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In order for researchers to be able to compare and contrast their findings there must be an agreement between them in what defines an alcoholic. Therefore most researchers use the definition of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, [DSM-IV] (APA 1994) and World Health Organizations International Classification of Diseases (ICD-10).
The ICD-10 definitions are similar to that of the DSM-IV. However, their diagnosis focuses more on an interrelation of psychological symptoms, such as craving; physiological signs, such as tolerance and withdrawal; and behavioral indicators, such as the use of alcohol to relieve withdrawal discomfort (Baber 1992).
A possible indication that there is a genetic predisposition towards alcoholism is that fact that biological offspring of alcoholics being approximately three to five times more likely to develop alcoholism during their lifetime than the biological offspring of nonalcoholics (Cotton, 1979). However, one can argue that the increase of rate of alcoholism in biological offspring of alcoholics is due to environmental influences. A positive family history can be merely just a result of shared environmental influences. Therefore, behavioral geneticist has used twin and adoption studies to identify the separate contributions of genetics and shared environmental factors.
Researchers have used analyses of genetically identical monozygotic twins (MZ), and fraternal dizygotic (DZ) twins to measure heritability of alcoholism. There have been eight major twin studies of alcoholism in men, and in all but one of these studies the concordance (same trait in both members of a pair of twins) rate for alcoholism was significantly greater in MZ than DZ twins (McGue, in press). For example, in a study by Kendler, Prescott, Neale, and Pedersen (1997) on nearly 9,000 Swedish male twins born from 1902 to 1949, MZ twin concordance always significantly exceeded DZ twin concordance.
Adoption studies can allow researchers to better separate the genetics and environmental influences on the development of alcoholism. Colninger and colleagues (Cloninger et al. 1987) uses a large-scale adoption study in Sweden to identify genetic and other variables that predicted alcohol abuse in adoptees. This study has been coined as the Stockholm Adoption Study. The study was done on 862 men and 913 women adopted by non-relatives at an early age in Sweden.Â The study distinguished two forms of alcoholism, type I and type II. Type I is characterized as late onset of alcoholism, after age 25, and marked by frequent psychological dependence, Type II alcoholism was characterized as relatively early onset of alcoholism, before age 25, and marked by spontaneous alcohol seeking and aggressive behavior. Analysis of data from male adoptees showed that although Type II alcoholism was strongly heritable (estimated heritability of 90%), Type I alcoholism was only moderately heritable (heritability estimate of less than 40%). Many of the key results from the original Stockholm Adoption Study were independently replicated in a second Swedish city, Gothenburg (Sigvardsson, Bohman, & Cloninger, 1996).
Due to the evidence that alcoholism is heritable, the next step would be identify the possible genetic factors that lead to the heritability. Two basic strategies are used to identify genetic risk factors for alcoholism, candidate gene approach and genome-wide studies. This approach involves assessing the association between a particular allele (or set of alleles) of a gene that may be involved in the disease (i.e. a candidate gene) and the disease itself. This approach often begins with the knowledge of potential physiological mechanisms that might be related to the endophenotype, and makes educated guesses about which of the known genes might be important. The genes most extensively examined by candidate gene studies have been those involved in alcohol (i.e., ethanol) metabolism and in neurological pathways responsible for increased risk taking and "reward" stimulation from ethanol.
A genome-wide study would scan the entire DNA contents (i.e., the genomes) of individual and identify for genetic variations ( i.e polymorphism). There are two main approaches to genome-wide analysis- association and linkage. Association studies examine genetic polymorphisms associated with case or control status, whereas linkage studies investigate the inheritance of specific locations on a chromosome (i.e., loci) within family lines. In association studies, if a given allele contributed to the risk for alcohol dependence, one would expect the allele and/or genotype frequencies to differ between the case and the control subjects. Linkage analysis scans the genome using a type of genetic variation called microsatellites. A microsatellites nucleotide pair combinations of DNA which repeat themselves and form groupings. Microsatellites can be highly polymorphic, making them useful for comparative genetic studies of organisms. Then the pattern of transmission of disease( e.g alcoholism) in families with multiple affected members is compared with the pattern of transmission of certain microsatellites. The underlying hypothesis in linkage analysis is that alcoholics within a family share many risk alleles; therefore, genes containing alleles that increase the risk for alcoholism reside within chromosomal regions that are inherited by most or all alcoholic family members.
A prime example of specific genes related to the alcoholism risk are those that
control the production of the enzymes that metabolize alcohol. . Ethanol is metabolized in the liver, where it is converted to acetaldehyde by the enzyme alcohol dehydrogenase (ADH). ADH is responsible for 80 percent of ethanol's metabolism to acetaldehyde, CYP2E1 metabolizes approximately 10 percent of ethanol and, because of its lower affinity for ethanol, is largely active only when ADH is saturated (Gemma et al. 2006). Acetaldehyde is then converted to acetate by the enzyme aldehyde dehydrogenase (ALDH). Because high levels of acetaldehyde in the blood are associated with the unpleasant effects of drinking (e.g., nausea, dizziness, headaches), variation in the genes coding for the ADH and ALDH enzymes might be expected to be associated with alcoholism risk. There is variation in the genes coding for both these enzymes. These variants affect a gene called ADH1B, which encodes a variant of ADH, and a gene called ALDH2, which encodes a variant of ALDH (Edenberg 2000, 2007; Hurley et al. 2002). The protective variant in the ALDH2 gene, known as ALDH2*2, involves a point mutation that results in the exchange of the amino acid glutamate at position 487 of the ALDH protein for the amino acid lysine. This mutation acts in a nearly dominant manner to render the enzyme almost inactive: even people who inherit only one copy of ALDH2*2 and one "normal" copy of the gene (i.e., people who are heterozygous for this mutation) produce an ALDH enzyme with extremely low enzyme activity (Crabb et al. 1989). As a result, these individuals exhibit highly elevated levels of acetaldehyde, which produces aversive reactions, including flushing, elevated heart rate (i.e., tachycardia), and nausea after consuming even a small amount of alcohol (Eng et al. 2007). Approximately 10% of Asian men and women (e.g., Japanese, Chinese, and Koreans) are homozygous for the mutation of ALDH2*2, although is not known to be found in any
other racial group (Wall and Ehlers 1995). An additional 40% of Asians are heterozygotes for the ALDH mutated enzyme (Wall and Ehlers 1995). Although these individuals represent almost half of the general population in their countries, they comprise less than 10% of Asian alcoholics, supporting the conclusion that even the heterozygotes have a relative protection from alcoholism (Murayama et al. 1998)
There also a coding variations in the ADH1B gene (called ADH1B*2 and ADH1B*3) that encode highly active enzymes which increase the rate at which acetaldehyde is produced (Li 2000). These variations also reduce the risk for alcohol dependence (Edenberg 2007; Thomasson et al. 1991). Similarly, studies in Asians, Israelis, and the Maori people indicate that either of these ADH genotypes might be associated with a more intense reaction to alcohol or negative sequelae of alcohol intake (Neumark et al. 1998; Tanaka et al. 1997; Higuchi 1996)
The evidence that an increase of acetaldehyde can be a deterrent to the development of alcohol abuse has lead researches to develop pharmacological treatments. Disulfiram blocks the enzyme aldehyde dehydrogenase, leading to an accumulation of
acetaldehyde following intake of alcohol. This in turn causes flushing, shortness of breath, tachycardia and other unpleasant symptoms. The point of disulfiram was not that the patients would actually experience these adverse symptoms, but rather that the anticipation of these symptoms help patients abstain. The logic being, that an accumulation of acetaldehyde would pose a possible medical risk. However, disulfiram has a limited and largely negative documentation for efficacy. A meta analysis by Hester & Miller (2003) concluded that evidence for its efficacy is lacking. Disulfiram merely reduces alcohol drinking by severely punishing drinking bouts. For optimal efficacy, punishment must be applied severely and consistently.
Researchers have also done candidate gene studies on genes for the binding sites (i.e., receptors) for the neurotransmitter gamma-aminobutyric acid (GABA); opioid receptors; components of the pathways for the neurotransmitters serotonin, dopamine, and glutamate. A full disscsion of each neurotransmitter would is out of the scope of this
paper, therefore I will discuss a few neurotransmitter and receptors and there relation to alcoholism.
Data suggest that ethanol increases opioid neurotransmission and that this activation is part of the mechanism responsible for its' reinforcing effects (Gianoulakis 2001; Herz 1997) The evidence linking the endogenous opioid system to the development and/or maintenance of alcoholism has led to several theories regarding the possible nature of an opioid abnormality in this disorder (Cowen and Lawrence 1999). The Opioid Deficit Hypothesis posits that low levels of endogenous opioid activity motivate compensatory ethanol consumption that serves to increase opioid activity in the brain (Trachtenberg and Blum 1987). Alternatively, the Opioid Surfeit Hypothesis maintains that vulnerability individuals inherit or acquire an excess of endogenous opioid activity (Reid et al. 1991)
The possibility that some effects of ethanol may be mediated through the endogenous opioid system was first proposed by Davis and Walsh (1970), who discovered that morphine-like alkaloids (tetrahydroisoquinolones) are formed in vivo as a result of the interaction of the ethanol metabolite, acetaldehyde, with certain metabolites of DA. Further research demonstrated that these alkaloids could bind to opioid receptors and produce opioid-like effects (Blum et al. 1978; Fertel et al. 1980). However, the pharmacological relevance of these compounds in opioidergic processes remains unclear because their concentrations in brain tissues is extremely low, and they also seem to have direct effects on dopamine neurotransmission unrelated to opioid receptor binding (Cowen and Lawrence 1999).
The best evidence to the linkage between endogenous opioid system and ethanol consumption is that pharmacological blockade of opioid receptors reducesÂ alcohol drinking in a dose-related fashion. Naltrexone is an opioid receptor antagonist that has been shown to reduce alcohol cravings and relapses to heavy drinking, but it does not necessarily produce total abstinence. The initial study done by Altshuler (1980) and colleagues reported the dose-related effect of naltrexone on decreasing ethanol drinking in 10 of 21 rhesus monkeys that were willing to self-administer alcohol and the treatment results were perfectly replicated by O'Malley in 1992. Based, in part, on the findings of these studies, naltrexone was approved by the Food and Drug administration (FDA) in 1995 for the treatment of ethanol dependence. Since naltrexone's approval for the treatmentÂ of alcoholism, the opioid antagonist has been tested in 29 controlledÂ clinical trials in unselected participants with alcoholism (Pettinati 2006). Most have shown a reduction in heavy drinking when taking theÂ medication, as would be expected if the alcohol reward wereÂ simply diminished.
The effects of naltrexone has lead to candidate gene studies one the opiod recoptors, specicly the Âµ-opioidÂ receptor. There are more than 25 identifiedÂ allelic variants of the gene that codes for the Âµ-opioidÂ receptor. In a human laboratory study (Ray and Hutchison 2004), volunteers with Asp40 allele reportedÂ greater subjective stimulation at a given ethanol blood level.Â In a more recent study of heavy drinkers,Â naltrexone attenuatedÂ the increased alcohol stimulation in those carrying the Asp40Â allele (Ray and Hutchison 2007).
GABA, by interacting with a molecule called the GABA-A receptor, mediates several effects of alcohol, including alcohol's sedative and anxiety reducing effects, motor coordination, tolerance, and dependence (Kumar et al. 2009). ). GABAA receptors undergo allosteric modulation by several structurally unrelated drugs, most with their own binding sites, including ethanol and benzodiazepines. Initial evidence that alcoholism was related to GABA-A receptors, was due to the fact that benzodiazepines showed effectiveness in treating alcohol withdrawal (Enoch 2007). GABA-A receptors are ligand-gated, chloride-ion channels that confer fast synaptic inhibition. The GABAA
receptor ion channel is lined by the TM2 segments from each of the five subunits that form the receptor. There appears be a pocket located between TM2 and TM3 of the GABAA Î± subunit that binds both alcohols and anesthetics (Mascia et al., 2000). From a pharmacological perspective, topiramate, which has a complex effect on GABAA receptors (Gordey et al., 2000) has been shown to reduce the percentage of heavy drinking days and other drinking outcomes in recovering alcoholics (Johnson et al., 2007).
Genome wide scans in American Indians and Caucasians have provided evidence for linkage of alcohol dependence and relapse-associated Î² EEG to chromosome 4p at the location of the GABA-A gene cluster (Ghosh et al., 2003; Zinn-Justin and Abel, 1999). Similarly, Edenberg et al. (2004) found that several genes that encode subunits of the GABA-A receptor are associated with an increased risk for alcoholism. His finding showed significant evidence that a gene called GABRA2, which with other GABA-A receptor genes is located in a cluster on chromosome 4, is associated with alcoholism. The evidence was based on family-based association study on 2282 individuals, 41%with lifetime alcoholism and 29% with lifetime illicit drug dependence, from 262 multiplex families with a high density of alcoholism.
Alcohol may be consumed in excess as a coping mechanism for stress and the altered homeostasis subsequent to addiction can result in stress upon withdrawal (Wand, 2005). GABA inhibits, whereas glutamate activates, the hypothalamic-pituitary-adrenal axis (HPA) responses to stress (Herman et al., 2004). A variety of ethanol's effects on the brain are mediated via the glutamate system, and thusÂ N-methyl-D-aspartate (NMDA) receptors are one of the primary targets of ethanol (Spanagel 2009). NMDA is anÂ amino acidÂ derivative which acts as a specificÂ agonistÂ at theÂ NMDA receptorÂ mimicking the action ofÂ glutamate.
Due to this direct interaction of ethanol with the glutamate system, adaptive changes occur with repeated intermittent alcohol exposure. Findings have led to the formulation of the glutamate hypothesis of alcohol addiction, which suggests that enhanced glutamate-mediated neuronal excitability during withdrawal and prolonged abstinence contributes to craving and relapse (Gass and Olive 2008).Â The metabotropic glutamate receptors (mGlur) regulate glutamate-mediated neuronal excitability (Schoepp 2001). Neuropharmacological studies have provided substantial evidence that the activation of predominantly presynaptically located Metabotropic glutamate receptor 2/3 by various selective agonists (e.g., LY379268) diminished ethanol-seeking behavior elicited by either stress (Zhao 2006) and reduces relapse-like drinking behavior (Vengeliene et al. 2008). Blockade of metabotropic glutamate receptor 5,predominantly located postsynaptically, by the reference compound 2-methyl-6(phenylethynyl)pyridine (MPEP) reduces ethanol-seeking in the reinstatement paradigm and relapse-like drinking behavior in the alcohol deprivation model (Bachteler et al. 2005). Besheer (2010) and colleagues did pharmacological mapping studies in alcohol-preferring P-rats-a well-defined genetic model of excessive alcohol consumption-by microinjecting MPEP and LY379268 into different brain sites. The study found that Intra- nucleus accumbens infusion of MPEP reduced operant ethanol self-administration in P-rats. These studies can lead to promising new treatments of alcoholism visa-vi the glutamate receptors of the brain.
The interaction of ethanol and glutamate has led to candidate gene studies on glutamate. An association study tested the candidate gene hypothesis that variation of the gene encoding the astroglial glutamate transporter EAAT2 confers vulnerability to alcohol dependence (Sander 2000). Sander and colleagues studied variants of the ionotropic glutamatergicÂ N-methyl-d-aspartate receptor (NMDAR), the silentÂ G2108AÂ andÂ C2664TÂ polymorphisms of theÂ NMDAR1Â and theÂ NMDAR2Bgenes, in exon 5 of the EAAT2 gene in 565 subjects of German descent, comprising 342 alcohol-dependent subjects and 223 control subjects. Â Genotype frequencies of the NMDAR1 polymorphism differed significantly between control and alcoholic subjects, the NMDAR2B polymorphism revealed a significantly reduced T allele in Cloninger type 2 alcoholics and in patients reporting an early onset compared with control subjects.
In 1989, the National Institute on Alcohol Abuse and Alcoholism initiated the Collaborative Study on the Genetics of Alcoholism (COGA), a large, systematic effort to identify the genes that predispose to alcoholism. COGA goal is to elucidate the genetic mechanisms that contribute to a person's susceptibility to alcohol abuse and dependence (Begleiter et al. 1995; Bierut et al. 2002; Edenberg 2002). ). The study was ground breaking in several ways, including its size, emphasis on families, and extensive characterization of subjects. Families were obtained by recruiting alcohol dependent probands (i.e., index cases) who were in treatment and who gave permission to contact. COGA generated a dataset of 1,857 families consisting of 16,062 individuals as of March 2010 ( at risk 00). Moreover, the researchers identified a genetically informative subset comprising 262 families with at least three first degree relatives who met lifetime criteria for both Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised
(DSM-III-R) (American Psychiatric Association 1987).
COGA data collected from families with alcoholism and has been used for both linkage and association analyses. . In 1998, COGA researchers published their initial linkage findings based on an analysis of nearly 300 genetic markers (Reich et al., 1998). Suggestive evidence for the existence of genes increasing alc holism risk was found for Chromosomes 1 and 7, while a third region on Chromosome 4 was implicated as containing a gene (or genes) that protects against alcoholism. At the same time as the COGA findings were published, a second large-scale linkage study of alcoholism, based on a sample of Native Americans, reported suggestive evidence of the existence of a predisposing gene (or genes) on Chromosome 11 and a protective gene (or genes) on Chromosome 4 (Long et al., 1998). Although only the Chromosome 4 findings over lap, the two studies sampled different ethnic groups, and the genes that underlie alcoholism risk might reasonably be expected to vary for groups having distinct evolutionary history ( cite mccue at behavioral). A COGA study by Yang (2005) and his collegues have identified candidate susceptibility regions on chromosomes 1, 2, and 7, including susceptibility and protective regions within the neurexin 1(NRXN1) gene on chromosome 2. Another study by Namkung and colleagues (2005) was able to show that association analysis of COGA data pointed to a significant gene on chromosome 7, as well as 13 genes associated with both alcoholism and schizophrenia.
Due to the evidence for the role of the ADH genes in alcoholism susceptibility, the COGA investigators initially focused on the 262 families from the study with a very strong history of alcoholism. In these families, they determined the genotype for 110 DNA markers known as single nucleotide polymorphisms (SNPs), which were distributed throughout the ADH gene cluster. These analyses detected significant evidence of association of alcoholism with 12 SNPs located in and around the ADH4 gene (Edenberg et al. 2006) and modest evidence of association with noncoding SNPs in ADH1A and ADH1B. The association of several non coding ADH polymorphisms with alcohol dependence has been replicated in other studies (Macgregor et al. 2009). Simalirly, linkage studies performed on non-Asian families detected linkage of alcoholism to a broad region on chromosome 4q that included the ADH gene cluster (Prescott et al. 2006; Reich 1996).
Genome-wide association study (GWAS), also known as whole genome association study, is an examination of all or most of the genes (the genome) of different individuals of a particular species to see how much the genes vary from individual to individual. Different variations are then associated with different traits, such as diseases. In humans, hundreds or thousands of individuals are tested single-nucleotide polymorphisms (SNPs). The advantage of GWAS is that it allows a comprehensive test of association across the genome, rather than testing only one gene at a time.
The first published GWAS study, conducted in Germany, compared 487 men in inpatient treatment for alcohol dependence to 1,358 control subjects (Treutlein et al. 2009). The study identified several SNPs in a region on chromosome 2 that previously had been linked to alcohol dependence, as well as SNPs in a gene called CDH13 that is located on chromosome 16 and the ADH gene ADH1C on chromosome 4. A recent study by COGA reported results of a GWAS that included 847 alcohol dependent case and 552 control subjects (Edenberg et al. 2010). The combined evidence from this case- control study, a follow up in families, and gene expression data, provided strongest support for the association with alcohol dependence of a cluster of genes on chromosome 11. However, the associations detected in the COGA GWAS did not reach the threshold for statistical significance for this type of analysis, and therefore additional studies must be conducted to further define the associated genes (Foroud 2010).
There have also been several found indicators related the risk or developing alcoholism. Studies have found a correlation between level of response to alcohol and the risk of developing alcohol dependency. Many alcoholics have an ability to consume large amounts of alcohol with relatively little effect from early in their drinking careers (Schuckit 1998). These reports have lead to a study of relationship between the level of response (LR) to alcohol and alcoholism risk (Schuckit 1996, 1998) A low LR is evaluated by giving alcohol to individuals and determining the intensity of response at a given blood alcohol concentration (BAC), or by indirectly measured through a self-report of a history of a higher number of drinks required to produce a specific effect (Schuckit 1999). Relatively low intensities of reaction to alcohol have been found in about 40% of the children of alcoholics compared with less than 10% of controls (Schuckit 1999). 8.2-year follow-up of 450 out of 453 (99.3%) sons of alcoholics and controls demonstrated that a low LR was a significant predictor of later alcoholism (Schuckit 1996)
There are several indications that LR is genetically influenced. First, genetic factors impact on the intensity of response to alcohol in insects and animals,
with evidence of higher levels of spontaneous alcohol intake associated with a low
LR (Moore et al. 1998; Baldwin et al.1991; Lumeng et al. 1993). A study in humans have reported a higher level of similarity on some aspects of LR in identical twins than in fraternal twins, with an estimated heritability between 40 and 60 percent (Martin 1988). A pilot study (Mazzanti et al. 1999) evaluated 17 men with low LR scores, comparing results to 24 individuals who were clearly high on LR. The high LR and low LR groups were then evaluated for the patterns of 5 candidate genes relating to serotonin and gamma-aminobutyric acid functioning. Two of these genes, the LL allele of the serotonin transporter gene and a form of the GABA a6 receptor gene, were each associated with a low response to alcohol, and each related to whether the individual developed alcoholism. Those men who carried both genetic alleles of interest had the lowest intensity of response and the highest rate of severe alcohol-related problems. However, the study results are considered tentative because of the possibility that the high LR and low LR groups might have differed on unknown characteristics that were not completely controlled for and that might impact on the distribution of the specific alleles across groups ( Schuckit 2000)
Another potential indictor has been related to certain brain wave characteristics of alcohol dependent people (Begleiter et al 1998; Bauer and Hesselbrock 2000). Event related potential (ERP) paradigms evaluate how specific pathways in the brain react to specific stimuli, such as sounds and visual images. The component most frequently studied in alcohol research is P300, a positive wave that occurs about 300 milliseconds after the stimulus. The height of the wave ( i.e amplitude) is related to the significance of the stimuli. Reduced amplitude of the P300 wave has been reported to characterize a substantial subgroup of alcoholics, with the finding often remaining even after extended periods of abstinence (Hill 1998).
Interest in the P300 wave is based on data that demonstrate that the P300 amplitude is genetically influenced. This conclusion is supported by at least three investigations, with heritability estimated to range between 0.50 and 0.60(Begleiter et al 1998). Most studies of children of alcoholics have reported a lower overall P300 amplitude in perhaps 20% to 35% of children with alcoholic parents, compared to controls( Hill 2000). These finding confirm that low P300 amplitudes may be a useful phenotypic marker for the risk of alcoholism.