|
INTRODUCTION
Alcohol dependence is associated with
maladaptive behaviors that result in the persistent, compulsive and
uncontrolled use of alcohol. Alcohol induces adaptive changes in the brain
function which form the bases for establishment of tolerance, craving,
withdrawal and affective disturbances which persist long after consumption
ceases (Roberts et al., 1997). This self-maintaining and progressive
neurobiology of alcohol dependence makes it a chronic and relapsing
disorder.
GENETIC EPIDEMIOLOGY
Genetic epidemiology is a discipline
closely related to traditional epidemiology that focuses on the familial, in
particular genetic, determinants of disease and the joint effects of genes
and non-genetic determinants (Burton et al., 2005). Both biological and
cultural factors are subsumed under the rubric of familial. The familial
nature of alcohol dependence has been recognized since the time of the
ancient Greeks, though the emphasis placed on it varied with times. The oft
quoted phrase Ebrii gignunt ebrios (one drunkard begets another) attributed
by Burton to the Greek historian Plutarch (110 AD) has been used to
emphasize the long-standing recognition that alcohol dependence runs in
families (Burton, 1972). In the 1930s and 40s the role of genetic factors in
the etiology of alcoholism was almost totally dismissed but it regained
acceptance in the 1950s and has remained popular since.
Evidence for the familial nature of a
disorder comes from four different types of studies: family studies of
biologically related individuals; twin studies; adoption studies and genetic
linkage studies (Merikangas, 1987).
FAMILY STUDIES
Higher prevalence of alcohol
dependence among family members of alcoholic patients has been consistently
documented (Amark, 1951; Goodwin, 1976; Cotton, 1979). The consistency of
this finding is remarkable considering the fact that the definitions of
alcoholism in these studies have varied widely and only 4 out of 40
published family studies have used standardized diagnostic interviews and
control groups (Hoghkinson et al., 1991).The risk of developing alcohol
dependence in first degree relatives of alcoholic patients has been reported
variously from two fold (Dawson et al., 1992) to five fold (Cotton , 1979),
the risk increasing to three fold if a second or third degree relative is
also affected (Dawson et al., 1992).The familial nature of the disorder
holds regardless of the nationality of the samples (Cotton, 1979) or
presence of a comorbid psychiatric disorder such as depression (Merikangas
et al., 1985), heroin addiction (Kosten et al., 1991) or antisocial
personality disorder (Reich et al., 1981). However, it should be borne in
mind that the familial resemblance could be due to shared family environment
rather than shared heredity.
TWIN STUDIES
Studying the rates of concordance for
a disorder in twins can disentangle the relative contributions of genetic
and environmental risk factors. If both members of a twin pair are affected,
they are classified as concordant; whereas if only one member of a twin pair
is affected, they are classified as discordant. A disorder is likely to be
under genetic influence if concordance rates are higher in monozygotic (MZ)
twins, who share 100% of their genes, than dizygotic (DZ) twins, who share
50% of their genes on average. Concordance between twins is estimated using
either pair-wise or proband-wise concordance rates. The pair-wise
concordance rate is calculated as the percentage of concordant pairs out of
the total number of twin pairs in which at least one member has the
disorder. The proband-wise concordance rate assesses the probability that a
twin will have the disorder given that his or her co-twin is affected and is
calculated by dividing the number of affected co-twins by the total number
of co-twins. This rate differs from the pair-wise concordance rate because
both members of an affected pair can be ascertained independently as
probands.
View Table 1
Grove et al. (1990)
reported a study of the heritability of substance use, including alcohol
related problems, on monozygotic twins reared apart. This method avoids
several of the problems regarding the potential sources of twin similarity
due to environmental factors. The proband-wise concordance rate for alcohol
use disorders (abuse and dependence) was 33%, for drug abuse/ dependence 36%
and for antisocial personality disorder 29%. Follow up after 16 years of an
early sample of twins by Reed et al. (1996) revealed an increase in the
number of twins with a lifetime diagnosis of alcoholism while maintaining
higher monozygotic concordance rates.
Observations of the twin
studies point strongly towards a genetic effect in alcohol dependence which
should be viewed in the light of adoption and half sib studies to further
disentangle the genetic from environmental effects.
ADOPTION STUDIES
A naturally occurring
experiment: the adopted child separated from the affected parent forms an
elegant method of study to separate genetic from environmental influences on
the transmission of alcoholism from an affected parent to biological off
springs. There are four basic separation study methods:
Adoptees with respect to
the prevalence of alcoholism in both the biological and adoptive relatives
Adoptee study
method—compares the prevalence of alcoholism among the adopted away children
of an alcoholic parent to either adoptees of controls or to the general
population
Cross-fostering
method—identifies two groups of adoptees (e.g., children of an alcoholic
parent raised by a nonalcoholic adoptive parent and children of a
nonalcoholic biological parent raised by an alcoholic parent) and then
compares them with respect to the prevalence of alcoholism in each group.
View Table 2
GENETIC
DETERMINANTS OF ALCOHOLIC TYPOLOGIES
Typology is defined as
systematically classifying alcohol dependent individuals according to the
methods which are derived from logical rules and conceptual clusters based
on one or more combinations of biological, psychological, social and
cultural characteristics (Babor and Dolinsky, 1988). A review of 39 articles
published between 1850 and 1941 describing typological classifications of
alcoholics by Babor and Lauerman (1986) revealed that these typologies were
mainly based on drinking patterns, chronicity and severity of dependence
with little emphasis on the heritability. Of the many typologies proposed;
Knight’s (1938) essential, reactive and symptomatic alcoholics, Fleeson and
Gildea’s (1942) primary, symptomatic and exogenous drinkers, Jellinek and
Jollifey’s (1940) intincto-mortice and emotivo-mortice sphere types, Bowman
and Jellinek’s (1941) steady and intermittent drinkers, Jellinek’s (1960)
alpha, beta, gamma and delta alcoholics, only Cloninger et al.’s(1981)
placed strong emphasis on the heritability of alcohol dependence.
GENETIC
CONTRIBUTION FROM CO-MORBID PSYCHIATRIC DISORDERS
The presence of comorbid
psychiatric conditions like antisocial personality disorder and depression
with alcoholism has been consistently demonstrated in studies of alcoholic
patients (Fowler et al., 1980; Hesselbrock et al., 1985; Roy et al., 1991)
as well as in the general population surveys (Regier et al., 1990). The
environmental catchment area (ECA) project (Regier et al., 1990) revealed
that antisocial personality has the closest relationship with alcohol
abuse/dependence. Other conditions like anxiety and affective disorders
showed lesser but significant correlations. These correlations could well be
etiological in nature or reflect the consequences of alcohol
abuse/dependence. The various correlations are shown below:
View Table 3
In addition,
borderline personality (Prasad et al., 1990; Dulit et al., 1990) and
some traits like impulsivity, risk taking and stress responsivity (Kreek
et. al., 2005) have also been associated with alcoholism. The fact
that many of the associated conditions like personality traits,
schizophrenia and affective disorders have been shown to have genetic
components in their etiology has both
enriched as well as complicated the role of genetic factors in the
etiology of alcohol dependence.
GENETIC
MARKER STUDIES
Genetic marker
studies offer the potential to identify the genetic location
(locus) or the gene(s) responsible for conferring a predisposition
to alcohol dependence. A good genetic marker should be of known
chromosomal location, preferably highly polymorphic, of known mode
of inheritance and readily determinable. A genetic marker may be
an observable characteristic of an organism, a protein, a gene or
a DNA sequence. Genetic marker studies are of two types:
Association studies and Linkage studies.
GENETIC
ASSOCIATION STUDIES
Genetic
association studies attempt to demonstrate a statistical
association between a genetic marker and a disorder or trait,
relative to a suitable control group, within a given population.
The presence of such an association may be indicative of a direct
causal effect between a genetic variation and the disorder, or it
may be evidence of linkage disequilibrium between a locus
predisposing to the disorder and a nearby marker on the same
chromosome. A large number of genetic markers have been studied to
find an association with alcohol dependence.
Personality Traits
Genetic
epidemiological studies are consistently showing the heritable
nature of personality traits. The instruments often used in
genetics research to quantify personality dimensions are the
Tridimensional Personality Questionnaire (TPQ) or the more
complete version, the Temperament and Character Inventory (TCI;
which measures novelty seeking, harm avoidance, reward dependence
and persistence), the NEO Personality Inventory-Revised (NEO-PI-R;
which measures neuroticism, extroversion, openness, agreeableness
and conscientiousness) and the Barratt Impulsiveness Scale. Of the
personality traits, low reward dependence, high novelty seeking
and low harm avoidance have been associated with alcohol
dependence (Kreek et. al., 2005).
Neurophysiological Markers
EEG
Studies
It is now well
established that some aspects of the spontaneous EEG are under
genetic influence (Vogel, 1970; Steinlein et al., 1991). The EEG
findings from abstinent alcoholics manifest a number of
abnormalities such as decreased alpha activity and increased
delta, theta and beta activity (Begleiter, 1972). As the studies
have been conducted in abstinent alcoholics it is difficult to
determine whether these findings are the consequence of alcohol
use or antecede the development of alcoholism. Studies of the
baseline EEG comparing high risk with low risk individuals have
shown conflicting findings (Gabrielli et al., 1982; Pollock et
al., 1983; Cohen et al., 1993). A study in our institute by Lakra
(2002) on power spectra and coherence analysis of abstinent
alcoholics and their first degree relatives compared with controls
revealed that the alcoholics had decreased power in delta and
theta bands and increased power in beta, beta1 and beta 2 bands
compared to first degree relatives and normal controls.
Event
Related Potentials
The P300
component has been demonstrated to be significantly more similar
in MZ twins than in controls (Polich and Burns, 1987) and similar
in abstinent alcoholic fathers and their younger sons (Whipple et
al., 1988). A review of the ERP data in individuals at risk for
developing alcoholism indicates that the P300 component is
characterized by low voltage which reflects an inability of high
risk subjects to differentiate relevant from irrelevant stimuli. A
meta-analysis of ERP studies in high risk and low risk subjects by
Polich et al. (1994) concluded that the amplitude of P300
component of ERP reliably discriminates between high risk and low
risk subjects. These findings suggest that the reduced P300
voltage may provide a phenotypic marker for alcoholism. A study
comparing the ERPs of abstinent alcoholics, their first degree
relatives and normal controls in our institute conducted by Basu
(2002) showed an increased latency ofN200 and P300 components in
the alcoholic group.
Neuropsychological Deficits
Studies
involving the assessment of neuropsychological functions in the
non-alcoholic sons of alcoholics have consistently shown some
deficits such as hyperactivity to external stimuli, larger
electrodermal orienting responses, shorter latency responses and
slower rates of habituation to novel non-aversive stimuli (Finn
and Pihl, 1988; Finn et al., 1990). The pattern of deficits
manifested by the high risk subjects is quite analogous to that
displayed by individuals with dysfunction of prefrontal cortex
(Peterson and Pihl, 1990).
Blood
Groups
Numerous studies
of alcohol dependence have been conducted in which blood groups
were used as genetic markers. The 12 different blood groups
employed are located on only eight of the 23 chromosomes and the
fact that these markers are not highly polymorphic, they are
greatly lacking in power to detect genetic defects. The findings
of association of blood group A with alcoholism by Nordmo (1959)
and Kojic et al.(1977) could not be replicated later. Similar
claims that the ss phenotype of the MNSs system may be protective
against alcoholism (Hill et al., 1975; Gleiberman et al., 1981)
have been disputed (Tanna et al., 1988).
Other
Blood Protein Markers
24 different
polymorphic serum proteins located on 15 different chromosomes
have been the subject of some association studies. Only complement
component 3 (C3; Hill et al., 1975) and Haptoglobin (hp; Kojic et
al., 1977) have yielded positive results which are yet to be
replicated.
HLA
Antigens
HLA antigens
have been employed as genetic markers to study alcohol related
liver disease, but the results have been inconsistent (Eddleston
and Davis, 1982; Aria et al., 1991).
GENETIC
LINKAGE STUDIES
Linkage analysis
attempts to demonstrate, within families, the co-segregation of an
allele of a marker locus with the allele of a gene determining the
disorder, disease or trait. Linkage studies offer a more powerful
approach to identify single gene effects than do association
studies. In particular, these are capable of detecting the
presence and effects of genes at a much greater genetic distance
along chromosomes than the genetic association method. At the
simplest level linkage may be detected merely by observing
co-segregation between a marker allele and a disease within a
family. However, such an inspection of the data offers no
indication of the probability that such co-segregation could have
occurred by chance and it does not readily accommodate the
difficulties introduced by complex modes of inheritance,
recombination between loci, incomplete penetrance, occurrence of
phenocopies, etc. Various statistical methods have been introduced
to quantify these probabilities and to allow incorporation of such
complexities into the analysis (Otto, 1991).
Parametric Linkage Analysis
Parametric or
model-based linkage analysis is the analysis of the co-segregation
of genetic loci in pedigrees. Loci that are close enough together
on the same chromosome segregate together more often than do loci
on different chromosomes. The main quantity of interest in
parametric linkage analysis is the recombination fraction θ (the
probability of recombination between two loci at meiosis).
LOD
Scores
Linkage is
usually reported as a logarithm of the odds (LOD) score. This
score was first proposed by Morton in 1955. It is a function of
the recombination fraction (θ) or chromosomal position measured in
Centimorgans (cM).This means that the LOD score is different
depending upon which value of θ is being considered. The LOD score
function is then defined as:
LOD (θ) = log10
[Like (θ)/Like (θ)=1/2]
The higher the
LOD score, the greater the evidence for linkage. Traditionally, a
score of 3 was regarded as significant evidence of linkage. This
is equivalent to p=0·0001. To conclude whether apparent linkage is
real, the concept of genome-wide significance has been
developed—the probability threshold that declares linkage after
testing many DNA markers used in a genome scan. Lander and
Kruglyak (1995) suggest 3 levels of genome-wide significance:
suggestive linkage, significant linkage and confirmed linkage,
though it is suggested that confirmed linkage only occurs when the
results are replicated in an independent study sample.
Model-Free (Non-Parametric) Linkage Analysis
For
multifactorial diseases, where several genes (and environmental
factors) might contribute to disease risk, there is no clear mode
of inheritance. Methods to investigate linkage have therefore been
developed that do not require specification of a disease model.
Such methods are referred to as non-parametric or model-free. The
rationale is that, between affected relatives excess sharing of
haplotypes that are identical by descent (IBD) in the region of a
disease-causing gene would be expected, irrespective of the mode
of inheritance. Various methods test whether IBD sharing at a
locus is greater than expected under the null hypothesis of no
linkage.
Sibling
Pairs
The simplest
approach is to study sibling pairs, both of whom are affected. At
any locus, according to the null hypothesis of no linkage, the
number of IBD alleles shared by a pair of siblings is none with
probability 0·25, one with probability 0·5 or two with probability
0·25. If IBD sharing in the families is known, the observed
proportion of pairs sharing no, one, and two alleles at a
candidate locus can be compared with these expectations. Linkage
would be suggested if the pairs of siblings, both of whom are
affected by a disease, share significantly more alleles IBD than
expected by chance. The best test for linkage to use depends on
the true mode of inheritance but in a wide range of situations the
most powerful test is the so-called mean test, in which the mean
number of alleles shared IBD is compared with the expected value
of 1.
Other
Groups of Relatives
Pair-wise
comparisons between relatives can easily be modified for types of
relative pair other than siblings. However, in studies that set
out to examine affected sibling pairs, additional affected
siblings are often recruited. Various methods have been proposed
to extend the pair-wise approach to sibships larger than two.
Selecting one pair at random or using only independent pairs means
discarding information, so using all possible pairs is preferred.
Linkage
Studies in Alcohol Dependence
Early interest
in the possibility of linkage between the MNSs blood group locus
and alcoholism was not subsequently replicated. Tanna et al (1988)
studied 30 polymorphic genetic markers, including eight blood
groups, in a group of 41 families. The LOD score and sib pair
linkage analysis revealed no significant evidence of linkage for
any of the blood groups studied. An inconsistent evidence for
linkage between esterase D and alcoholism was found by Tanna et
al. (1988) and Hill et al. (1988) using sib pair method. A weak
(non-significant) evidence of linkage with Haptoglobin has been
found (Tanna et al., 1979). Initial reports of linkage between
DRD2 locus and alcoholism were offset by later studies which
yielded consistently negative results (Bolos et al., 1990; Parsian
et al., 1991; Neiswanger et al., 1995; Edenberg et al., 1998).
a study of
paired siblings (sib-pairs) in Finland, alcohol dependence showed
weak evidence of linkage with a location on chromosome 6 and
significant evidence of linkage to the serotonin receptor 1B G861C
(Lappalainen, 1998). The field of linkage analysis is progressing
rapidly and efforts to clone and sequence the various
susceptibility and modifying genes are soon likely to be
successful.
CANDIDATE
GENE APPROACH
The candidate
gene approach requires the selection of genes that may have
relevance to the phenotype in question. These studies examine
candidate genes in people with or without dependence, to look for
differences between these groups.
Alcohol
Metabolising Enzymes
Alcohol
Dehydrogenase
The major
pathway of metabolism of ethanol involves oxidation by alcohol
dehydrogenase to acetaldehyde which is further oxidized by
aldehyde dehydrogenase to acetate. There are five different
classes of Alcohol dehydrogenase. Allelic variants of alcohol
dehydrogenase, which exists as a polygene family on chromosome 4p,
have been found that alter metabolic rates and influence risk for
alcoholism. Specifically, ADH1B*47his (previously ADH2-2) has been
shown to confer protection against alcoholism, presumably through
accumulation of acetaldehyde in the blood and a resultant
‘flushing response’ to alcohol consumption (Thomasson, 1994;
Maezawa, 1995; Nakamura, 1996; Chen, 1999; Cook et al., 2005).
However, ADH1B*47his is present at significant frequencies in only
Asian and Jewish populations, where its physiological and
protective role appears similar (Agarwal et al., 1981; Neumark et
al., 1997). Low frequencies of ADH1B*47his have been detected in
European, North African and Middle Eastern populations and, in
some cases, have been significantly associated with alcohol
dependence (Whitfeld, 1998; Borras et al., 2000; Osier et al.,
2002). Two ADH1C variants, ADH1CHaeIII allele 2 and ADH1C*349Ile,
have been associated with an increase in alcohol dependence.
Aldehyde
Dehydrogenase
Several
different aldehyde dehydrogenases exist. ALDH1 represents the
major cytosolic form and ALDH2, the major mitochondrial form.
ALDH2 plays the dominant role in the metabolism of acetaldehyde.
Allelic variants of ALDH2 located on chromosome 12 have been
strongly associated with risk of alcoholism. ALDH2*1 is a very
active form and is found in high frequency in most ethnic
populations while the ALDH2*2 has low activity and is found at
high frequency among Asians (Chinese, Japanese and Koreans). The
ALDH2*2 variant has been demonstrated to be associated with
substantial protection from alcohol in Japanese (Maezawa, 1995;
Nakamura, 1996; Okamoto, 2001), Han Chinese (Chen, 1999), Koreans
(Lee, 2001) and Asian Americans (Cook et al., 2005). Allelic
variations at the ALDH1A1 have been reported to be associated with
risk of alcoholism, though the associations are weak. The
ALDH1A1*2 allele has been reported to confer protection from the
development of alcoholism (Ehlers et al., 2004).
Cytochrome P4502E1
Cytochrome
P4502E1 is a hepatic enzyme that also metabolises ethanol to
acetaldehyde. In humans, the levels of CYP2E1 have been found to
vary by 15 fold. The 2e1 gene appears to be genetically
polymorphic and rare 2e1 allelic variants are assocaiated with
altered ethanol metabolism (Watanabe et al., 1994; Fairbrother,
1998; Mccarver et al., 1998; Hu, 1999; Sun, 1999; Yoshihara et
al., 2000a). Nicotine induces CYP2E1 which is consistent with the
findings from twin studies of cigarette smoking contributing to
the development of tolerance to the effects of ethanol and a
diminished sense of intoxication (Madden, 1995; Howard, 2001).
Genetic variants of CYP2E1 can alter the relative inducibility,
which may alter the impact on risk for alcohol dependence (Lucas,
1995; Ueno, 1996).
GABAergic
System
Inhibition of
GABAergic systems in the substantia nigra fine-tunes the amount of
dopamine released at the nucleus accumbens, an important site for
the effects of all psychoactive substances. GABA A receptor
blockers reduce some ethanol-induced behaviours, such as motor
impairment and sedation. The role of this receptor in alcohol
dependence is further supported by effective alleviation of
alcohol withdrawal symptoms by GABA A agonists (Parsian &
Cloninger, 1997). The association of various GABA receptors with
alcohol dependence has been studied. Associations have been found
between alcohol dependence and GABA A receptor α 3 (Parsian &
Cloninger, 1997), GABA A receptor α 6 (Iwata, Virkkunen & Goldman,
2000), GABA A receptor β1 (Parsian & Zhang, 1999), GABA A receptor
β3 (Noble, 1998).
Dopaminergic System
Because of its
importance in brain reward circuits, the mesolimbic dopaminergic
system has been implicated in the reinforcing effects of many
substances including ethanol (Uhl, 1998; Merlo Pich, Chiamulera &
Carboni, 1999; Comings & Blum, 2000). Accordingly, polymorphisms
of genes in the dopaminergic system are plausible functional
candidate genes for alcohol dependence. Studies over the past
decade have shown that alleles of the dopamine receptor system are
associated with alcohol dependence, novelty- seeking and several
personality traits. An association between polymorphism at
dopamine receptor 1 locus (DRD1) and alcohol use was shown in a
study by comings (1997), although not all studies confirm a role
for DRD1 in alcohol use (Hietala, 1997; Sander, 1995). Variants of
the dopamine receptor D2 (DRD2) gene have been associated with
dependence on alcohol and novelty-seeking but the results have not
been consistent (Noble, 1998; Noble , 2000). It is hypothesized
that the DRD2 gene is involved in reinforcement and that it may
not alter risk for alcohol dependence, but alcohol dependent
patients with the DRD2 A1 allele may have greater severity of
their disorder across a range of problem drinking indices (Connor,
2002). There are a few examples where the DRD2 genetic variation
has been examined in conjunction with other genes. Variants of
both the DRD2 and GABA A receptor subunit β3 genes have been
associated with risk for alcohol dependence; however, the risk for
alcohol dependence is more robust when these variants are combined
than when they are considered separately (Noble, 1998). Similarly,
DRD2 variant and ADH2 have been shown to have a stronger
association with risk for alcohol dependence when combined than
when alone (Amad, 2000). Some studies have shown an association
between alcohol dependence and DRD4 receptor variation (George,
1993; Hutchison, 2002), while others have not (Parsian, 1997;
Ishiguro, 2000; Albanese, 2001). Interestingly, the DRD4 variation
increases the risk for alcohol dependence in individuals with
protective ALDH2*2 variants, indicating the overriding of the
protective effects of ALDH2*2 by the DRD4 variant (Muramatsu,
1996).
metabolism with
alcohol depence have been the subject of many studies. There are
two distinct forms of MAO: MAO-A and MAO-B both are encoded in
genes on the X chromosome. Low platelet MAO activity has been
associated with alcohol dependence, making genetic variation in
these genes of interest. Variations in the MAO-A and MAO-B genes
differ between people with alcohol dependence and controls (Parsian,
1995). A variant of the MAO-A gene is associated with a risk for
alcohol dependence and lower age of onset of substance dependence
in males (Vanyukov, 1995). Significant associations of alcohol
dependence with MAO-A alleles were found among the Han Chinese
people, but not among aboriginal Taiwanese groups (Hsu, 1996). A
functional polymorphism in the MAO-A allele was identified and the
frequency was increased in males with antisocial personality
disorder and alcohol dependence, but not in those with alcohol
dependence alone or in controls (Samochowiec, 1999; Schmidt,
2000).
Serotonergic System
Genes in the
serotonin system are plausible candidates for association with
alcohol dependence because of the role of serotonin in mood
regulation, impulse control, appetite and aggression (Veenstra-VanderWeele
et al., 2000). While functional polymorphisms have been identified
in serotonin receptors and associated with relevant personality
dimensions (e.g. harm-avoidance, reward dependence), studies of
association of serotonin receptor variants with alcohol dependence
has revealed some positive but many negative findings (Yoshihara,
2000b). For people with alcohol dependence with inactive ALDH2,
but not for those with active ALDH2, an association with the 5HT1B
receptor variant has been found, suggesting its involvement in the
development of some types of alcohol dependence (Hasegawa, 2002).
A relatively small genetic variability in the serotonin receptor
gene (HTR2A) involved in the development of alcohol dependence has
been reported.(Nakamura, 1999; Hwu & Chen, 2000; Preuss, 2001;
Hasegawa, 2002).
Opioid
Receptors
Both ethanol and
opioids activate the mesolimbic dopamine reward system, and
genetic differences in the sensitivity of the endogenous opioid
system to alcohol may be an important factor in determining the
risk for the development of alcohol dependence or excessive
alcohol consumption (Gianoulakis, 2001). No consistent
associations have been identified.
Glutamate
Transporter
Glutamate-mediated excitatory pathways play an important role in
the pathogenesis of alcohol dependence. The astroglial glutamate
transporter EAAT2 confers vulnerability to alcohol dependence;
however, no association of a polymorphism with alcohol dependence,
or with alcohol dependence with severe physiological withdrawal
symptoms, or alcohol dependence with antisocial behaviour, was
observed (Sander, 2000).
LABORATORY MODELS OF ALCOHOLISM
Tissue and
animal models have been used more often in the field of alcohol
genetics than in any other area of psychiatric genetics. The
wealth of data obtained through these studies has proven useful
for the discovery of molecular targets of alcohol action as well
as for the characterization of genetic and environmental factors
that influence alcohol’s neural actions.
The
Direct Approach: Pharmacological Methods
Heterologous
expressions of molecules allow to examine the effects of ethanol
on the function of proteins expressed in a cellular context free
of many neural proteins. Heterologous expressions combined with
examination of the function of the same protein in neurons have
been used to characterize ethanol sensitivity of a variety of
proteins including neurotransmitter receptors, ion channels and
neurotransmitter transporters (Diamond et al., 1997; Lovinger et
al., 1997).
Animal
Models
Animal models
have a great advantage in that the history of exposure to alcohol
and most other environmental factors can be controlled and
manipulated allowing the use of powerful statistical analysis. In
addition, genetic studies in animals allow for specific breeding
studies that cannot be done with humans, and the results of these
studies can be obtained in a relatively short period of time. The
various animal models used in alcohol research are:
-
Selectively
bred strains
-
Inbred strains
-
Transgenic
strains
-
Knockout
strains
Results
From Animal Studies
Several genes
that influence acute alcohol sensitivity and tolerance have been
identified in mutant Drosophila melanogaster fruit flies.
Intracellular signaling pathways involving cAMP and protein kinase
A, as well as transcription associated proteins are beginning to
be implicated (Wolf et al., 2003; Scholz et al., 2005). The LUSH
Drosophila mutant, lacking an olfactory protein involved in
detecting ethanol, provides one of the best models for direct
ethanol binding to a protein. Flies lacking the LUSH protein do
not avoid alcohol in contrast to the wild flies.
Quantitative Trait Locus
Substance
dependence is considered to be a quantitative trait in which a
combined action of multiple alleles leads to predisposition to
dependence. This approach does not assume any prior knowledge of
genes involved in substance-related disorders, and seeks to find
them based on related phenotypes. QTL analysis is analogous to
linkage studies in humans. As an example, inbred strains of mice
that are genetically identical can be crossed with other inbred
strains, and the absence or presence of a mapped sequence of DNA
(marker) in each strain can be correlated with a quantitative
measure of a phenotype (e.g. amount of alcohol self administered).
Strong correlation of a phenotype with the presence of a genetic
marker suggests that the genetic sequence in the proximity of this
marker is involved in the regulation of this measure. Since the
location of the marker sequence is mapped on mouse chromosomes,
such analysis allows researchers to create genetic maps of loci
important for the traits (Gora-Maslak, 1991; Grisel, 2000).
SUMMARY
AND CONCLUSION
Family, twin and
adoption studies provide strong evidence for a significant, but
not exclusive, genetic contribution to the development of alcohol
use and dependence. Twin studies consistently show higher
monozygotic than dizygotic concordance for alcohol dependence,
indicating a genetic effect. The genetic association studies have
identified potential markers like personality traits,
neurophysiological markers (P300, EEG changes) for alcohol
dependence. Linkage studies using powerful statistical tools have
implicated chromosomes 1, 7, 2 and 4 in alcohol dependence.
Polymorphisms at various loci like alcohol metabolizing enzymes (ADH,
ALDH), GABAergic, Dopaminergic and Serotonergic systems have been
identified as candidate genes influencing the risk of alcohol
dependence.
REFERENCES
|
