As with any behaviour, genetics are believed to play a crucial role in shaping the behaviour of alcohol dependence (AD). According to the study conducted by Prescott et al., the heritability of AD in the Irish twin population ranged from 51% to 64% (1). Although there is documented heritability, it has been hard for scientists to pinpoint a particular gene or set of genes that cause AD in human populations. Scientifically, there have been two types of AD, Type I and Type II, currently identified which are significantly different from each other in terms of biology and physiology (2). This poses an additional challenge for the researchers to identify the effector genes for these two disorder types. Type I alcoholics show a tendency for AD at a later stage of their lives, usually in their 20s, and are influenced largely by the social environment around them (3). Alcohol in these subjects is used mostly for stress relief (3). Type II alcoholics have a high genetic pre-disposition and show AD at an early age (3). These subjects are characteristic for their personal traits and their use of alcohol for euphoric effects (3).

Serotonin


As it has been noted by McHugh et al., most of the research on alcohol dependence has been focussed on genes that affect neurotransmitter activity in the brain similar to the activity of ethanol intake (4).With the help of animal models and twin studies, researchers have been able to direct their attention to those genes, which are thought to have an impact on the development of alcohol dependence in humans due to manipulations of the neurotransmitters. These genes include – the Serotonin Transporter Gene (SLC6A4), GABA decarboxylase genes and Chlorine Intracellular Channels (CLICs), Dopamine transporter gene, and others. In this paper, the main focus will fall on the SCLC6A4, GABA decarboxylase and CLICs.
Serotonin (5-HT) is a monoamine neurotransmitter that is synthesized from the amino acid tryptophan, by an enzyme – tryptophan hydroxylase (TH) (5). 5-HT has a very broad spectrum of activity. Its functions range from modulating mood to controlling biological processes such as ejaculation (5).To have any influence in the brain, 5-HT must be able to leave and enter cells (10). These processes are aided by serotonin receptors (5-HTT) (6). A single gene, SLC6A4, on is responsible for the coding of the human 5-HTT; however there have been noted differences between the versions (polymorphism) of the gene (6). It has been noted that a 44 base pair insertion/deletion mutation in the non-coding, promoter region of the gene differentiates a fully functional transporter from a partially functioning one (6). This mutation affects the transcription and results in a two-fold decrease in activity of the mutated gene (5). The mutated gene has been termed the “Short” allele versus the non-mutated “Long” allele (7).
Hallikainen and colleagues have shown that there was an association between type II alcoholism, which is early onset, and increased frequency of the Short allele. In this study, 219 subjects had their transporter genotype examined by PCR (5). 114 subjects were categorized as type I, 51 as type II and 54 subjects being healthy controls. The categorizations were based on DSM-IV. It has been found that the Short polymorphism has been predominantly found in type II categorized alcoholics in comparison to type I and healthy controls. Thus, it was concluded that the short polymorphism is associated with increased risks for an early onset of alcohol dependence (Type II). The group has also proposed that the Short allele alters the uptake of 5-HT leading to disturbance of serotonergic systems in the brain which in turn correlates with impulsive behaviors (5).

In a different study conducted by Johnson et al., the effect of a different polymorphism, the L allele, was modulated using a 5-HT receptor antagonist – ondansetron (8). It has been noted that the two polymorphisms, Long and Short, have long been associated with psychiatric disorders including obsessive-compulsive disorders and anxiety-related disorders (9). In healthy subjects with the Long polymorphism, an increased uptake of 5-HT and β-CIT has been noted. However in alcohol dependent patients with the Long polymorphism, the opposite

was noted. In addition, the Long polymorphism alcohol dependent subjects had a reduced 5-HT uptake than those with Short polymorphism (9). This results in an upregulation of the 5-HT receptors and a greater alcohol consumption during the subject’s lifetime (9). The researchers proposed that ondasetron will reduce the severity of substance consumption along with increased periods of abstinence (8). 283 alcoholic subjects were separated based on their genotypic polymorphism in the regulat
ory area of the 5-HTT gene (9). The subjects received either ondansetron for 11 weeks or a placebo treatment along with cognitive behavior therapy (9). Those taking ondasetron had a reduced drink intake along with increased abstinence period (9). The authors have concluded that there is a way to manage the genetic predisposition to alcohol dependence along with ondasetron being a good therapeutic method for this particular situation of Long polymorphism (9).
In a study conducted by van der Zwaluw in 2010, the age of alcohol consumption was examined in relation to a polymorphic allele the subjects possessed (6). As it has been previously stated, the Short polymorphism was associated with Type II alcohol dependence which is characterized by an early onset of alcohol use (2). In this study, 202 non alcoholic, adolescent subjects were sampled. The subjects were genotyped and a model of latent curve growth was used to examine alcohol use development over time by estimating the level of use and the change in consumption over time (6). It has been found that adolescents with a Short allele polymorphism showed larger alcohol consumption than those without the Short allele both longitudinally and cross-sectionally (6).

By reviewing the mentioned studies, it is clear the serotonin transporter polymorphism has an impact on alcohol dependence, as well as other psychiatric and psychological maladies. However, it is not the only gene of interest when speaking about alcohol dependence.

GABA decarboxylase


A second gene of interest, GAD, is involved in the process of transforming glutamate to GABA (11). There are two isoforms of this gene in humans – GAD1 and GAD2 and both have been extensively studied for their effect on alcohol addiction (12). GABA is an inhibitory neurotransmitter that is responsible for the sedation under influence of alcohol, as its activity is enhanced (13). However, as one may expect, the effect of GABA is reduced under prolonged alcohol (ab)use due to downregulation of GABA pathways (14). As mentioned before GAD produces GABA from glutamate and it is a rate-limiting step and as a result controls how much GABA is produced (11). In previous studies, GAD knockout mice have been show to experience similar phenotypic behaviours as alcoholics during abstinence – seizures, anxieties (15). This knockout resulted in low GABA levels (15).GAD1 or GAD67 is responsible for basal GABA levels and in mouse models the GAD1 knockouts were, for the most part, lethal (15). Such, findings suggest an important role for this gene in the substance dependence cases.
In their study Loh et al., looked into an association between GAD1+GAD2 and alcohol dependence in the Taiwanese male population (16). 286 subjects of whom 140 were diagnosed with alcohol dependence were genotyped (16). They have found that GAD1 gene had nine polymorphisms of which three were associated with alcohol dependence and GAD2 had no association between fourteen SNPs and the substance use (16). The researchers have concluded that a possible deficiency in GAD1 function could lead to insufficient GABA levels leading to subjects being more prone to anxieties which are precedents for alcoholism (16). Another possible explanation was proposed after it was discovered
that subjects with alcohol dependency had low plasma GABA levels. These subjects may be more likely to administer alcohol to raise GABA levels (16).


In the study conducted by Terranova et al., 283 Italian men, from the same region in Italy, had their GAD1 gene studied (17). 107 of these men were diagnosed with alcohol dependence based on the DSMIV standards (17). All had their DNA genotyped and twenty-six SNPs were selected in the GAD1 gene (17). After statistical analysis, the researchers noted an association between one SNP of the GAD1 gene and alcohol dependence. This polymorphism is thought to interfere with either splicing or the stability of the GAD1 mRNA (17). The researchers support the Loh’s proposed model of “self-medication” (16), in which patients unknowingly raise the lowered plasma GABA levels. They have also suggested investigation of regions up- and downstream of this SNP (17).

In a multinational study, involving scientists from four different countries, Kuo et al. have looked at the association between GAD genes and alcohol dependence in the Irish sibling population (12). A total of 1105 subjects were recruited for this study and of those 575 subjects met the DSM-IV criteria for alcohol dependence (12). The subjects were administered only if all of their grandparents were born in the U.K and/or Ireland (12). The subjects filled out a questionnaire that rated their alcohol consumption, and was used a retrospective assessment tool of alcohol effects on them (12). The DNA was genotyped and SNPs were studied on both the GAD1 and GAD2 genes – a total of twenty-nine polymorphisms (12). The researchers have found an association of GAD1 with at-age onset and initial sensitivity to alcohol (12). However, they did not find convincing evidence for alcohol dependence and the GAD genes (12). They concluded that their findings relate to the pathophysiology processes that form alcohol dependence rather than th
e disorder itself, meaning that GAD genes may play a role in the development of the disorder (12).

As studies suggest GABA and GABAergic system plays an important role in alcohol addiction. Further research is needed to pinpoint the exact effects of different polymorphisms but nevertheless, GAD1 gene has been associated with alcohol dependence across different populations as is suggested in the studies done on the Italian, Taiwanese and Irish subjects (16, 17 ,12).

Intracellular Chlorine Channels


The third and last gene of interest expresses intracellular chloride channels. These channels are thought to have many functions such as growth factor signalling and regulation of receptors and anchoring proteins (18). This is a brand new area of research and not much work has been done on this particular case. In 2012, Bhandari et al. published a paper outlining their work on CLICs in different animal models (18). It has been previously noted that short-term and/or long-term alcohol intake by some animals leads to the same behavioral output as in humans (19). As a result, the researchers proposed that there may be an analogical mechanism that could relate to humans (18). In this study, three animal models were used to identify genes that influence behaviour in relation to alcohol addiction, as it necessary for understanding the basis of alcohol dependence (18). Drosophila, C. elegans, and a mouse were all used to study the roles of chloride intracellular channels (CLICs) in alcohol related behaviour (18). After alcohol treatment, the Clic4 expression was increased in the mice PFC and also the basal PFC expression had a correlation with locomotor activation and overexpression of Clic4 decreased the sedative effect of alcohol (18). In the C. elegans model, mutations in the analog genes altered the behavior response to acute alcohol intake (18). In the Drosophila model, it was found that the disruption of Clic gene analogs has a significant decrease on sensitivity to alcohol (18). The researchers have established that CLICs gene is a key modulator of behavior related to alcohol in the animals studied. They have found that the mammalian CLIC4 had a higher expression when saline solution was replaced by ethanol, suggesting that CLIC4 might be important factor in alcohol response. They have concluded that results like these can further our understanding of the genetic basis of alcohol addiction, which in turn should help developing the ultimate tools for alcohol dependence elimination.
In this review, the reader was presented with the current research on alcohol addiction related genes and their possible manipulations. For many years, scientists have been trying to pinpoint the genes responsible for the disorder that has been affecting a number of people world-wide. Unfortunately, the human genome is an extremely vast place and as a result one could compare this search to searching a needle in stack of hay. Nevertheless, scientists have been succeeding and target genes have been identified. The further understanding of the biochemical basis of alcohol addiction may help to create more effective treatments for the disorder.

Extras:


Alcohol Addiction Self-Test

References:


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