), but can also reflect inter-causation.
- Finding the genes involved in our responses to alcohol and understanding their effects may thus illuminate a broader array of conditions, too.
An alternative metabolic pathway is the direct conversion of pyruvate into acetyl-CoA via the pyruvate dehydrogenase complex. 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. Several transcription factors have been implicated in alcohol sensitivity and/or induction of tolerance in flies. The hangover gene encodes a transcription factor that contributes to the induction of alcohol tolerance 90. Similarly, dLmo/Beadex, which encodes a transcriptional regulator, contributes to behavioral responses to ethanol 91. The mouse ortholog gene encoding LIM domain only 3 (Lmo3) also affects alcohol sensitivity; reduced Lmo3 expression correlates with increased sedation time and reduces voluntary consumption of ethanol 91.