© Kamla-Raj 2008
Int J Hum Genet, 8(1-2): 181-197 (2008)
Genetics of Alcohol Use in Humans: An Overview
Jayanta Kumar Nayak1, B. N. Sarkar1, P. K. Das2 and V. R. Rao1
1. Anthropological Survey of India, Kolkata, India,
2. Department of Anthropology, Utkal University, Bhubaneswar, India
KEYWORDS Family studies; twin studies; adoptee; candidate genes; case-control studies; linkage studies; SNPs;
GABA; Dopamine system; CYP2E1; Alcohol dehydrogenase
ABSTRACT Alcoholism is an extremely complex disease for which no generally accepted definition exists. There is
a complex interaction between the socio-environmental context, the individual at risk, and the availability of
alcohol. The result of family, twin and adoption studies suggest a significant genetic predisposition to the disease.
Identifying novel genetic risk factors for common diseases is a global challenge in the post genomic era. Recent
molecular genetic research into the causes of alcoholism has drawn attention to the potential role of alcohol and
acetaldehyde metabolizing enzymes. Functional polymorphisms have been observed at various genes encoding these
enzyme proteins that act as one of the biological determinants significantly influencing drinking behavior and the
development of alcoholism and alcohol-induced organ damage. Most ethanol elimination occurs by alcohol
dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) systems via oxidation of ethanol to acetaldehyde and
acetic acid. However, the legacy of alcoholism among certain ethnic groups suggests that genetic factors can increase
an individual’s vulnerability for this disease. An association study in patient cohorts and controls, from large populations
involving whole genome scans, is the preferred approach for complex traits. To understand the molecular epidemiology
and role of cofactors in alcoholism the standard phenotype-genotype correlation may be a useful tool. The present
paper reviews various aspects of alcoholism including both the behavioural and molecular etiologies.
INTRODUCTION
A necessary condition for the development
of alcoholism is the availability of alcohol.
Humans have probably been alcohol users from
the pre-historical times. After the introduction of
agriculture (between 10,000 to 5,000 B.C.),
systematic alcohol production became possible
by fermentation of barley, honey, milk and grapes
by various populations. At that time, alcohol was
mainly used as a food because of its vitamin and
mineral content. The preserving qualities of
alcoholic solutions enabled long-term storage of
food, an important property in the early stages
of civilization. Presumably, an essential
motivation for utilizing the psychotropic effects
of alcohol was to cope with existential fear, which
certainly was omnipresent in ‘primitive’ societies.
This might also have been the cause for early
integration of alcohol use in religious rites.
Invention of the method of distillation of alcohol
around 1000 AD made the production of
concentrated alcoholic beverages possible.
Address for correspondence: Dr V. R. Rao,
Director-in-Charge, Anthropological Survey of India,
Government of India, 27, Jawaharlal Nehru Road,
Kolkata 700 016, West Bengal, India
Telephone: 91 33 2286 1796, 2286 1781
Fax: 91 33 2286 1799
E-mail: drraovr@yahoo.com
During the thirteenth and fourteenth centuries
this technique spread over Europe and paved
the way for alcohol abuse and the development
of alcoholism.
Alcoholism is thought to be a multifactorial
disease with complex mode of inheritance in
addition to the influence of psychological and
social factors (WHO 1993). Many family, adoptee
and twin-based studies in relation to alcoholism
revealed hereditary factors as important determinants of alcoholism. Genetics and pharmacokinetics of alcohol determine variations of
alcohol metabolism among alcohol users and
therefore, influence alcohol drinking behavior and
risk of alcoholism. As per the definition proposed
by National Council on Alcoholism and Drug
Dependence (NACDD) and the American Society
of Addiction Medicine (ASAM), alcoholism is a
primary, chronic disease with genetic, psychosocial, and environmental factors influencing its
development and manifestations. It is well
recognized that the primary alcohol, ethanol, can
be absorbed unchanged along the whole length
of the digestive tract, that absorption takes place
rapidly from the stomach (about 20%), and most
rapidly from the small gut (about 80%). The rate
of absorption after drinking is affected by several
factors, for example the volume, concentration
(10 – 20% solutions are most rapidly absorbed)
and nature of the alcoholic drink, the presence or
182
JAYANTA KUMAR NAYAK, B. N. SARKAR, P. K. DAS AND V. R. RAO
absence of food in the stomach, rate of gastric
emptying, pylorospasm, permeability of the
gastric and intestinal tissues, individual
variations. After absorption into the blood stream,
alcohol is distributed quickly throughout the total
body water (Pawan 1972). The disease is often
progressive and fatal. It affects so many vital
organs of our body like liver and heart. It is
characterized by continuous or periodic impaired
control over drinking, pre-occupation with the drug
alcohol, use of alcohol despite adverse
consequences, and distortions in thinking, most
notably denial. Alcoholism is a common
etiologically complex disorder (Kessler et al. 1994)
involving complex gene-with-gene and gene with
environmental interactions (Chen et al. 1999). The
genes underlying human alcohol metabolism
provides a rare example of how allelic variations
contribute to a complex disease through
intervening physiology and behavior. Ethanol
elimination occurs mostly by alcohol dehydrogenase (ADH) (Eriksson et al. 2001) and aldehyde
dehydrogenase (ALDH) systems via oxidation of
ethanol to acetaldehyde and acetic acid (Bosron
and Li 1986). Most of the metabolism of alcohol
and aldehyde is carried out in the liver, although
extra-hepatic metabolism has also been
demonstrated in the stomach, gut and upper aerodigestive tract (Wight and Ogden, 1998) including
some potential metabolism due to oral microflora
in the oral cavity (Homann et al. 1997, 2000 and
Muto et al. 2000). Pawan (1972) clearly sketched
the pathways of alcohol metabolism in man (Fig.
1). Genetic variation in alcoholic liability can be
Fig. 1. Pathways of alcohol (ethanol) metabolism in man. ADH: Alcohol Dehydrogenase;
MEOS: Microsomal Ethanol Oxidizing System; SER, Smooth Endoplasmic Reticulum.
GENETICS OF ALCOHOL USE
used to investigate some of the underlying
mechanisms, which may aid in identifying
individuals at increased risk and provide
information about systems involved in the health
consequences of alcohol dependence. In addition,
genetic variations are being investigated with
respect to treatment with the goal of personalizing
treatment approaches, hence minimizing adverse
reactions and optimally identifying novel
treatment approaches. Findings from the human
genome project, and large investments in
biotechnology, have strengthened the belief of
scientists and the public in realizing this goal in
the near future (Weiland 2000). Genetic studies
utilizing twin and family approaches have clearly
shown considerable role of genetics in alcohol
dependence, albeit only few gene variants have
been identified unambiguously (Stoltenberg and
Burmeister 2000 and Nestler 2000). Risk for
alcohol dependence is likely to be the result of a
large number of genes, each contributing a small
fraction to the overall risk. The problem of genetic
heterogeneity has been overcome in other areas
of medicine and thus we are optimistic that this
will also be true for investigations of alcohol
dependence (Stoltenberg and Burmeister 2000;
Wahlsten 1999; and Crabbe 2002).
TYPOLOGY OF ALCOHOLISM
Alcohol addiction is a common, complex
disorder; many other traits that are associated
with the risk for alcoholism also cluster in families
and have genetic underpinnings. Addictions are
psychiatric disorders that are associated with
maladaptive and destructive behaviors, and that
have in common the persistent, compulsive and
uncontrolled use of alcohols or an activity.
Addictive agents induce adaptive changes in
brain function. These changes are the basis for
tolerance and for the establishment of craving,
withdrawal and affective disturbance, which
persist long after consumption ceases (Roberts
and Koob 1997). This self-maintaining and
progressive neurobiology of addictions makes
them chronic and relapsing disorders.
The alcohol addiction is a worldwide publichealth crisis, and exerts corrosive effects at family
and societal levels, leading even to the narcopolitical and narco-economic domination of
countries and religions. World Health
Organization in the year 1983 declared Alcohol
related problems as major health problems which
183
are responsible for 3.5% of disability adjusted
life years (DALYs) lost globally (Murray and
Lopez 1996). Alcohol affects all aspects of human
life and causes hazards to health and welfare.
Heavy alcohol reduces life expectancy by 10 –
12 years besides affecting productivity in
developed and developing nations (Grant 1985).
Alcohol as a disease agent causes acute and
chronic intoxication, cirrhosis of liver, toxic
psychosis, gastritis, pancreatitis, cardiac
myopathy and peripheral neuropathy. Also
mounting is the evidence that it is related to
cancers of mouth, pharynx, larynx and
oesophagus. Alcohol is an important etiological
factor in suicide, accidents, social and family
disorganization, crime and loss of productivity.
Increasing percentage of young people have
started drinking alcohol in increased frequency
and quantity thus constituting serious hazards
to health, welfare and life (WHO, 1980). The World
Health Organization (WHO) estimated that there
are two billion alcohol users (WHO-Global Status
Report on alcohol, 2004: http://www.who.int/sub
stance_abuse/publications/en/global_status_
report_2004_overview.pdf). Drinking prevalence,
mortality and morbidity from alcohol use in
South-East Asia Region and some parts of India
is furnished in Table 1. Traits, or phenotypes,
include a person’s response to alcohol, the
maximum amount of alcohol a person consumes
on a single occasion and biological measurements,
such as brain electro-physiological measures.
Researchers rely on personality questionnaires
to determine the alcoholic category of the subjects.
Seven frequently used questionnaires are: the
Minnesote Multiphasic Personality Inventory
(MMPI), the MaC Andrew Alcoholism Scale
(MAC), the Eysenck Personality Questionnaire
(EPQ), the Tri-dimensional Personality
Questionnaire (TPQ), the Connecticut Typology
Questionnaire (CTQ), the Alcohol Use Disorders
Identification Test (AUDIT) and the Michigan
Alcoholism Screening Test (MAST).
Alcoholism is categorized into three types:
type-I, II, and III. Cloninger (1990) distinguished
type-I of alcoholism (low novelty seeking, high
harm avoidance, high reward dependence) from
type-II (male-limited) alcoholism (high novelty
seeking, low harm avoidance, low reward
dependence). Hill (1992) proposed a third type
of alcoholism. Like type-II alcoholism, it is
significantly influenced by genetic factors, but
is not associated with any abnormal behavior.
JAYANTA KUMAR NAYAK, B. N. SARKAR, P. K. DAS AND V. R. RAO
184
India
16.7% 58.3%
India
Arunachal Pradesh
50.2%
Goa
49%
Andhra Pradesh
21%
Rural Punjab
74%
Northern India
60%
Western India
24.7%
Southern India
26%-50%
Bangladesh
Indonesia
Myanmar
Nepal
Sri Lanka
Thailand
1% 2%
11.5 % 16% liver cirrhosis,
1.43% cancer,
25% accident,
10% suicide
3%
Delhi
26%
Balinese and
Jakarta populations
40%
0.2%
2.7%
10%
10%
25%-34%
31.4%
Genetic Epidemiology of Alcoholism
1) Family Studies: Alcoholism was regarded
as a distinct disease that may be transmitted from
generation to generation (Dawson and Archer
1992). A familial association could result from
cultural factors tending to encourage heavy
drinking in family members. On the other hand,
drinking may be discouraged in some families for
religious, cultural or climatic grounds while in
other families constraints on heavy drinking may
be virtually non-existent. So “familial” does not
necessarily mean “hereditary”. A critical review
of studies of the familial incidence of alcoholism
summarized 39 investigations published in
English that comprised family data on 6,251
alcoholics and 4,083 non-alcoholics (Cotton
1979). They clearly showed that regardless of
the nature of the population of non-alcoholics
studied, an alcoholic is more likely to have a
mother, father or a distant relative who is an
alcoholic. When lifetime prevalence of alcoholism
in relatives of alcoholics was compared to that in
the general population, a four-fold increased risk
20%
~10%
~8%
6% 0.12%
liver cirrhosis
0.6 Cancer
4.7%
Reference
Morbidity due to
alcohol consumption
Mortality
Alcohol
dependency rate
Prevalence rate
Parts of country
or population
Country
Table 1: Drinking prevalence, mortality and morbidity from alcohol use in South-East Asia Region and
some parts of India.
Saxena 2004
WHO 2004
Deswal et al. 2006
Dhupadale et al. 2006
WHO 2004
Deb and Jindal 1975
Varma et al. 1980
Sundaram et al. 1984
Chakravarthy 1990 and
Bang and Bang 1991
Mohan et al. 1992
WHO 2004
WHO 2004
WHO 2004
WHO 2004
WHO 2004
WHO 2004
in first-degree relatives and a two-fold increased
risk in second-degree relatives were observed.
Higher family incidence of alcohol use and abuse
does not necessarily reflect a genetic determination of alcoholism. Heritable familial
attributes as well as similarities in social
environment of family members also appear to
play a role in familial transmission of alcoholism.
2) Twin Studies: The twin study paradigm is
a powerful method to understand complex and
heterogeneous trait disorders. Twin studies are
based on the fact that monozygotic twins (MZ)
share identical genetic material, while dizygotic
twins (DZ) share the same degree of genetic
similarity as non-twin siblings. If genetic effects
are present then monozygotic twins should be
more alike than dizygotic twins allowing an
estimation of the genetic contribution. Differences
between identical twins would presumably reflect
environmental influences while differences
between non-identical twins may be due to
heredity, environment or both (Agarwal 2001).
Therefore, if alcoholism has a hereditary basis,
MZ twin pairs should tend to be more similar in
GENETICS OF ALCOHOL USE
their drinking behavior and alcohol-related
problems than DZ twin pairs (Pickens et al. 1991).
It has been clearly demonstrated that both genetic
and environmental factors influence alcohol
dependence (Heath et al. 1999). These studies
examine traits that are not inherited in a Mendelian
fashion, but nevertheless show non-random
familial distributions indicating genetic
contributions (Vanyukov and Tarter 2000; and
Jacob et al. 2001). Twin studies strongly indicate
the presence of genetic risk factors for multiple
aspects of alcohol dependence including
initiation, contribution, amount consumed and
cessation. In addition to estimating genetic
liability, these studies provide further information
about environmental contributions, identifying
that which is shared and that which is non-shared.
3) Adoption Studies: A systematic approach
to separate “nature” from “nurture” is to study
individuals separated from their biological
relatives soon after birth and raised by nonrelated foster parents and to compare them with
respect to characteristics of alcohol abuse with
both their biological and adoptive parents. It is
based upon the premise that the genetic trait
present in the affected biological parent will still
be expressed in adoptees, regardless of the
genotypic status and environmental circumstances of the foster parents. In studies of intact
families, the effects of genetic and common
environment are not separable. Adoption studies
separate these effects because adoptees receive
their genetic heritage from one set of parents
and their rearing environment from another set.
The degree to which adoptees resemble their
biological relatives is a direct measure of genetic
influence, while the degree to which they resemble
their adoptive relatives is a measure of the influence
of family environment. Adoption studies are
capable of delimiting almost completely genetic
and environmental influences on the variation in
the liability to a disorder (except contributions of
ante- and early postnatal environmental factors)
(Heath et al. 1998). Extensive adoption studies
conducted in Denmark and Sweden have provided
substantial evidence that alcoholism is genetically
influenced, and that there are distinct patterns of
alcoholism with different genetic and environmental causes (Goodwin et al. 1974; Cloninger et
al. 1981; Bohman et al. 1987). When the adopted
away sons of alcoholic parents were compared to
their siblings raised by the alcoholic biological
parent, a remarkably similar rate of alcoholism was
185
noted in both groups. Subsequent adoption
studies from other countries have clearly shown
that children born to alcoholic parents but adopted
away during infancy were at greater risk for
alcoholism than adopted-away children born to
nonalcoholic parents (Sigvardsson et al. 1996).
4) Gender Differences in Transmission of
Alcoholism: There is consistent evidence that
relatives of women treated for alcoholism have
higher risk for alcoholism than relatives of treated
males (Prescott and Kendler 1999). Twin studies
provide estimates of heritability of the liability to
alcoholism in the range of 51% - 65% in females
and 48% - 73% in males (Johnson et al. 1998;
Prescott et al. 1999; Prescott and Kendler 1999;
Kendler et al. 1994). Early studies found that
genetic influences on alcoholism risk were clear
in men but were less certain in women (McGue et
al. 1992). However, subsequent studies, which
explicitly addressed gender difference, found
evidence for 64% heritability for women and men,
even when data were weighted to adjust for
selective attrition (Prescott et al. 1999). In
addition, it has been noted that the genetic
sources of vulnerability to alcoholism are partially,
but not completely overlapping in men and
women (Prescott et al. 1999). Heritability
estimates were 66% in women and 42% - 75% in
men for frequency of alcohol consumption, and
57% in women and 24% - 61% in men for average
quantity consumed when drinking. Men (but not
women) who are at increased genetic risk of
alcohol dependence exhibited reduced alcohol
sensitivity (Heath et al. 1999). This suggests that
women in treatment tend to have higher liability
than their male counterparts. Some evidence from
molecular genetic studies supports the existence
of sex-specific loci (Paterson and Petronis 1999),
and a definitive answer to this issue will probably
come from molecular rather than epidemiological
studies.
5) Mode of Inheritance: Although adoption
and twin studies have proven useful in
answering the question of nature versus nurture,
the mode of inheritance of alcoholism is still an
unresolved issue. Heritability estimates vary
somewhat depending on diagnostic criteria, with
the highest heritability estimates obtained for
Feighner Probable alcoholism (63%), Cloninger
type II alcoholism (54%), and DSM – III alcohol
dependence (52%) (Van den Bree et al. 1998).
Certain diagnostic systems are more sensitive
for detecting genetic influences and may be more
186
JAYANTA KUMAR NAYAK, B. N. SARKAR, P. K. DAS AND V. R. RAO
appropriate for studies attempting to find genes
for alcoholism (Van den Bree et al. 1998). While
environmental effects explain most of the
variation in initiation of drinking, genetic factors
are more important in explaining frequency of
intoxication (Viken et al. 1999). This study also
observed similar genetic risk for males and
females in the initiation of drinking, but suggested
that either different genetic factors or different
shared environmental factors were influencing
the two sexes (Viken et al. 1999). It was also noted
that specific genes are influencing the heritability
for alcohol withdrawal syndrome (Schuckit 2000).
None of the evidence hitherto put forward
suggests that susceptibility to alcoholism is
inherited via a simple Mendelian dominant/
recessive or sex-linked transmission. Even if the
inheritance of certain biological factors involved
in alcoholism is assumed to be Mendelian, the
effect of these factors on the development of
complex disorders may still not fit a simple genetic
model. A substantial degree of etiological
heterogeneity in the alcoholism phenotype
results in the ultimate manifestation of the
disorder dependent on poorly understood geneenvironment interactions.
6) Characterization of High Risk and Low
Risk Individuals: It is not clear if genetic risk is
a major factor in initiation of drinking or drinking
during adolescence (Stallings et al. 1999). In the
past years, a number of investigators have tried,
in prospective studies, to identify possible trait
markers by studying young men and women at
high risk for the future development of alcoholism
based on their family history of this disorder.
Having an alcoholic biological father is the best
single predictor of future alcoholism in male
offspring. One method of determining whether
there are neuro-psychological deficits prior to
the onset of alcoholism is to study children who
are at risk for becoming alcoholic. In a typical
prospective study young men and women at high
risk for the future development of alcoholism are
divided into Family History Positive (FHP) group,
(who report an alcoholic parent or siblings) and
Family History Negative (FHN) group (men and
women who report no close alcoholic relative).
The subjects are matched for demography and
alcohol drinking history.
Gene Identification
Family, twin and adoption studies have
indicated that alcoholism has a strong genetic
component (Reich et al. 1999). In searching for
genes that contribute to alcoholism risk, several
approaches like a) polymorphic markers, b) linkage
mapping and c) the candidate gene approach,
may be utilized in order to identify the genetic
loci underlying alcoholism susceptibility.
a) Polymorphic Markers: As part of the
Human Genome Project, a large number of
markers called micro-satellites have been mapped
on the human genome. These markers are short
stretches of two to four nucleotides and are
repeated several times. These markers are highly
polymorphic and transmitted across successive
generations of a family. To find chromosomal
regions and genes influencing alcoholism,
researchers look for certain micro-satellite markers
that may co-inherit with the disease across
multiple generations.
b) Identifying Chromosomal Locations of
Interest (Linkage Studies): Linkage mapping,
also called positional cloning, is the process of
systematically scanning the entire DNA contents
(i.e., the genomes) of various members of families
affected by the disorder using regularly spaced,
highly variable (i.e., polymorphic) DNA segments
whose exact position is known (i.e., genetic
markers). Using those families, investigators can
identify genetic regions associated or “in linkage”
with the disease by observing that affected family
members share certain marker variants (i.e., alleles)
located in those regions more frequently than
would be expected by chance. These regions can
then be isolated, or cloned, for further analysis
and characterization of the responsible genes.
Linkage mapping techniques have already
resulted in the identification of several potential
DNA regions that may contain susceptibility
genes for alcoholism (Reich et al. 1999). The
primary advantage of linkage mapping is that
investigators need no prior knowledge of the
physiology or biology underlying the disorder
being studied, which is important for complex
disorders like alcoholism.
A very close location of the alcohol dehydrogenase (ADH) genes was identified on
chromosome 4q (Long et al. 1998; Reich et al.
1998; Saccone et al. 2000); the ADH genes have
been associated with protective effects in Asians
(Reich et al. 1998). Evidence for linkage to
chromosome 4q in both a South-Western
American Indian tribe and in Americans of
European descent strongly supports a role for
GENETICS OF ALCOHOL USE
genes in this location in influencing risk for
alcohol dependence. Linkage to chromosome 4p
has also been seen near the b1 GABA receptor
gene (Long et al. 1998). In a Finnish sib-pairs
study (Lappalainen et al. 1998), antisocial
alcoholism showed weak evidence of linkage with
a location on chromosome 6 and significant
evidence of linkage to the Serotonin receptor 1B
G861C. In a South-Western American Indian tribe,
significant sib-pair linkage to chromosome 6 was
also seen (Lappalainen et al. 1998). Multipoint
methods provided the strongest suggestions of
linkage with susceptibility loci for alcohol
dependence on chromosomes 1 and 7, and more
modest evidence for a locus on chromosome 2
(Reich et al. 1998). The best evidence for linkage
has been seen on chromosome 11p (D11S1984),
in close proximity to the DRD4 dopamine receptor
and tyrosine hydroxylase (TH) genes (Long et
al. 1998). Results from numerous studies
analyzing sib-pair linkage for alcoholism are published in an issue of Genetic Epidemiology,1999;
17 Supplement 1; many identified sites on
chromosome 10q, which may be related to genetic
variation in the CYP2E1 gene (10q24.3) that can
inactivate ethanol.
To understand genetic contributions to
alcohol drinking behaviors many aspects of the
behavior need to be assessed as independent
endo-phenotypes since different gene variants
may affect these various behavioral aspects of
alcohol dependence differentially. Large studies
of multiple gene variants and clearly defined
phenotypes will lead to better understanding of
the specific genes and the mechanisms involved.
Whereas the linkage mapping approach is an
unbiased search of the entire genome without
any preconceptions about the role of a certain
gene, the candidate gene approach allows
researchers to investigate the validity of an
“educated guess” about the genetic basis of a
disorder. 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. The major difficulty with this approach is
that in order to choose a potential candidate gene,
researchers must have an understanding of the
mechanisms underlying the disease (i.e., disease
pathophysiology). In contrast with linkage
mapping studies, however, studies of candidate
genes do not require large families with both
affected and unaffected members, but can be
187
performed with unrelated cases and control
subjects or with small families (e.g., a proband
and parents). Further more, candidate gene
studies are better suited for detecting genes
underlying common and more complex diseases
where the risk associated with any given
candidate gene is relatively small (Collins et al.
1997; Risch and Merikangas 1996).
c) Candidate Genes Involved in Alcohol
Dependence: Candidate gene studies are better
suited for detecting genes underlying common
and more complex diseases where the risk
associated with any given candidate gene is
relatively small. Association studies with
candidate genes remain conceptually the
simplest of genetic studies where specific
biological hypotheses can be tested in a design
similar to a classical case-control study (Kwon
and Goate 2000; Stoltenberg and Burmeister
2000). Candidate gene studies often test one
gene, and often one allele, at a time. More
recently, multiallelic / multigenic interactions have
been examined by testing for the effect of two
markers and their statistical interaction (Longmate
2001). This new approach makes particular sense
when the genes / proteins studied are known to
belong to interacting systems and when the
phenotype, such as dependence, is thought to be
oligogenic (e.g., dopamine receptors and dopamine
biosynthetic and degradative enzymes). As novel
techniques develop (e.g., single nucleotide
polymorphisms (SNPs) scored on DNA chips),
extremely large datasets will be required for
sufficient statistical power, but the findings will
be much more informative than testing single alleles
and single genes (Stoltenberg and Burmeister
2000). Currently the best candidate allelic variants
(as everyone has the same genes) fulfill at least
two criteria: a) the variant has been shown to alter
function or regulation, and b) the variant has a
good likelihood of being biologically relevant
(Stoltenberg and Burmeister 2000) (Table 2).
GABA: The principal inhibitory neurotransmitter in the brain is γ-aminobutyric acid
(GABAA). Binding of GABA to ionotropic GABAA
receptors causes the opening of an integral
chlorideion channel, thus changing the membrane
potential of neurons and thereby exerting a crucial
role in regulating brain excitability. GABAA
receptors are sensitive to ethanol and are believed
to mediate many of its effects, including anxiolysis,
sedation, motor in-coordination, tolerance, and
dependence (Grobin et al. 1998).
JAYANTA KUMAR NAYAK, B. N. SARKAR, P. K. DAS AND V. R. RAO
188
Table 2: Different genes implicated in alcoholism.
Gene
Variant(s)
Phenotype
Reference
ADH2 (ADH1B)
Arg47His
Protects from alcoholism
Chen et al. 1999;
Osier et al. 2002;
ADH3 (ADH1C)
ALDH2
Ile349Val
ALDH2*2
CYP2E1
5’ variant *1D repeat
polymorphism
Dra 1-C
c2
repeat polymorphism
repeat polymorphism
P385S
GABAAreceptor R1
S489 exon 7, exon 11
Dopamine receptor
(DR) D1
DRD2
DRD3
DRD4
Dopamine transporter
A48G
Protects from alcoholism
Protects from alcoholism
Decreases amount of
alcohol consumed
Increased risk for
alcoholism
Alcoholism
Alcoholic liver disease
Alcoholism
Alcoholism
Alcoholism
Alcoholism and Type II
Alcohol dependence
Severe Alcoholism
Alcohol dependence
with antisocial
personality
Alcoholism and
personality disorders
Alcohol Use
A1
S9G
VNTR in exon3
SLC6A3-93’UTR G2319A
Alcoholism
Alcoholic delirium
Alcoholism
Alcoholism
Alcoholism
GABAAreceptorá1
GABAAreceptorá3
GABAAreceptorá6
GABAAreceptorβ1
GABAAreceptorβ2
GABAAreceptorβ3
GABAAreceptorγ2
BanI RFLP
G1 allele
NciI RFLP
GABAA receptors are pentameric assemblies
of subunits; 17 mammalian subunits are know,
which are classified into α (1-6), β (1-3), γ (1-3), δ,
ε, and ρ (1-3) types. In addition, the β2, β3 and γ2
varieties occur in alternatively spiced forms.
Most GABA receptors contain α, β and γ
subunits (Mehta and Ticku 1992). Most of the
genes encoding human GABA A receptor
subunits are organized in clusters. GABRA2,,
GABRA4, GABRB1 and GABRG1 on chromosome
4p12 (Russek 1999). GABRA5, GABRB3 and
GABRG3 encoding the α5, β3 and γ3 subunits,
are on chromosome 15q11.2-q12 (Sinnett et al.
1993). The findings of Wallner et al. (2003)
demonstrate that high alcohol sensitivity of
GABAA receptors requires the co-expression of
either δ or the β3 subunit with β2, markedly
decreases the alcohol sensitivities of GABAA
receptors. The δ subunit may play an important
role in determining the enhancing actions of
modulatory agents other than alcohol.
There have been several studies of the
potential association of genes encoding GABAA
receptor subunits with alcoholism. Parsian and
Cloninger (1997) examined microsatellite
polymorphisms in GABRA1 and GABRA3 in a
Okamoto et al. 2001;
Nakamura et al. 1996;
Maczawa et al. 1995;
Chen et al. 1999;
Lee et al. 2001.Sun et al.
1999; Howard et al. 2002.
Parsian and Cloninger 1997
Sander et al. 1999
Parsian and Zhang 1999
Sander et al. 1999
Noble et al. 1998
Loh et al. 2000
Sander et al. 1999
Sander et al. 1995;
Hietala et al. 1997
Hietala et al. 1997
Sander et al. 1995
Hutchison et al. 2002
Pastorelli et al. 2001
Ueno et al. 1999
sample of alcoholics and controls of Western
European descent, and found no significant
association with alcoholism or with type I and
type II subunits of alcoholics. Parsian and Zhang
(1999) found association between a microsatellite
polymorphism in the GABRB1 gene and
alcoholism in the same population. There have
been several papers examining the gene cluster
on chromosome 5. Sander et al. (1999) examined
single nucleotide polymorphisms in GABRA6,
GABRB2 and GABRG2 in 349 German alcoholics
and 182 ethnically matched controls, and found
no significant association with alcohol
dependence or withdrawal or familial alcoholism.
Loh et al. (2000) carried out association studies
of five polymorphisms in GABA subunit genes
on chromosome 5 in Japanese, and found no
association of any with alcoholism or alcoholism
without concurrent antisocial personality
disorder, but a marginal association of one
polymorphism in GABRG2 for alcoholism with
antisocial personality disorder. In a Scottish
population, Loh et al. (1999) reported association
between alcoholism and polymorphisms in
GABRA6 and GABRB2.
Dopamine System: Polymorphisms of genes
GENETICS OF ALCOHOL USE
in the dopamine system are plausible functional
candidate genes for alcohol dependence. An
association was made between a 5’ polymorphism
(A48G) and alcohol use, but not all studies
conform a role for Dopamine receptor D1 (DRD1)
in alcohol use (Sander et al. 1995; Hietala et al.
1997). The results for both the DRD1 and DRD2
genes, which have opposing effects on cyclic
AMP, were consistent with negative and positive
heterosis, respectively. These results suggest a
role for genetic variants of the DRD1 gene in
some addictive behaviors, and suggest an
interaction of genetic variants at the DRD1 and
DRD2 genes.
The DRD2 minor A1 allele was, a decade ago,
first reported to have association with severe
alcoholism (Hietala et al. 1997; Dobashi et al.
1997). Although many studies have not found
an association with dependence, some
association with severity of drinking may exist
(Pastorelli et al. 2001; Sander et al. 1995; Noble et
al. 2000). However, no association was found
between the A1 polymorphism and age at onset
of alcohol dependence (Anghelescu et al. 2001).
In family association studies no evidence for a
role of DRD2 was found (Edenberg et al. 1998;
Goldman et al. 1997). In summary, DRD2 may not
alter risk for alcohol dependence, but alcoholdependent patients with the DRD2 A1 allele may
have greater severity of their disorder across a
range of the drinking problem indices (Connor et
al. 2002). There are few examples where the DRD2
genetic variation has been examined in
conjunction with other genes. For example
variants of both the DRD2 and GABAA receptor
subunit genes were associated with risk for
alcoholism; however, when combined, the risk
for alcoholism was more robust than when these
variants were considered separately (Noble et al.
1998). Likewise there was a stronger association
of a DRD2 and ADH2 variants together on risk
for alcoholism than either gene variant alone
(Amad et al. 2000).
Reddy et al. (2007) studied SNPs at the two
sites of NPY and DRD2-Taq1 loci among 28
hierarchical caste and tribal groups of India and
try to correlate with their traditionally known
average drinking behaviors. Assuming that NPYC confers protection against alcoholism and
DRD2-TaqA1 allele is susceptible to alcoholism,
they concluded that although the trend of allele
frequency in the hierarchical groups suggests
an association with their drinking behaviors, case
189
control studies are required to infer the nature of
this association. As these two alleles at NPY and
DRD2-Taq1 show opposing trends of average
allele frequency with hierarchical positions of the
studied populations the authors have tested
further for possible co-adaptation of these alleles
but could not find convincing evidence.
Studies of DRD3 and alcoholism demonstrated no significant association (Parsian et al.
1997; Henderson et al. 2000), regardless of
sensation seeking score, addictive or psychiatric
co morbidity, alcoholism typology, and clinical
specifics of alcoholism. Even when tested in
alcoholics in the presence of active or inactive
ALDH2, no association with DRD3 was observed
(Higuchi et al. 1996). One study found a
significantly increased allele frequency of DRD3
S9 in alcohol-dependent individuals with delirium
suggesting it may confer genetic susceptibility
to some aspects of the effects of alcohol (Sander
et al. 1995).
Van Tol et al. (1992) described the existence
of at least 3 polymorphic variations in the coding
sequence of the human D4 receptor. A 48-bp
sequence in the putative third cytoplasmic loop
of the receptor was found to exist either as a
direct repeat sequence (D4.2), as a 4-fold repeat
(D4.4), or as a 7-fold repeat (D4.7). Two other
variant alleles were detected. Expression of the
cDNA for the 3 cloned receptor variants showed
different properties for the long form (D4.7) as
contrasted with the shorter forms with respect to
clozapine and spiperone binding. These
variations among humans may underlie individual differences in susceptibility to neuropsychiatric disease and in responsiveness to
antipsychotic medication.
Human personality traits that can be reliably
measured by rating scales show a considerable
heritable component. One such instrument is the
tridimensional personality questionnaire (TPQ),
which was designed by Cloninger et al. (1993) to
measure 4 distinct domains of temperament—
novelty seeking, harm avoidance, reward dependence, and persistence—that are hypothesized
to be based on distinct neurochemical and
genetic substrates. Cloninger et al. (1993)
proposed that individual variations in the novelty
seeking trait are mediated by genetic variability
in dopamine transmission. Individuals who score
higher than average on the TPQ novelty seeking
scale are characterized as impulsive, exploratory,
fickle, excitable, quick-tempered, and extravagant,
190
JAYANTA KUMAR NAYAK, B. N. SARKAR, P. K. DAS AND V. R. RAO
whereas those who score lower than average
tend to be reflective, rigid, loyal, stoic, slowtempered, and frugal.
Hutchison et al. (2002) found an association
between alcoholism and DRD4 receptor variation.
In a study of 20 abstinent alcohol-dependent men,
a significant correlation was found between
apomorphine-induced growth hormone release
and the ‘novelty seeking’ score of the individual
(Wiesbeck et al. 1995). This supported Cloninger’s
hypothesis by giving neuroen-docrine evidence
that this personality dimension is related to
dopaminergic activity, albeit in the tuberoinfundibular dopaminergic system which is not
directly associated with human personality traits.
In two groups of Finnish subjects (193 psychiatrically screened normal controls and 138
alcoholic offenders), Malhotra et al. (1996)
determined DRD4 genotypes and assessed
novelty seeking with the TPQ. In the control
individuals, they found no significant association
between novelty seeking and the 7-repeat allele
despite similar allele frequencies and the use of
the same personality measure as employed by
Ebstein et al. (1996). The group of alcoholic
offenders had significantly higher novelty
seeking than control individuals; however,
Malhotra et al. (1996) could not replicate the
previous association in this group. They
suggested that DRD4 may require reevaluation
as a candidate gene for personality variation.
The ALDH2*2 allele of the aldehyde
dehydrogenase-2 gene is considered to be a
genetic deterrent for alcoholism; however,
Muramatsu et al. (1996) found that 80 of 655
Japanese alcoholics had the mutant allele. They
postulated that these alcoholics had some other
factor which overcame the adverse effects of
acetaldehydemia and that this factor might reside
in the ‘reward system’ of the brain in which
dopamine plays a crucial role. Therefore,
Muramatsu et al. (1996) studied variation at the
DRD4 locus and found in the alcoholics a higher
frequency of a 5-repeat (5R) allele of the DRD4
receptor 48-bp repeat polymorphism in alcoholics
with ALDH2*2 than in 100 other alcoholics and
144 controls. They found that alcoholics with
the 5R allele also abused other drugs more often.
Chang et al. (1996) presented data that urged
caution in the interpretation of DRD4 association
studies in mixed populations. They focused
particularly on the expressed polymorphism in
exon 3 which may have functional relevance. This
polymorphism (an imperfect 48-bp tandem repeat
coding for 16 amino acids; alleles had been
reported with 2 to 10 repeats) was found to be
universal, suggesting that it is ancient and arose
before the global dispersion of modern humans.
They described diversity of allele frequencies
for this expressed polymorphism among different
populations and emphasized the importance of
population considerations in the design and
interpretation of association studies using the
polymorphism.
DRD4 is one of the most variable human
genes known. Most of this diversity is the result
of length and single-nucleotide polymorphism
(SNP) variation in a 48-bp VNTR in exon 3, which
encodes the third intracellular loop of this
dopamine receptor. Variant alleles containing 2
(2R) to 11 (11R) repeats are found, with the
resulting proteins having 32 to 176 amino acids
at this position. The frequency of these alleles
varies widely. The 7R allele, for example, has an
exceedingly low incidence in Asian populations
yet a high frequency in the Americas (Chang et
al. 1996). Although initial studies suggested that
the 7R allele of the DRD4 gene might be
associated with the personality trait of novelty
seeking (Ebstein et al. 1996; Benjamin et al. 1996),
the most reproduced association is that between
the 7R allele and attention deficit-hyperactivity
disorder. Ding et al. (2002) stated that 8 separate
replications of the initial observation of an
increased frequency of the DRD4 7R alleles in
ADHD probands had been reported.
Dopamine transporter (DAT) 7 repeats
tended to be higher, and that of 9 repeats lower,
in alcoholic Japanese patients (Dobashi et al.
1997); however, no association was found
between DAT and alcoholism (Pastorelli et al.
2001; Parsian and Zhang 1997) even in familybased studies (Schmidt et al. 1998). An increased
prevalence of the 9-repeat allele in alcoholics
displaying withdrawal seizures or delirium has
been observed (Schmidt et al. 1998). A
polymorphism in the 3’-UTR (G2319A) of the
DAT gene was associated with alcoholism (Ueno
et al. 1999).
CYP2E1: Cytochrome P450 2E1 (CYP2E1) is
an enzyme that is also able to metabolize ethanol
to acetaldehyde and acetaldehyde to acetate
(Howard et al. 2002). In humans, the levels of
hepatic CYP2E1 were found to vary 50-fold in
vitro while in vivo CYP2E1 activity was found to
vary by 15-fold. The CYP2E1 gene is genetically
GENETICS OF ALCOHOL USE
191
polymorphic and CYP2E1 variant alleles have
been associated with altered ethanol metabolism
(Sun et al. 1999).
Aldehyde Dehydrogenase: So far 17 ALDH
genes have been identified in nine ALDH
genotype groups (Brennan et al. 2004). The
isozyme mainly responsible for acetaldehyde
oxidation is the mitochondrial class II ALDH
(ALDH2) that has a micro molar Km value and
high affinity for acetaldehyde (Lands, 1998)
located on chromosome 12q24.2. The ALDH2
enzyme is polymorphic in humans, having two
allelic forms, ALDH2*1 and ALDH2*2 caused
by a point mutation at amino acid position 487,
where substitution of Lysine for Glutamic acid
that results from a transition of G to A at nucleotide
1510 (Hsu et al. 1985; Yoshida et al. 1991). The
ALDH2 deficiency leads to an aversive response
to alcohol due to elevated levels of acetaldehyde
resulting in increased hangover symptoms (Wall
et al. 2000) and the alcohol flush response (Li,
2000; Tanaka et al. 1997). ALDH2*1 is a very active
form found at high frequency among most ethnic
groups, while the ALDH2*2 is inactive (or has
very low activity) and is found at high frequency
among Asians (e.g. Chinese, Japanese, Koreans).
The ALDH2*2 has been demonstrated to be
associated with substantial protection from
alcoholism in Japanese (Okamoto et al. 2001;
Nakamura et al. 1996; Maczawa et al. 1995), Han
Chinese (Chen et al. 1999) and Koreans (Lee et
al. 2001). Genetic variation in ALDH2, tested in
multiple ethnic groups, alters the amount of
ethanol consumed (Tanaka et al. 1997; Okamoto
et al. 2001; Sun et al. 1999) and risk for binge
drinking (Luczak et al. 2001). An association with
alcoholic liver disease was observed in some but
not all studies, and may be due to the effect on
levels of consumption. ALDH2*2 homozygous
individuals are unable to oxidize acetaldehyde
and who are heterozygous do so inefficiently
(Yoshida et al. 1984; Novoradovsky et al. 1995).
About 50% of oriental people are different in the
ALDH2 isozyme that can most efficiently detoxify
acetaldehyde (Harada et al. 1981; 1985). ALDH2
genotype and gene frequency among various
populations of Mongoloid and Caucasoid and
other Indian origins including different linguistic
groups are presented in Table 3.
Alcohol Dehydrogenase: Alcohol dehydro-
Table 3: Distribution of ALDH2 genotype and gene frequency among various populations of Mongoloids
and Caucasoids origin.
Subjects
n
Mongoloids
Thais(Northeast)
124
113
11
0
0.956
0.044
111
86
73
218
132
50
58
53
58
424
129
100
85
68
156
92
26
56
29
32
235
70
11
1
5
58
38
18
2
23
21
160
48
0
0
0
4
2
6
0
1
5
29
11
0.95
0.994
0.966
0.849
0.841
0.7
0.98
0.764
0.73
0.743
0.729
0.05
0.006
0.034
0.151
0.159
0.3
0.02
0.236
0.27
0.257
0.271
Mongconthawornchai
et al. 2002
Goedde et al. 1992
Goedde et al. 1992
Goedde et al. 1992
Goedde et al. 1992
Goedde et al. 1992
Thomasson et al. 1991
Chen et al. 1998
Goedde et al. 1992
Yamamoto et al. 1993
Takeshita et al. 1994
Yuasa et al. 1997
193
99
117
179
40
95
47
133
34
48
193
99
114
173
40
95
47
133
34
48
0
0
3
5
0
0
0
0
0
0
0
0
0
1
0
0
0
0
0
0
1
1
0.987
0.98
1
1
1
1
1
1
0
0
0.013
0.02
0
0
0
0
0
0
Goedde et al. 1992
Goedde et al. 1992
Goedde et al. 1992
Goedde et al. 1992
Bhasker et al. 2007
Bhasker et al. 2007
Bhasker et al. 2007
Bhasker et al. 2007
Bhasker et al. 2007
Bhasker et al. 2007
Thais(North)
Fillipinos
Malays
Koreans
Chinese
Chinese
Taiwanese aborigine
Japanese
Japanese
Japanese
Japanese
Caucasoids
Germans
Swedes
Hungarians
Indians
Onge
Pattapu
Gond
Korku
Bhil
Sahariya
Genotype frequency
ALDH2 ALDH2 ALDH2
*1/*1
*1/*2
*2/*2
Gene frequency
ALDH2
ALDH2
*1
*2
Reference
JAYANTA KUMAR NAYAK, B. N. SARKAR, P. K. DAS AND V. R. RAO
192
genase (ADH) metabolizes alcohol to
acetaldehyde. It exists as a polygene family on
chromosome 4q, which has been linked to
alcoholism. Variants of different class I ADH
genes have been shown to be associated with
an effect that is protective against alcoholism
(Osier et al. 2002). There are seven ADH genes
with two polymorphic genes, ADH2 and ADH3
(Li, 2000). All seven genes exist in a cluster
extending ≅380kb on the long arm of chromosome
4 (i.e., 4q21-23) (Osier et al. 2002). The class I
ADH genes [ADH1A(α), ADH1B(β), ADH1C(γ)]
exist in a tighter cluster of ≅77kb, flanked
upstream by ADH7(µ or σ) in class IV and
downstream by ADH6 in class V, ADH4(π) in
class II and ADH5(x) in class III, in the order of
magnitude (Rao et al. 2007). Although the greatest
similarity seen among the class I genes, all seven
ADH enzymes are very similar in amino-acid
sequence and structure but differ in preferred
substrates (Edenberg 2000). Two of the three class
I genes are known to have alleles that produce
enzymes that catalyze the oxidation of ethanol at
different rates (Edenberg and Bosron 1997). At
the protein level, the allelic series for ADH1B
(previously called “ADH2”) encodes the β
subunit of the dimeric enzyme and is generated
by variation at two different sites at the genomic
level: the ADH1B*1 allele is composed of 47Arg
and 369Arg, the ADH1B*2 allele is composed of
Table 4: Gene frequency of ADH1B and ADH1C gene of some Indian populations.
Population
Onge
Pattapu
Gond
Korku
Bhil
Sahariya
Brahmin
Kshatriya
Vysya
Akuthota
Kamma
Kapu
Pokanati
Panta
Vanne
Balija
Ekila
Kurava
Thogata
Yadava
Ediga
Gandla
Jangam
Devangapattur
Chakli
Mangali
Vadde
Madiga
Mala
Erukala
Sugali
Yanadi
Dudekula
Sheik
Gene frequency of ADH1B*47
(ADH2*2)
Gene frequency of ADH1C*349
(ADH3*349)
A allele
G allele
A allele
0.000
0.045
0.000
0.000
0.000
0.020
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
1.000
0.955
1.000
1.000
1.000
0.980
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
0.750
0.5714
0.5791
0.6250
0.5918
0.556
0.692
0.583
0.697
0.767
0.667
0.603
0.541
0.683
0.79
0.667
0.645
0.688
0.683
0.533
0.583
0.5
0.559
0.673
0.577
0.619
0.672
0.663
0.56
0.703
0.652
0.7
0.81
Reference
G allele
0.000
0.250
0.4286
0.4209
0.3750
0.4082
0.444
0.308
0.417
0.321
0.233
0.333
0.397
0.459
0.317
0.21
0.333
0.355
0.313
0.317
0.467
0.417
0.5
0.441
0.327
0.423
0.381
0.328
0.337
0.44
0.297
0.348
0.3
0.19
Rao et al. 2007
Rao et al. 2007
Rao et al. 2007
Rao et al. 2007
Rao et al. 2007
Rao et al. 2007
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy, et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
Reddy et al. 2006
GENETICS OF ALCOHOL USE
47His and 369Arg, and the ADH1B*3 allele is
composed of 47Arg and 369Cys. Osier et al. 2002,
had not seen the “double variant” (composed of
47His and 369Cys), but they assumed that it
could exist. ADH1B*1 have high affinity and low
capacity in contrast to ADH1B*2 and ADH1B*3
which have low affinity for ethanol and high
capacity. The functional variants in the
corresponding metabolic enzymes make the class
I ADH genes obvious candidates for risk of
developing alcoholism. Alleles at two ADH genes
that encode enzymes with higher Vmax valuesnamely, ADH1B*47His (previously called
“ADH2*2”), at the Arg47His (exon 3) SNP, and
ADH1C*349Ile (previously called “ADH3*1”),
encodes the γ subunits and at the Ile349Val (exon
8) SNP – have consistently been found at
significantly lower frequencies in alcoholic
individuals than in non-alcoholic controls in
Eastern-Asian samples (Thomasson et al. 1991;
Chen et al. 1996; Shen et al. 1997; Tanaka et al.
1997; Osier et al. 1999; Li et al. 2001).
ADH1B*2 / (ADH2*2) allele frequency is
lower in alcoholic populations indicating a
protective role (Nakamura et al. 1996; Maczawa et
al. 1995; Chen et al. 1999; Thomasson et al. 1994):
the influence of this genetic variant is easier to
demonstrate in populations which have low
prevalence of the ALDH2*2 (Li 2000). There is
evidence that ADH1C*349Ile may play an
important role related to alcohol abuse, health and
disease. Hines et al. (2001) demonstrated that
ADH1C*349Ile homozygous individuals are more
protected from heart disease by moderate drinking
than ADH1C*349Val homozygotes. In contrast to
it Visapaa et al. (2004) reported highest
ADH1C*349Ile allele frequency in patients with
oral cancer and cancer of the larynx. The allele
ADH1C*349Ile is a considerable risk factor for
female breast cancer, especially when ethanol
consumption is high (Freudenheim et al. 1999).
The gene frequency of the protecting ADH1B and
ADH1C genes in some Indian populations is
presented in Table 4. Altogether 34 different
population groups were studied from India (Reddy
et al. 2006 and Rao et al. 2007) of which majority of
the groups were from the southern part of India.
CONCLUSION
The genetic data can be, and have been, used
to improve our understanding of the etiology of
alcohol dependence and inter-individual
193
variation in the risk for alcoholism. Once genes
are identified which alter the predisposition to
alcohol dependence, a major challenge will be to
understand how the functions of these genes
interact with the environmental influences on
dependence. The unique Indian population
structure with strictly defined endogamous
castes and tribes maintaining isolated gene pools
may aid in precise understanding of the genetic
mechanisms underlying the alcoholic phenotypes. Analysis of specific genes will allow a
rational exploration of biochemical underpinnings of the actions of alcohol and makes
possible a link between behavioral change,
genetic predisposition and biochemical action.
Such genes, and the proteins they encode, will
become primary targets for creating novel
diagnostic tools as well as the basis of novel
behavioral and pharmacological treatments.
Genetic information may be useful for identifying
individuals at increased risk for alcohol dependence and for the health consequences of alcohol
dependence. By gaining a better understanding
of genes that are involved in initiation, maintenance and cessation of alcohol dependence,
novel pharmacological and behavioral treatment
approaches may be designed. In summary, the
improved understanding of genetic influences
on alcohol dependence promises to increase our
understanding of addictive processes, and
should provide novel prevention and treatment
possibilities.
REFERENCES
Agarwal DP 2001. The Genetics of Alcohol Metabolism
and Alcoholism. IJHG, 1(1): 25-32.
Amad S, Noble EP, Fourcade-Amad ML, et al. 2000.
Association of D2 dopamine receptor and alcohol
dehydrogenase2 genes with Polynesian alcoholics.
Eur Psychiatry, 15: 97-102.
Anghelescu I, Germeyer S, Muller MJ, et al. 2001. No
association between the dopamine d2 receptor taqi
a1 allele and earlier age of onset of alcohol
dependence according to different specified criteria.
Alcohol Clin Exp Res, 25: 805-809.
Bang AT, Bang RA 1991. Community participation in
research and action against alcoholism. World Health
Forum, 12: 104 -109.
Benjamin J, Li L, Patterson C, et al. 1996. Population
and familial association between the D4 dopamine
receptor gene and measures of novelty seeking.
Nature Genet, 12: 81-84.
Bhaskar LVKS, Thangaraj K, Osier M, et al. 2007. Single
nucleotide polymorphisms of the ALDH2 gene in
six Indian populations. Annals of Human Biology,
(in press).
194
JAYANTA KUMAR NAYAK, B. N. SARKAR, P. K. DAS AND V. R. RAO
Bohman M, Cloninger CR, Sigvardsson S, Von Knorring
AL 1987. The genetics of alcoholism and related
disorders. J Psychiatric Res, 21: 447- 452.
Bosron WF, Li TK 1986. Genetic polymorphism of
human liver alcohol and aldehyde dehydrogenases,
and their relationship to alcohol metabolism and
alcoholism. Hepatology, 6: 502-510.
Brennan P, Lewis S, Hashibe M, et al. 2004. Pooled
analysis of alcohol dehydrogenase genotypes and
head and neck cancer: A HuGE Review: Am J
Epidemiol, 159: 1-16.
Chakravarthy C 1990. Community workers estimate of
drinking and alcohol-related problems in rural areas.
Indian Journal of Psychological Medicine, 13: 49
– 56.
Chang FM, Kidd JR, Livak KJ, et al. 1996. The worldwide distribution of allele frequencies at the human
dopamine D4 receptor locus. Hum Genet, 98: 91101.
Chen CC, Lu RB, Chen YC, et al. 1999. Interaction
between the functional polymorphisms of the
alcohol-metabolism genes in protection against
alcoholism. Am J Hum Genet, 65: 795-807.
Chen WJ, et al. 1998. Self-reported flushing and
genotypes of ALDH2, 15 ADH2, and ADH3 among
Taiwanese Han. Alcoholism: Clin Exp Res, 22: 1048
– 1052.
Chen WJ, Loh EW, Hsu YP, et al. 1996. Alcoholmetabolizing genes and alcoholism among
Taiwanese Han men: independent effect of ADH2,
ADH3 and ALDH2. Br J Psychiatry, 168: 762- 767.
Cloninger CR, Bohman M, Sigvardsson S 1981.
Inheritance of alcohol abuse - Cross-fostering
analysis of adopted men. Arch Gen Psychiatry, 38:
861-868.
Cloninger CR, Svrakic DM, Przybeck TR 1993. A
psychobiological model of temperament and
character. Arch Gen Psychiat, 50: 975-990.
Cloninger CR 1990. Genetic Epidemiology of
alcoholism: observations critical in the design and
analysis of linkage studies. In: CR Cloninger, H
Begleiter (Ed.): Genetics and Biology of
Alcoholism: Banbury Report 33. New York: Cold
Spring Harbour Laboratory Press, pp. 105- 133.
Collins FS, Guyer MS, Charkravarti A 1997. Variations
on a theme: Cataloging human DNA sequence
variation. Science, 278: 1580- 1581.
Connor JP, Young RM, Lawford BR, et al. 2002. D (2)
dopamine receptor (DRD2) polymorphism is
associated with severity of alcohol dependence. Eur
Psychiatry, 17: 17-23.
Cotton NS 1979. The familial incidence of alcoholism:
a review. J Stud Alcohol, 40: 89- 116.
Crabbe JC 2002. Genetic contributions to addiction. Annu
Rev Psychol, 53: 435- 462.
Dawson DA, Archer L 1992. Gender differences in alcohol
consumption: effects of measurement. Brit J
Addiction, 87: 119- 123.
Deb PC, Jindal BR 1975. Drinking in Rural Areas. Study
in selected villages of Punjab. Ludhiana, Punjab
Agricultural University Monograph.
Deswal BS, Jindal AK, Gupta KK 2006. Epidemiology of
Alcohol use among residents of remote hills of
Arunachal Pradesh. IJCM, 31 (2): 88 – 89.
Dhupdale NY, Motghare DD, Ferreira AMA, Prasad YD
2006. Prevalence and pattern of Alcohol
consumption in rural Goa. IJCM, 31 (2): 104 –
105.
Ding YC, Chi HC, Grady DL, et al. 2002. Evidence of
positive selection acting at the human dopamine
receptor D4 gene locus. Proc Nat Acad Sci, 99:
309-314.
Dobashi I, Inada T, Hadano K 1997. Alcoholism and
gene polymorhisms related to central dopaminergic
transmission in Japanese population. Psychiatr
Genet, 7: 87-91.
Ebstein RP, Novick O, Umansky R, et al. 1996.
Dopamine D4 receptor exon III polymorphism
associated with the human personality trait of
novelty seeking. Nature Genet, 12: 78-80.
Edenberg HJ, Bosron WF 1997. Alcohol dehydrogenase.
In: FP Guengerich (Ed.): Comprehensive toxicology.
Vol 3: Bio-transformation. Pergamon Press, New
York, pp 119- 131.
Edenberg HJ, Foroud T, Koller DL, et al. 1998. A familybased analysis of the association of the dopamine
D2 receptor (DRD2) with alcoholism. Alcohol Clin
Exp Res, 22: 505-512.
Edenberg HJ 2000. Regulation of the mammalian alcohol
dehydrogenase genes. Prog Nucleic Acid Res Mol
Biol, 64: 295- 341.
Eriksson CJ, Fukunaga T, Sarkola T, et al. 2001.
Functional
relevance
of
human
ADH
polymorphism. Alcohol Clin Exp Res, 25(suppl):
157s-163s.
Freudenheim JL, Ambrosone CB, Moysich KB, et al.
1999. Alcohol dehydrogenase 3 genotype
modification of the association of alcohol
consumption with breast cancer risk. Cancer Causes
Control, 10: 369- 377.
Goedde HW, et al. 1992. Distribution of ADH2 and
ALDH2 genotypes in different populations. Hum
Genet, 88: 344-346.
Goldman D, Urbanck M, Guenther D, Robin R, Long JC
1997. Linkage and association of a functional DRD2
variant [Ser311Cys] and DRD2 markers to
alcoholism, substance abuse and schizophrenia in
Southwestern American Indians. Am J Med Genet,
74: 386-394.
Goodwin DW, Schulsinger F, Moller N, et al. 1974.
Drinking problems in adopted and non-adopted sons
of alcoholics. Arch Gen Psychiatry, 31: 164-169.
Grant M 1985. Establishing priorities for action; In:
Alcohol Policies WHO Reg. Publication, European
Series No. 18: 6.
Grobin AC, Mathews DB, Devaud LL, Morrow AL 1998.
The role of GABA A receptors in the acute and
chronic effects of ethanol. Psychopharmacology,
139: 2-19.
Harada S, Agarwal DP, Goedde HW 1981. Aldehyde
dehydrogenase deficiency as cause of facial flushing
reaction to alcohol in Japanese. (Letter) Lancet, ii:
982.
Harada S, Agarwal DP, Goedde HW 1985. Aldehyde
dehydrogenase polymorphism and alcohol
metabolism in alcoholics. Alcohol, 2: 391-392.
Heath AC, Madden PA, Bucholz KK, et al. 1999. Genetic
differences in alcohol sensitivity and the inheritance
of alcoholism risk. Psychol Med, 29: 1069-1081.
Heath AC, Madden PA, Grant JD, et al. 1999. Resiliency
GENETICS OF ALCOHOL USE
factors protecting against teenage alcohol use and
smoking: influences of religion, religious
involvement and values, and ethnicity in the
Missouri Adolescent Female Twin Study. Twin Res,
2: 145-155.
Heath AC, Madden PA, Martin NG 1998. Statistical
methods in genetic research on smoking. Stat
Methods Med Res, 7: 165-186.
Henderson AS, Korten AE, Jorm AF, et al. 2000. COMT
and DRD3 polymorphisms, environmental
exposures, and personality traits related to common
mental disorders. Am J Med Genet, 96: 102-107.
Hietala J, Pohjalainen T, Heikkila-Kallio U, et al. 1997.
Allelic association between D2 but not D1 dopamine
receptor gene and alcoholism in Finland. Psychiatr
Genet, 7: 19-25.
Higuchi S, Muramatsu T, Matsushita S, Murayama M
1996. No evidence of association between structural
polymorphism at the dopamine D3 receptor locus
and alcoholism in the Japanese. Am J Hum Genet,
67: 412- 414.
Hill SY 1992. Is there a genetic basis of alcoholism? Biol
Psychiatry, 32: 955-957.
Hines LM, Stampfer MJ, Ma J, et al. 2001. Genetic variation
in alcohol dehydrogenase and the beneficial effect of
moderate alcohol consumption on myocardial
infarction. New Eng J Med, 344: 549-555.
Homann N, Jousimies-Somer H, Jokelainen K, et al.
1997. High acetaldehyde levels in saliva after
ethanol consumption: methodological aspects and
pathogenetic implications. Carcinogenesis, 18:
1739-43.
Homann N, Tillonen J, Meurman JH, et al. 2000.
Increased salivary acetaldehyde levels in heavy
drinkers and smokers: a microbiological approach
to oral cavity cancer. Carcinogenesis, 21: 663-668.
Howard LA, Sellers EM, Tyndale RF 2002. The role of
pharmacogenetically-variable cytochrome P450
enzymes in drug dependence. Pharmacogenomics,
3: 185-199.
Hsu LC, Tani K, Fujiyoshi T, Kurachi K, Yoshida A
1985. Cloning of cDNAs for human aldehyde
dehydrogenases 1& 2. Proc. Nat. Acad. Sci., 82:
3771-3775.
Hutchison KE, Mc Geary J, Smolen A, Bryan A, Swift
RM 2002. The DRD4 VNTR polymorphism
moderates craving after alcohol consumption.
Health Psychol, 21: 139-146.
Jacob T, Sher KJ, Bucholz KK, et al. 2001. An integrative
approach for studying the etiology of alcoholism
and other addictions. Twin Res, 4: 103-118.
Johnson EO, Van den Bree MB, Gupman AE, Pickens
RW 1998. Extension of a typology of alcohol
dependence based on relative genetic and
environmental loading. Alcohol Clin Exp Res, 22:
1421-1429.
Kendler KS, Neale MC, Heath AC, Kessler RC, Eaves LJ
1994. A twin-family study of alcoholism in women.
Am J Psychiatry, 151: 707-715.
Kessler RC, McGonagle KA, Zhao S, et al. 1994. Lifetime
and 12- month prevalence of DSM-III-R Psychiatric
Disorders in the United States: Results from the
National Co-morbidity Survey. Archives of General
Psychiatry, 51: 8-9.
Kwon JM, Goate AM 2000. The candidate gene approach.
195
Alcohol Research and Health, 24: 164-168.
Lands WE 1998. A review of alcohol clearance in
humans. Alcohol, 15: 147-160.
Lappalainen J, Long JC, Eggert M, et al. 1998. Linkage
of antisocial alcoholism to the Serotonin 5- HT1B
receptor gene in 2 populations. Archives of General
Psychiatry, 55: 989-994.
Lee HC, Lee HS, Jung SH, et al. 2001. Association between
polymorphisms of ethanol-metabolizing enzymes
and susceptibility to alcoholic cirrhosis in a Korean
male population. J Korean Med Sci, 16: 745-750.
Li TK, Yin SJ, Crabb DW, O’Connor S, Ramchandani VA
2001. Genetic and environmental influences on
alcohol metabolism in humans. Alcohol Clin Exp
Res, 25: 136-144.
Li TK 2000. Pharmacogenetics of responses to alcohol
and genes that influence alcohol drinking. J Stud
Alcohol, 61: 5-12.
Loh E-W, Higuchi S, Matsushita S, et al. 2000.
Association analysis of GABAA receptor subunit
genes cluster on 5q33-34 and alcohol dependence in a
Japanese population. Mol Psych, 5: 301-307.
Loh E-W, Smith I, Murray R, et al. 1999. Association
between variants at the GABAAbeta2, GABAAalpha6
and GABA A gamma2 gene cluster and alcohol
dependence in a Scottish population. Mol Psych, 4:
539-544.
Long JC, Knowler WC, Hanson RL, et al. 1998. Evidence
for genetic linkage to alcohol dependence on
chromosomes 4 and 11 from an autosome-wide scan
in an American Indian Population. Am J Med Genet,
81: 216-221.
Longmate JA 2001. Complexity and power in casecontrol association studies. Am J Hum Genet, 68:
1229-1237.
Luczak SE, Wall TL, Shea SH, Byun SM, Carr LG 2001.
Binge drinking in Chinese, Korean, and White college
students: genetic and ethnic group differences.
Psychol Addict Behav, 15: 306-309.
Maczawa Y, Yamauchi M, Toda G, Suzuki H, Sakurai S
1995.
Alcohol-metabolizing
enzyme
polymorphisms and alcoholism in Japan. Alcohol
Clin Exp Res, 19: 951- 954.
Malhotra AK, Virkkunen M, Rooney W, et al. 1996.
The association between the dopamine D(4)
receptor (D4DR) 16 amino acid repeat
polymorphism and novelty seeking. Molec.
Psychiat., 1: 388-391.
McGue M, Pickens RW, Svikis DS 1992. Sex and age
effects on the inheritance of alcohol problems: a
twin study. J Abnorm Psychol, 101: 3-17.
Mehta AK and Ticku MK. 1992. An update on GABAA
receptors. Brain Res. Rev.; 29: 196-217.
Mohan D, et al. 1992. A rapid survey of substance abuse
disorders in the urban slums of Delhi. IJMR, 96:
122-127.
Mongconthawornchai P, Nanakorn S, Nishiyori A 2002.
Aldehyde Dehydrogenase – 2 genotype detection
in fingernails among non-alcoholic Northeastern
Thai population and derived gene frequency. Science
Asia, 28: 99-103.
Muramatsu T, Higuchi S, Murayama M, Matsushita S,
Hayashida M 1996. Association between alcoholism
and the dopamine D4 receptor gene. J. Med. Genet.,
33: 113-115.
196
JAYANTA KUMAR NAYAK, B. N. SARKAR, P. K. DAS AND V. R. RAO
Murray CJL, Lopez AD 1996. Quantifying the burden of
disease and injury attributable to ten major risk
factors. In: CJL Murray and AD Lopez (Ed.): The
Global burden of disease: a comprehensive
assessment of mortality and disability from disease,
injuries and risk factors in 1990 and projected to
2020 Cambridge, M.A. Harward School of Public
Health: 295-314.
Muto M, Hitomi Y, Ohtsu A, et al. 2000. Acetaldehyde
production by non-pathogenic neisseria in human
oral microflora: implications for carcinogenesis in
upper aerodigestive tract. International Journal of
Cancer, 88: 342-350.
Nakamura K, Iwahashi K, Matsuo Y, et al. 1996.
Characteristics of Japanese alcoholics with the
atypical aldehyde dehydrogenase 2*2.1. A
comparison of the genotypes of ALDH2, ADH2,
ADH3 and Cytochrome P-450 2E1 between
alcoholics and non-alcoholics. Alcohol Clin Exp
Res, 20: 52-55.
Nestler EJ 2000. Genes and addiction. Nat Genet, 26:
277-281.
Noble EP, Zhang X, Ritchie T, et al. 1998. D2 dopamine
receptor and GABA(A) receptor beta3 subunit genes
and alcoholism. Psychiatry Res, 81: 133-147.
Noble EP, Zhang X, Ritchie TL, Sparkes RS 2000.
Haplotypes at the DRD2 locus and severe
alcoholism. Am J Med Genet, 96: 622-631.
Novoradovsky A, Tsai SJ, Goldfarb L, et al. 1995.
Mitochondrial aldehyde dehydrogenase polymorphism in Asian and American Indian Populations:
detection of a new ALDH2 alleles. Alcohol Clin
Exp Res, 19: 1105-1110.
Okamoto K, Murawaki Y, Yuasa, Kawasaki H 2001.
Effect of ALDH2 and CYP2E1 gene polymorphisms on drinking behavior and alcoholic liver
disease in Japanese male workers. Alcohol Clin Exp
Res, 25(6 suppl.): 19s-23s.
Osier MV, Pakstis AJ, Kidd JR, et al. 1999. Linkage
disequilibrium at the ADH2 and ADH3 loci and risk
of alcoholism. Am J Hum Genet, 64: 1147-1157.
Osier MV, Pakstis AJ, Soodyall H, et al. 2002. A global
perspective on genetic variation at the ADH gene
reveals unusual patterns of linkage disequilibrium
and diversity. Am J Hum Genet, 71: 84-99.
Parsian A, Chakraverty S, Fisher L, Cloninger CR 1997.
No association between polymorphisms in the
human dopamine D3 and D4 receptors genes and
alcoholism. Am J Hum Genet, 74: 281-285.
Parsian A, Cloninger CR 1997. Human GABA-A receptor
á1 and á2 subunit genes and alcoholism. Alcohol
Clin Exp Res, 21: 430-433.
Parsian A, Zhang ZH 1997. Human dopamine transporter
gene polymorphism (VNTR) and alcoholism. Am J
Hum Genet, 74: 474-478.
Parsian A, Zhang ZH 1999. Human chromosomes 11p15
and 4p12 and alcohol dependence: Possible
association with the GABRB1 gene. Am J Med Genet
Neuropsych Genet, 88: 533-538.
Pastorelli R, Bardazzi G, Saieva C, et al. 2001. Genetic
determinants of alcohol addiction and metabolism: a
survey in Italy. Alcohol Clin Exp Res, 25: 221-227.
Paterson AD, Petronis A 1999. Sex-based linkage analysis
of alcoholism. Genet Epidemiol, 17 (suppl. 1): s289s294.
Pawan GLS 1972. Metabolism of alcohol (ethanol) in
man. Proc Nutr Soc, 3x: 83-89.
Pickens RW, Svikis DS, McGue M, et al. 1991.
Heterogeneity in the inheritance of alcoholism. A
study of male and female twins. Arch Gen Psychiatry,
48: 19-28.
Prescott CA, Aggen SH, Kendler KS 1999. Sex differences
in the sources of genetic liability to alcohol abuse
and dependence in a population-based sample of
U.S. twins. Alcohol Clin Exp Res, 23: 1136-1144.
Prescott CA, Kendler KS 1999. Genetic and
environmental contributions to alcohol abuse and
dependence in a population-based sample of male
twins. Am J Psychiatry, 156: 34-40.
Rao VR, Bhaskar LVKS, Annapurna C, et al. 2007. Single
nucleotide polymorphisms in alcohol dehydrogenase
genes among some Indian populations. Am J Hum
Biol, 19: 338-344.
Reddy BM, Reddy ANS, Nagaraja T, et al. 2006. Single
Nucleotide Polymorphisms of the Alcohol
Dehydrogenase genes among the 28 caste and tribal
populations of India. Int J Hum Genet, 6: 309-316.
Reddy BM, Reddy ANS, Nagaraja T, et al. 2007.
Anthropological Perspective of the Single
Nucleotide Polymorphisms in the NPY and DRD2
Genes among the Socio-Economically Stratified
Populations of Andhra Pradesh, India. Int J Hum
Genet, 7: 277-284.
Reich T, Edenberg HJ, Goate A, et al. 1998. Genomewide search for genes affecting the risk for alcohol
dependence. Am J Med Genet, 81: 207-215.
Reich T, Hinrich A, Culverhouse R, Bierut L 1999.
Genetic studies of alcoholism and substance
dependence. Am J Hum Genet, 65: 599-605.
Risch N, Merikangas K 1996. The future of genetic
studies of complex human diseases. Science, 273:
1516-1517.
Roberts AJ, Koob GF 1997. The neurobiology of
addiction: an overview. Alcohol Health Res. World,
21: 101-106.
Russek SJ 1999. Evolution of GABAA receptor diversity
in the human genome. Gene, 227: 213-222.
Saccone NL, Kwon JM, Corbett J, et al. 2000. A genome
screen of maximum number of drinks as an
alcoholism phenotype. Am J Med Genet, 96: 632637.
Sander T, Ball D, Murray R, et al. 1999. Association
analysis of sequence variants of the GABAA, ?6, ?2
and ?2 gene cluster and alcohol dependence. Alcohol
Clin Exp Res, 23: 427-431.
Sander T, Harms H, Podschus J, et al. 1995. Dopamine
D1, D2 and D3 receptor genes in alcohol
dependence. Psychiatr Genet, 5: 171-176.
Sander T, Samochowiec J, Ladehoff M, et al. 1999.
Association analysis of exonic variants of the gene
encoding the GABAB receptor and alcohol
dependence. Psychiatr Genet, 9: 69-73.
Saxena S 2004. Country profile on alcohol in India.
WHO Global Status Report on Alcohol. 37-60.
Schmidt LG, Harms H, Kuhn S, Rommelspacher H, Sander
T 1998. Modification of alcohol withdrawal by the
A9 allele of the dopamine transporter gene. Am J
Psychiatry, 155: 474-478.
Schuckit MA 2000. Genetics of the risk for alcoholism.
Am J Addict, 9: 103-112.
GENETICS OF ALCOHOL USE
Shen YC, Fan JH, Edenberg HJ, et al. 1997. Polymorphisms
of ADH and ALDH genes among four ethnic groups
in China and effects upon the risk for alcoholism.
Alcohol Clin Exp Res, 21: 1272-1277.
Sigvardsson S, Bohman M, Cloninger CR 1996.
Replication of the Stockholm Adoption Study of
alcoholism. Confirmatory cross-fostering analysis.
Arch Gen Psychiatry, 53: 681-687.
Sinnett D, Wagstaff J, Glatt K, et al. 1993. High-resolution
mapping of the γ-aminobutyric acid receptor β3 and
α5 gene cluster on chromosome 15q 11 -q 13 , and
localization of break-points in two Angelman
syndrome patients. Am J Hum Genet, 52: 1216- 1229.
Stallings MC, Hewilt JK, Beresford T, Heath AC, Eaves
LJ 1999. A twin study of drinking and smoking onset
and latencies from first use to regular use. Behav
Genet, 29: 409- 421.
Stoltenberg SF, Burmeister M 2000. Recent progress in
psychiatric genetics – some hope but no hype. Hum
Mol Genet, 9: 927-935.
Sun F, Tsuritani I, Honda R, Ma ZY, Yamada Y 1999.
Association of genetic polymorphisms of alcoholmetabolizing enzymes with excessive alcohol
consumption in Japanese men. Hum Genet, 105:
295-300.
Sundaram KR, Mohan D, Advani G 1984. Alcohol abuse
in a rural community in India, Part I: Epidemiological
study. Drug and Alcohol Dependence, 14: 27-36.
Takeshita T, et al. 1994. Characterization of the three
genotypes of low K m aldehyde dehydrogenase in
Japanese population. Hum Genet, 94: 217-223.
Tanaka FY, Shiratori Y, Yokosuka O, et al. 1997.
Polymorphism of alcohol- metabolizing genes affects
drinking behavior and alcoholic liver disease in
Japanese men. Alcohol Clin Exp Res, 21: 596-601.
Thomasson HR, Crabb DW, Edenber HJ, et al. 1994.
Low frequency of the ADH2*2 allele among atyal
natives of Taiwan with alcohol use disorders. Alcohol
Clin Exp Res, 18: 640-643.
Thomasson HR, Edenber HJ, Crabb DW, et al. 1991.
Alcohol and aldehyde dehydrogenase genotypes and
alcoholism in Chinese men. Am J Hum Genet, 48:
677-681.
Ueno S, Nakamura M, Mikami M, et al. 1999.
Identification of a novel polymorphism of the
human dopamine transporter (DAT1) gene and the
significant association with alcoholism. Mol
Psychiatry, 4: 552-557.
Van den Bree MB, Johnson EO, Neale Mc, et al. 1998.
Genetic analysis of diagnostic systems of alcoholism
in males. Biol Psychiatry, 43: 139-145.
Van Tol HHM, Wu CM, Guan HC, et al. 1992. Multiple
dopamine D4 receptor variants in the human
population. Nature, 358: 149-152.
197
Vanyukov MM, Tarter RE 2000. Genetic studies of
substance abuse. Drug Alcohol Depend, 59: 101-123.
Varama VK, et al. 1980. Extent and pattern of alcohol
use and alcohol-related problems in North India.
Indian Journal of Psychiatry, 22: 331-337.
Viken RJ, Kaprio J, Koskenvuo M, Rose RJ 1999.
Longitudinal analyses of the determinants of
drinking and of drinking to intoxication in
adolescent twins. Behav Genet, 29: 455-461.
Visapaa JP, Gotte K, Benesova M, et al. 2004. Increased
cancer risk in heavy drinkers with the alcohol
dehydrogenase 1C*1 allele, possibly due to salivary
acetaldehyde. Gut, 53: 871-876.
Wahlsten D 1999. Single-gene influences on brain and
behavior. Annu Rev Psychol, 50: 599- 624.
Wall TL, Horn SM, Johnson ML, Smith TL, Carr LG
2000. Hangover symptoms in Asian Americans with
variations in the aldehyde dehydrogenase (ALDH2)
gene. J Stud Alcohol, 61: 13-17.
Wallner M, Hanchar HJ, Olsen RW 2003. Proc Natl
Acad Sci USA, 100: 15218-15223.
Weiland AJ 2000. The challenges of genetic advances.
Healthplan, 41: 24-30.
WHO 1980. Problems related to alcohol consumption,
Technical Report Series, 650: 10-16.
WHO 1993. International classification of Disease, Ed.
10. Geneva, World Health Organization.
WHO-Global Status Report on alcohol 2004.<http://
www.who.int/substance_abuse/publications/en/
global_status_report_2004_overview.pdf>
Wiesbeck GA, Mauerer C, Thome J, Jakob F, Boening J
1995. Neuroendocrine support for a relationship
between ‘novelty seeking’ and dopaminergic
function in alcohol-dependent men. Psychoneuroendocrinology, 20: 755-761.
Wight AJ, Ogden GR 1998. Possible mechanisms by
which alcohol may influence the development of
oral cancer: A review. Oral Oncology, 34: 441-447.
Yamamoto K, et al. 1993. Genetic polymorphism of
alcohol and aldehyde dehydrogenase and the effects
on alcohol metabolism. Jpn J Alcohol Drug
Depend, 28: 13-25.
Yoshida A, Hsu LC, Yasunami M 1991. Genetics of human
alcohol metabolizing enzymes. Prog Nucleic Acid
Res Mol Biol, 40: 255-287.
Yoshida A, Huang IY, Ikawa M 1984. Molecular
abnormality of an inactive aldehyde dehydrogenase
variant commonly found in Orientals. Proc Natl
Acad Sci, 81: 258-261.
Yuasa I, et al. 1997. Simple and rapid determination of
the acetaldehyde dehydrogenase (ALDH2) genotypes
by non-radioactive single-strand conformation
polymorphism analysis. Electrophoresis, 18: 19401941.