ArticlePDF AvailableLiterature Review

Genetics of Alcohol Dependence: A Review of Clinical Studies

October 2014
Neuropsychobiology 70(2):77-94

October 2014
70(2):77-94

DOI:10.1159/000364826

Source
PubMed

Authors:

Agnieszka Samochowiec

University of Szczecin

Przemyslaw Bienkowski

Medical University of Warsaw

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Background/aims: Alcohol dependence is a common severe psychiatric disorder with a multifactorial etiology. Since the completion of the human genome project and with the increased availability of high-throughput genotyping, multiple genetic risk factors for substance-related disorders, including alcohol dependence, have been identified, but not all results could be replicated. Methods: We systematically review the clinical literature on genetic risk factors for alcohol dependence and alcohol-related phenotypes, including candidate gene-based studies, linkage studies and genome-wide association studies (GWAS). Results: Irrespectively of the methodology employed, the most robust findings regarding genetic risk factors for alcohol dependence concern genetic variations that affect alcohol metabolism. GWAS confirm the importance of the alcohol dehydrogenase gene cluster on chromosome 4 in the genetic risk for alcohol dependence with multiple variants that exert a small, but cumulative influence. A single variant with strong influence on individual risk is the aldehyde dehydrogenase 2 ALDHD2*2 variant common in Asian populations. Other robust associations have been found with previously uncharacterized genes like KIAA0040, and such observations can lead to the identification of thus far unknown signaling pathways. Converging evidence also points to a role of glutamatergic, dopaminergic and serotonergic neurotransmitter signaling in the risk for alcohol dependence, but effects are small, and gene-environment interactions further increase the complexity. Conclusion: With few exceptions like ALDH2*2, the contribution of individual genetic variants to the risk for alcohol-related disorders is small. However, the concentration of risk variants within neurotransmitter signaling pathways may help to deepen our understanding of the underlying pathophysiology and thereby contribute to develop novel therapeutic strategies.

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Neuropsychobiology 2014;70:77–94

DOI: 10.1159/000364826

Genetics of Alcohol Dependence:

A Review of Clinical Studies

Jerzy Samochowiec a Agnieszka Samochowiec b Imke Puls d

Przemyslaw Bienkowski c Björn H. Schott d, e

a Department of Psychiatry, Pomeranian Medical University, and

b Institute of Psychology, Department of

Clinical Psychology, University of Szczecin, Szczecin , and

c Institute of Psychiatry and Neurology, Warsaw , Poland;

d Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin , and

e Leibniz Institute for Neurobiology, Magdeburg , Germany

multiple variants that exert a small, but cumulative influence.

A single variant with strong influence on individual risk is the

aldehyde dehydrogenase 2 ALDHD2 * 2 variant common in

Asian populations. Other robust associations have been

found with previously uncharacterized genes like KIAA0040 ,

and such observations can lead to the identification of thus

far unknown signaling pathways. Converging evidence also

points to a role of glutamatergic, dopaminergic and seroto-

nergic neurotransmitter signaling in the risk for alcohol de-

pendence, but effects are small, and gene-environment in-

teractions further increase the complexity. Conclusion: With

few exceptions like ALDH2 * 2, the contribution of individual

genetic variants to the risk for alcohol-related disorders is

small. However, the concentration of risk variants within neu-

rotransmitter signaling pathways may help to deepen our

understanding of the underlying pathophysiology and there-

by contribute to develop novel therapeutic strategies.

Key Words

Alcohol-related phenotypes · Alcohol dependence ·

Genetic risk factors

Abstract

Background/Aims: Alcohol dependence is a common severe

psychiatric disorder with a multifactorial etiology. Since the

completion of the human genome project and with the in-

creased availability of high-throughput genotyping, multiple

genetic risk factors for substance-related disorders, including

alcohol dependence, have been identified, but not all results

could be replicated. Methods: We systematically review the

clinical literature on genetic risk factors for alcohol depen-

dence and alcohol-related phenotypes, including candidate

gene-based studies, linkage studies and genome-wide asso-

ciation studies (GWAS). Results: Irrespectively of the method-

ology employed, the most robust findings regarding genetic

risk factors for alcohol dependence concern genetic varia-

tions that affect alcohol metabolism. GWAS confirm the im-

portance of the alcohol dehydrogenase gene cluster on chro-

mosome 4 in the genetic risk for alcohol dependence with

Received: October 7, 2013

Accepted after revision: May 24, 2014

Published online: October 30, 2014

Björn H. Schott, MD, PhD

Department of Psychiatry and Psychotherapy

Campus Charité Mitte, Charité Universitätsmedizin Berlin

Charitéplatz 1, DE–10117 Berlin (Germany)

E-Mail bjoern.schott  @  charite.de

0302–282X/14/0702–0077$39.50/0

www.karger.com/nps

Jerzy Samochowiec and Agnieszka Samochowiec contributed equal-

ly to this work.

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Introduction

While alcohol consumption at moderate levels is so-

cially widely accepted in many cultures, excessive drink-

ing ultimately leading to alcohol dependence is a severe

health problem both at the individual and large-scale so-

cioeconomic levels. According to World Health Organi-

zation recommendations, the limit of risky consumption

is for men not to consume more than 4 standard drinks a

day or 28 standard drinks a week and for women not to

consume more than 2 standard drinks a day or 14 stan-

dard drinks a week. It is estimated that every fourth per-

son in Europe aged 15–64 regularly consumes alcohol at

harmful levels, and over 14 million people are alcohol de-

pendent

[1] . The US data from the 2001–2002 National

Epidemiological Survey on Alcohol and Related Condi-

tions showed a 12-month prevalence of 3.8% for alcohol

dependence defined by DSM-IV: 5.4% in men and 2.3%

in women

[2] . The lifetime prevalence of alcohol depen-

dence is 12.5% in the USA.

Alcohol use disorders (AUDs) can be defined as ‘mal-

adaptive patterns of alcohol use leading to clinically sig-

nificant impairment or stress’

[3] . Diagnostic criteria,

both from the Diagnostic and Statistical Manual of Men-

tal Disorders [4] and from the International Classification

of Diseases [5] divide AUDs into alcohol dependence and

abuse/harmful use. The major change proposed for DSM-

V (and introduced in May 2013) has replaced the 2 sepa-

rate DSM-IV (substance-specific) categories of depen-

dence and abuse with a single (substance-specific) cate-

gory, substance use disorder (SUD). The criteria for SUD

merge the previous lists of 7 criteria for dependence and

4 criteria for abuse into a single list of 11 criteria. SUD is

now additionally defined by the presence of craving,

while the criterion of recurrent legal problems has been

discarded. Severity of the illness is graded by the number

of criteria met: 0–1, no diagnosis; 2–3, mild SUD; 4–5,

moderate SUD; 6 or more, severe SUD. Tolerance and

withdrawal remain as symptoms of SUDs

[6] .

Alcohol dependence is defined across all versions of

the DSM, despite the recent changes in its definition, as a

disorder characterized by physiological and psychologi-

cal effects in individuals who consume large amounts of

alcohol

[7] .

The discrepancy between the widespread occurrence

of risky or harmful alcohol consumption and the fre-

quent, yet substantially lower, prevalence of clinical alco-

hol dependence raises the question why certain individu-

als become dependent on alcohol, sometimes in a rather

short time, while others do not seem to be affected by

regular alcohol consumption. There is nowadays little

doubt that alcohol dependence is a disorder of complex

etiology with multiple risk factors contributing to it. The

susceptibility to alcohol dependence is subject to consid-

erable interindividual variability, and it is shaped by both

including environmental (e.g. cultural, social political, re-

ligious, economic, legal including alcohol accessibility,

price and social norms) and genetic factors

[8–11] . The

biological processes that make one person more suscep-

tible to addiction than another are subject to intense in-

vestigations. Twin and adoption studies quantify the her-

itable component at 50–60%

[12–14] .

While in early adolescence the initiation and use of al-

cohol and other addictive drugs is primarily influenced

by environmental, i.e. familial and social, factors, the role

of environmental influences progressively decreases dur-

ing the transition to adulthood, when the impact of ge-

netic contribution reaches its peak

[15] . This observation

suggests that adolescence may be the optimal time point

for educational interventions.

A complex pattern of genetic associations indicates a

combined contribution of many genes as well as gene-

gene and gene-environment (GxE) interactions. To dis-

tinguish between environmental and genetic factors,

adoption and twin studies have been conducted. Adop-

tion studies demonstrate that adoptees more closely re-

semble their biological parents than their adoptive par-

ents in terms of susceptibility to alcohol dependence

[16–

19] . Twin studies reveal greater concordance between

monozygotic as compared to dizygotic twins, highlight-

ing a major genetic impact

[10, 19–21] . (Note: important-

ly, not all monozygotic cotwins of alcohol-dependent pa-

tients are alcohol-dependent themselves, also highlight-

ing the influence of environmental factors and GxE

interactions in the etiology of the disorder.) A third line

of evidence for a substantial genetic contribution to alco-

hol dependence comes from animal research. In selec-

tively bred rodent lines, a considerable proportion of her-

itability in the development of addiction-related behavior

has been observed, including strong preference for alco-

hol over water, willingness to work for alcohol, sensitiv-

ity to the hypnotic or activating effects of alcohol and to

withdrawal, and demonstrations that alcohol is reward-

ing even in the presence of food and water

[22–26] . A

fourth line of evidence comes from early genetic studies

in humans that demonstrated genetic variations in genes

related to alcohol metabolism that affect the predisposi-

tion to alcohol dependence

[27–30] .

The environmental contributions to alcohol-related

phenotypes include peer influence

[31–35] , availability

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of alcohol [31, 32, 36–38] , early first drink [32, 39] and

marital status

[32, 40] . Religious belief has been shown

to affect alcohol initiation

[32, 41] . The pattern of alco-

hol drinking is thought to contribute to the risk of alco-

hol dependence. The alcohol dependence risk grows al-

most linearly with the frequency of binge drinking [42] .

Data from the National Epidemiologic Survey on Alco-

hol and Related Conditions confirm the finding

[3, 42] .

However, one should remember that the pattern of

drinking can be modulated by both environmental and

genetic factors.

Risk loci for AUDs can be grouped into genes involved

in alcohol pharmacokinetics and pharmacodynamics,

and genes moderating addiction-related traits and behav-

iors such as sensation seeking, impulsivity, externalizing

behaviors and disinhibition. Our insight into the causes

of alcoholism is limited due to heterogeneity of its clinical

features, including a frequent co-occurrence with other

addictions and also with other psychiatric disorders, both

internalizing (e.g. depression and anxiety) and external-

izing (e.g. antisocial personality disorder, conduct disor-

der and attention deficit hyperactivity disorder)

[43–46] .

This heterogeneity may also be reflected by various AUD

subtypes used in current typologies and in the diverse

patterns of psychiatric and medical comorbidity observed

among AUD patients. Empirically derived typologies

typically identify 2–5 consistent subtypes classified by

their most prominent symptoms: early onset, externaliz-

ing behavior, affective instability and antisocial personal-

ity disorder. Multidimensional typologies differentiate

alcoholism by symptom severity. Typologies have com-

monly been derived from clinically based samples of al-

cohol-dependent persons, as the precise identification of

genetic loci has, at least so far, proven to be too complex

a task to accomplish

[47–50] . The genetic contribution to

the risk for AUDs is subject to nonmendelian transmis-

sion, and recent studies have concluded that there is a

wide range of genetic factors that might influence the risk

for AUDs

[51–54] .

Intermediate phenotypes – or endophenotypes – of

AUDs have been identified that are believed to be bio-

logically more directly related to the majority of the ge-

netic risk factors compared to the disorder itself. At least

3 reliable endophenotypes have been identified for AUDs:

(a) alcohol-induced skin flushing reaction associated

with lower AUD risk;

(b) a low response level to alcohol;

crine and neuroimaging phenotypes predictive of AUD

and other types of addiction

[55–60] .

There are 3 main techniques used to identify genetic

variations affecting alcohol dependence: candidate gene

studies, linkage studies and genome-wide association

studies (GWAS). The following review is based on a

search for PubMed-indexed articles reporting such stud-

ies. Candidate gene studies of alcohol dependence were

obtained from PubMed (http://www.ncbi.nlm.nih.gov/

pubmed) using the term ‘candidate gene’ combined with

‘alcohol dependence’, ‘alcohol use disorder’ or ‘alcohol

addiction’. Similarly, we searched for PubMed-indexed

articles describing linkage-based studies of genetic influ-

ences on alcohol dependence. Finally, we searched for

PubMed-indexed articles describing GWAS of alcohol

dependence by using the term ‘GWAS’ combined with

‘alcohol dependence’, ‘alcohol use disorder’ or ‘alcohol

addiction’. In each thus identified article, the reference

list was reviewed for similar studies. Only English-lan-

guage articles published before July 2013 (December 2013

in case of GWAS) in peer-reviewed journals were accept-

ed. Articles were identified and reviewed by 2 of the au-

thors, and their final decision was made by consensus. In

the case of GWAS of alcohol dependence, all relevant ar-

ticles identified in PubMed met the above criteria and

were included in this review.

Candidate Gene Studies

Genes Related to Alcohol Metabolism

The earliest genetic association studies in alcohol de-

pendence were candidate gene studies targeting coding

variations in genes that metabolize alcohol. Alcohol is

mostly metabolized in the liver, in a 2-step reaction: oxi-

dation to acetaldehyde, which is further oxidized to ace-

tate. The first step is primarily to be catalyzed by alcohol

dehydrogenases (ADHs), a reaction accompanied by re-

duction of NAD

+ to NADH. The second step is mainly to

be catalyzed by aldehyde dehydrogenases (ALDHs), with

reduction of another molecule of NAD

+ to NADH. Hu-

mans have 7 ADHs, with ADH1 being most important for

ethanol oxidation. ADH1 consists of 3 subunits, α, β and

γ, which are encoded by the genes ADH1A, ADH1B and

ADH1C. ALDHs constitute a group of enzymes, out of

which ALDH2 is primarily involved in the oxidation of

acetaldehyde. Variations in these genes have long been

known to affect the risk for alcoholism

[27–30, 61] .

A variation in the ALDH2 gene has striking effects on

alcohol metabolism. ALDH2 encodes the mitochondrially

localized ALDH2. An amino acid substitution from gluta-

mate to lysine at position 504 (NCBI accession No.: rs671),

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called ALDH2 * 2, leads to a drastic activity reduction of the

catalytically active subunit and additionally increases the

turnover of the tetrameric enzyme. The ALDH2 * 2 variant

is dominant, and the presence of at least 1 allele renders

the ALDH2 catalytic activity (measured in vitro ) below

the usual limit of detection

[62, 63] . In individuals carry-

ing the ALDH2 * 2 allele, consumption of even small

amounts of alcohol leads to accumulation of acetaldehyde

to toxic levels resulting in symptoms like flushing, tachy-

cardia and nausea, similar to the effects of alcohol in pa-

tients taking the ALDH2 inhibitor disulfiram.

The genes of the ADH s that catalyze the first step in

ethanol metabolism, clustered at chromosome 4, also

harbor genetic variations that strongly affect the risk for

alcohol-related disorders. After low to moderate intake of

alcohol, the ADH1 enzyme which consists of subunits en-

coded by ADH1A, ADH1B and ADH1C genes plays the

major role in alcohol metabolism

[27–29, 64] . At higher

(toxic) levels of alcohol, the ADH4 enzyme (encoded by

the ADH4 gene on chromosome 4) becomes more impor-

tant in alcohol metabolism

[64] . Genetic variations of

ADH4 have been linked to alcohol elimination

[65] , as

well as the risk for alcohol dependence in several different

populations

[66–68] . ADH7, located in the esophagus

and stomach lining, can contribute to ‘first pass’ metabo-

lism and thereby influence blood alcohol concentration

[27] .

However, these successfully replicated findings do not

explain risk differences in European populations in which

the alleles with the strongest effects are rare.

Genes Implicated in the Neurobiology of Addiction

The positive reinforcing effects of alcohol are gener-

ally believed to be critically mediated by the mesolimbic

reward pathway, a dopaminergic projection from the

ventral tegmental area to the nucleus accumbens that is

further modulated by several other neurotransmitters. In

addition to its effect on the dopaminergic system, alcohol

can affect the principal neurotransmitter glutamate and

γ-aminobutyric acid (GABA) as well as neuromodulatory

transmitters including acetylcholine, opioids and sero-

tonin

[69–74] .

It is therefore conceivable that genetic variations of the

dopaminergic system have been in the focus of candidate

gene-based association studies for a long time. For ex-

ample, genetic variations in the dopamine-metabolizing

enzymes catechol-O-methyltransferase and monoamine

oxidase A (MAOA) have been found to be associated with

the risk for alcohol dependence

[75–77] , although these

results could not be uniformly replicated

[78–80] . Other

studies have linked genetic variations in the dopamine

transporter 1 gene to the severity of withdrawal symp-

toms

[81, 82] .

One key problem in many candidate gene studies is the

poor replicability, which becomes evident in markedly

mixed results. Perhaps the best-known example is the as-

sociation of the Taq1A allele of the dopamine D

2 receptor

gene ( DRD2-Taq1A; rs1800497) with alcohol disorder,

which was first reported in a small study in 1990

[83, 84] .

Numerous groups have attempted to replicate this find-

ing, but most replication studies have yielded negative or

inconclusive results

[85–90] . A recent meta-analysis has

suggested a small but significant effect. The authors cau-

tioned that the positive result might have been caused

by publication bias

[91] , but a more recent meta-analysis

by a different group has confirmed the association and

largely ruled out publication bias

[84] . The example of

rs1800497 highlights another important problem of ge-

netic association studies, namely that inconclusive results

can result from linkage disequilibrium with other vari-

ants that might actually be causally related to a phenotype

(Note: linkage disequilibrium refers to the nonrandom

association and coupled inheritance of allelic variants at

two loci that may or may not have a large genetic distance

[92] ). The so-called DRD2 Taq1A polymorphism is actu-

ally located downstream of the DRD2 gene, within the

adjacent and closely linked ANKK1 (ankyrin repeat and

kinase domain containing 1) gene region

[93, 94] . There-

fore, associations of Taq1A with alcohol dependence

might result from linkage disequilibrium with other caus-

ative genetic variations in either DRD2 or ANKK1 or

both. A recent family study showed that a different ge-

netic variation in DRD2 (rs6277, a synonymous single

nucleotide polymorphism) that affects mRNA stability

[95] did indeed show an association with alcohol depen-

dence, while rs1800497 was not significantly associated

[96] . On the other hand, another family-based analysis

showed that the association of the ANKK1/DRD2 region

on chromosome 11q23 with alcohol dependence might in

fact be strongest in a part of the ANKK1 gene that is not

in linkage disequilibrium with DRD2 [35] . A further fam-

ily and case-control study suggested that a gene cluster in

this region consisting of NCAM1, TTC12 and ANKK1

might be involved in the etiology of alcohol dependence

[97–99] . The complexity and the inconclusive character

of these data point to a need for basic research to investi-

gate the biological processes underlying these associa-

tions. Such investigations might also help to identify in-

termediate phenotypes that are more closely related to the

genetic variations than a clinical phenotype per se. In the

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case of DRD2 and ANKK1, it has meanwhile been dem-

onstrated that the two molecules interact at protein levels

and that ANKK1 is upregulated by the dopamine agonist

apomorphine [100, 101] .

Beyond the dopaminergic system, numerous candi-

date gene studies of alcohol dependence and alcohol-re-

lated phenotypes have focused on molecules involved in

neurotransmitter pathways interacting with dopaminer-

gic transmission. These include genes involved in cholin-

ergic neurotransmission, such as the muscarinic cholin-

ergic receptor 2 (CHRM2) [102] and the α

5 -subunit of the

nicotinergic cholinergic receptor (CHRNA5) [103–105] ,

components of the GABAergic system like the α

2 -subunit

of the GABA-A receptor ( GABRA2 )

[106] and GABA re-

ceptor genes

[107–110] , genes coding for components of

glutamatergic transmission like the metabotropic gluta-

mate receptor 8 ( GRM8 )

[111] , genes involved in seroto-

nergic neurotransmission like the solute carrier family 6

member 4 (SLC6A4) gene that encodes the serotonin

transporter

[112, 113] , and components of the endocan-

nabinoid system such as cannabinoid receptor 1.

In addition to these genetic variants, which all affect

small-molecule neurotransmitters, numerous genetic as-

sociation studies have been conducted on genes related to

peptide neurotransmitters. Most notably, the opioid sys-

tem has repeatedly been found to be implicated in alcohol

addiction

[114–118] . There are 3 main opioid receptors

and 3 main genes encoding endogenous ligands. OPRM1

encodes the μ-receptor, and its primary ligand β-endorphin

is cleaved from the proopiomelanocortin protein, which

is encoded by the POMC gene. OPRK1 encodes the

κ-opioid receptor, and PDYN encodes the primary endog-

enous κ-opioid agonist (pro-)dynorphin. The δ-opioid re-

ceptor is encoded by OPRD1, and its primary ligand met-

enkephalin is synthesized as a propeptide, proenkephalin

A, which is encoded by the PENK gene [119] .

The μ-opioid receptor gene OPRM1, and especially the

coding variation Asn40Asp (rs1799971), has been exten-

sively studied in relation to alcohol dependence

[85] . Re-

sults have been inconclusive and partly conflicting, and a

meta-analysis concluded that there was no reliable evi-

dence for association

[120] . On the other hand, a more

recent meta-analysis has provided evidence for a role of

the Asn40Asp variation in the therapeutic response to the

μ-opioid antagonist naltrexone for prevention of relapse

[121] . The κ-opioid system has also been linked to AUDs

with both the PDYN gene coding for the κ-opioid agonist

prodynorphin and the κ-opioid receptor gene OPRK1

showing a genetic association with alcohol dependence

[122] .

Beyond the endogenous opioid system, research has

provided evidence for NPY , which encodes the peptide

neurotransmitter neuropeptide Y, as a candidate gene for

AUD. NPY modulates alcohol dependence in a rat mod-

[123–125] , and NPY knockout mice show increased

preference for alcohol

[126] . In humans, some but not all

genetic association studies have found evidence for an

association between polymorphisms in the NPY gene on

chromosome 7 and the risk for AUDs

[127–130] . Three

NPY receptor genes on chromosome 4 have also been

investigated in relation to AUDs, yielding 2 positive as-

sociations: NPY2R was associated with alcohol depen-

dence and alcohol withdrawal symptoms, and NPY5R

was associated with seizures during alcohol withdrawal

[130] . Other genetic association studies of peptide neu-

rotransmitter systems have found evidence for an asso-

ciation of AUDs with polymorphisms of the brain-de-

rived neurotrophic factor

[131] and the tachykinin re-

ceptor 3

[132] .

In light of the multitude of identified risk variants to

date, it must be kept in mind that there are numerous ex-

amples of associations that cannot be replicated. This

problem has occasionally led to scepticism about the use-

fulness of candidate-based association studies. Reasons

contributing to this lack of reproducibility include poor

study design, incorrect assumptions about the underlying

genetic architecture and simple overinterpretations of the

data. The most common errors in association studies of

complex diseases relate to small sample sizes and result-

ing low power, poorly matched control groups, data-driv-

en subgroup analyses (‘double dipping’) and insufficient

statistical control for multiple testing. To some extent, a

positive publication bias and unwarranted ‘candidate

gene’ declaration after identifying an association in an ar-

bitrary genetic region also contribute to poor replicability

[133, 134] .

Moreover, there might also be a biological reason for

heterogeneous results of association studies between

AUDs and genes related to neurotransmitter systems,

namely the fact that most neural cells express multiple

receptors that activate converging complex signaling cas-

cades, and potential risk mechanisms at receptor level

might be compensated at the level of intracellular signal-

ing. Therefore, genes affecting intracellular signaling in

response to receptor activation could also potentially af-

fect the risk for alcohol dependence. For example, the

gene encoding the nuclear factor of κ light polypeptide

gene enhancer in B cells 1 ( NFKB1 ), a transcription factor

activated by growth factor signaling

[135] , and the gene

encoding the matrix metallopeptidase 9, which plays a

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role in the remodeling of the perineuronal extracellular

matrix during synaptic plasticity

[136] , have both been

found to be associated with the risk for alcohol depen-

dence.

Gene-Environment Interactions

The association of single molecular-genetic variations

with psychiatric disorders including AUDs is modulated

by nongenetic influences, and the interplay between spe-

cific candidate genes and environmental factors has been

subject to numerous GxE interaction studies

[32] . Envi-

ronmental determinants that enhance the risk for AUD

differ in both proximity to the disorder and its mecha-

nism. Important risks for alcohol dependence include

prenatal exposure to alcohol, growing up in a home with

an alcoholic parent and being poorly monitored by one’s

parents

[137] . Other environmental factors exert their in-

fluence on an individual’s risk later in life. For instance,

genetic effects on drinking are greater in urban versus

rural residential settings

[36, 37] , as social restrictions in-

hibit development of genetically determined patterns of

behavior. Findings from a Collaborative Study on the

Genetics of Alcoholism (COGA) further suggest that

variation within an AUD susceptibility gene ( GABRA2;

rs279871) also depends on a person’s marital status, with

individuals carrying the high risk variant being less likely

to be married. Marital status also abated the influence of

other variants within GABRA2 [108] .

GxE interactions have been reported for several gene

variants that have previously been found to be associated

with alcohol dependence including genes with inconsis-

tent results in association studies like the DRD2 / ANKK1

gene region, 5-HTTLPR , MAOA , catechol-O-methyl-

transferase, GABRA2 and the corticotropin-releasing

hormone receptor 1 ( CRHR1 )

[138–142] . Therefore, GxE

interactions might contribute to the complexity of genet-

ic associations, and systematic assessment of environ-

mental factors might help to explain the difficulties in

replicating certain results.

Notably, GxE interactions are not limited to genes

with weak associations, but even genetic variations with

strong influence on alcohol-related behaviors and disor-

ders exert their influences in the interaction with envi-

ronmental factors. In fact, one of the most robust GxE

interactions was observed in carriers of the ALDH2 * 2

variant. A substantial GxE interaction with respect to

ALDH2 in the Japanese population was reported by Hi-

guchi et al.

[30] . The protective effect of the ALDH2 * 2

allele seemed to decrease substantially from 1979 to 1992

when the proportion of Japanese AUD patients heterozy-

gous for the ALDH2 * 2 soared from 2.5 to 13%

[30] . Giv-

en the short time interval of observation, a hypothetical

shift in allele frequencies within the Japanese population

could not explain this result. More likely, the protective

effect of the ALDH2 * 2 allele was reduced due to environ-

mental influences, most likely social changes favoring al-

cohol consumption. In the same study, no alcohol-de-

pendent patients homozygous for the ALDH2 * 2 were

identified, although 120 patients would have been expect-

ed based on the allele frequency. It was concluded that the

protective influence of the ALDH2 * 2 allele was so sub-

stantial in homozygotes that further modulation by envi-

ronmental influences did not occur

[30] .

Genetic Linkage Studies

Genetic linkage studies provide an unbiased method-

ology toward identifying genetic variations that affect the

risk for a complex genetic disease such as alcohol depen-

dence. The linkage approach is employed to identify ge-

netic risk variants for a disorder in families with several

affected members. Linkage studies test markers distrib-

uted across the genome, and if one such marker variant is

located near a causal genetic variation, family members

with the phenotype of interest would be expected to share

larger numbers of the same marker allele than those with-

out the phenotype. This provides information about the

broad chromosomal region in which the causal variants

are located, but, in most cases, not about specific genes.

The linkage method is most effective in phenotypes with

a mendelian inheritance pattern, which is rare in psychi-

atric disorders where common variants are unlikely to

have large effects

[143] . On the other hand, linkage stud-

ies are well suited for detecting genetic variants associated

with a major risk increase (at least 5- to 10-fold)

[144] .

Although nowadays largely of historic interest, linkage

studies have provided some useful information regarding

chromosomal risk loci for alcohol dependence. The earli-

est whole-genome linkage studies on alcohol dependence

were reported in 1998

[145, 146] . Large-scale linkage

studies like the COGA

[146] or the study by Long et al.

[145] in a relatively homogeneous Native American pop-

ulation have pointed to a risk locus on chromosome 4q,

which contains the ADH region. Additional evidence for

a risk locus on chromosome 4q was found in the Irish Af-

fected Sib Pair Study of Alcohol Dependence that addi-

tionally provided weaker, suggestive evidence for linkage

on chromosomes 1q, 13q and 22q for alcohol depen-

dence, on 2q, 9q and 19p for symptom count

[147] . Fur-

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ther loci identified in the COGA that were replicated in a

follow-up

[148] include chromosomes 1 and 7.

Other linkage studies have focused on disease-related

phenotypes rather than on the diagnosis per se. An anal-

ysis combining the diagnostic phenotype with an electro-

physiological variable (amplitude of the P300, an event-

related potential related to the processing of rare or nov-

el events) also pointed to a risk locus on chromosome 4q

[149] . A quantitative trait, maximum drinks in a 24-hour

period, also showed linkage on chromosome 4q

[150] , on

chromosome 9 for age of onset, on chromosomes 1 and

11 for initial response to alcohol, on chromosomes 1, 6

and 22 for tolerance, on chromosomes 12 and 18 for max-

imum drinks, and on chromosome 2 for withdrawal

symptoms

[151] . As these linkage studies only provide

information about chromosomal regions associated with

a disorder, a challenge for future research remains the

identification of the specific risk genes at these chromo-

somal loci.

Genome-Wide Association Studies

Recent advances in large-scale array-based genotyping

have opened up the possibility to conduct GWAS that by

now largely replaced linkage studies as the method of

choice for detecting genetic risk loci in an unbiased man-

ner. These studies combine several advantages of linkage

studies and candidate gene-based association studies: (a)

the coverage of the entire genome without the need for

strong a priori hypotheses and of candidate gene ap-

proaches; (b) the high resolution providing information

about single genes; (c) the possibility to include sporadic

and not only familial cases. In GWAS, several hundred

thousands or millions of markers across the entire ge-

nome are analyzed in order to identify differences in allele

or genotype frequencies between individuals positive or

negative for a phenotype of interest.

Since their introduction, GWAS have proven to be

successful in identifying numerous genetic factors con-

tributing to the risk for complex somatic diseases like

breast cancer

[152, 153] , colorectal cancer [154] , type 2

diabetes

[155, 156] or heart disease [157] , but also for psy-

chiatric disorders like schizophrenia or bipolar disorder

[158–160] . The GWAS approach is not without limita-

tions, however. Due to the risk of false positives resulting

from the extraordinary amount of multiple testing inher-

ent to the method, conservative statistical corrections of

the significance level are required that are likely to result

in false-negative data. To overcome this limitation, very

large sample sizes are required to obtain the necessary

statistical power. Moreover, GWAS are designed to iden-

tify relatively common polymorphisms associated with

the risk for a disease. Rare genetic variants with poten-

tially high influence on individual risk might thus be

overlooked by GWAS, but can be still captured by linkage

studies.

Regarding alcohol-related disorders, GWAS have

identified a number of chromosomal regions and candi-

date genes for AUDs, alcohol-related phenotypes and co-

morbid disorders. Johnson et al.

[161] published in 2006

a pioneering GWAS of alcohol dependence from the

COGA. The study was performed on 100,000 markers in

120 patients and 160 healthy controls. Fifty-one clusters

of polymorphisms were identified that provided informa-

tion about novel candidate genes for alcohol dependence,

including genes involved in gene regulation, cell signal-

ing, brain development and cell adhesion. Among these

were the genes of the cell adhesion molecules cadherin 11

(CDH11) and cadherin 13 (CDH13) . In the following

years, several GWAS have been conducted to identify risk

factors for alcohol dependence ( table1 , first part) as well

as genetic modifiers of alcohol consumption in the healthy

population ( table 1 , second part). Additionally, a few

GWAS have been aimed to identify associations with al-

cohol-related phenotypes, including both clinical fea-

tures like withdrawal severity and basic behavioral and

neurophysiological measures ( table1 , third part).

Several risk loci identified by GWAS confirm previ-

ously observed associations of genes involved in alcohol

metabolism with a risk for alcohol dependence and drink-

ing behavior. For example, Frank et al.

[162] detected ge-

nome-wide significance for marker rs1789891 in the

ADH gene cluster on chromosome 4q in a sample of 1,333

patients and 2,168 controls. This finding is well in line

with prior results of linkage analyses reporting an asso-

ciation of this chromosomal region with alcohol depen-

dence and alcohol-related phenotypes

[147] . rs1789891 is

also in high linkage disequilibrium with the functional

ADHC1 Arg272Gln polymorphism that has been shown

to affect alcohol oxidation in vitro. Further genome-wide

evidence for a role of the ADH gene on the chromosome

4q cluster in the risk of alcohol dependence was provided

by Park et al.

[163] , who additionally found genome-wide

significance for the functional ALDH2 rs671 that has re-

peatedly been associated with alcohol consumption levels

and risk for alcohol dependence (see above). This asso-

ciation was also confirmed at the genome-wide level in a

2-stage GWAS for alcohol use in a Japanese population

performed by Takeuchi et al.

[164] . For both, nominally

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Authors, year Study name Number of patients/controls Identified gene loci

GWAS of alcohol dependence

Johnson et al.

[161], 2006

COGA 120 patients, 160 controls 51 gene loci remain significant after Monte Carlo simulation-

based correction, including CDH11, CDH13

FDR threshold less conservative than in later GWAS

Treutlein et al.

[182], 2009

n.a. Initial sample: 487 patients, 1,358 controls;

follow-up sample: 1,024 patients, 966 controls

Genome-wide significance for 2 intergenic loci on chromosome

2q35: rs7590720, rs1344694 in the combined sample

15 nominally significant SNPs were replicated, including SNPs

in CDH13 and ADH1C

Edenberg et al.

[169], 2010

COGA Initial sample: 1,192 patients, 692 controls;

follow-up in 292 pedigrees

No SNP with genome-wide significance

Initial sample and follow-up sample provide converging

evidence for a gene cluster on chromosome 11, encompassing

SLC22A18, PHLDA2, NAP1L4, SNORA54, CARS, OSBPL5

Bierut et al.

[168], 2010

SAGE (includes

COGA, FSCD,

COGEND)

1,897 patients, 1,932 controls; 2 replication

samples

No SNP with replicated genome-wide significance

Replicated nominal significance for GABRA2 SNPs

Lind et al.

[200], 2010

OZALC Initial sample: 1,224 patients, 1,162 controls

from the Australian Twin Registry; replication

sample: 555 patients, 2,768 controls from the

Netherlands

No replicated genome-wide significance

Meta-analysis of initial and replication samples provides

evidence for risk variants in genes coding ion channels and cell

adhesion molecules

Kendler et al.

[186], 2011

MGS2 3,169 controls from the MGS2 study screened

for symptoms of alcohol dependence

No genome-wide significance

Most significant loci KCNMA1 (Caucasians) and SLC35B4

(African-Americans)

Wang et al.

[166], 2011

COGA, OZALC 272 nuclear families from 116 pedigrees

(COGA); replication in the OZALC cohort

(twin study)

Low density GWAS with 11,120 SNPs and less conservative

threshold (p < 10 – 3)

Genome-wide significance at p < 10 – 8 for DSCMAL1

Further replicated loci include TPARP, CYFIP2, THEMIS,

PSG11

Wang et al.

[167], 2011

COGA, SAGE,

OZALC

COGA: 1,025 patients, 569 controls; SAGE: 637

patients, 1,032 controls; replication in OZALC:

1,650 patients, 1,684 controls from 778 nuclear

families

No genome-wide significance

Replicated novel associations with KIAA0040, THSD7B, NRD1

Confirmed association with PKNOX2

Frank et al.

[162], 2012

n.a. 1,333 patients, 2,168 controls Genome-wide significance for rs1789891 in ADH1 gene cluster,

in LD with functional ADH1C Arg272Gln, nominally replicated

in COGA sample

Feasibility of polygenic score analysis was demonstrated

Zuo et al.

[172, 173],

2011, 2012

COGA, SAGE 2,090 patients, 2,026 controls Genome-wide significance for KIAA0040 (chromosome 1q)

Replicated association for 90-Mb region around the PHF3-

PTP4A1 locus on chromosome 6q12

Biernacka et al.

[201], 2013

SAGE 1,165 patients, 1,379 controls Gene set enrichment analysis, not aimed at single genome-wide

significant loci

Pathway analysis points to potential involvement of ketone

metabolism and ligand-receptor interactions

Zuo et al.

[202], 2013

COGA, SAGE Initial sample: 1,409 patients, 1,518 controls;

replication sample: 6,438 European-Australian

family subjects including 1,645 alcohol-

dependent patients

Genome-wide significance for NKAIN1-SERINC2 in subjects of

European, but not African descent

471 SNPs nominally associated, 53 survived region- and cohort-

wide correction, 92 were replicated

Zuo et al.

[203], 2013

SAGE, COGA Initial sample: 818 European-American patients

with alcohol and nicotine codependence, 1,396

controls; 2 replication samples

Genome-wide significant association of combined alcohol and

nicotine dependence with rs7445832 in IPO11-HTR1A region

on chromosome 5q

4 genome-wide significant SNPs in IPO11-HTR1A region

revealed by meta-analysis of discovery and replication samples

Park et al.

[163], 2013

n.a. Initial sample: 117 alcohol-dependent patients,

279 controls; replication sample: 504 patients,

471 controls

Genome-wide significane for rs1442492 and rs10516441 in

ADH7 gene region and ALDH2 rs671

Multiple nominally significant SNPs in ADH gene cluster on

4q22–q23

Table 1. Overview of GWAS on alcohol-related disorders

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Table 1 (continued)

Authors, year Study name Number of patients/controls Identified gene loci

Quillen et al.

[165], 2014

n.a. 352 males, 243 females from an isolated rural

Chinese population

Genome-wide significance for ALDH2*2

ALDH2*2 also shows genome-wide significant association with

maximum alcohol intake and flushing response

Gelernter et al.

[171], 2014

GCD Initial sample: 379 European-Americans, 3,318

African-Americans; replication sample: 1,746

European-Americans, 803 African-Americans;

further replication in SAGE sample and in a

German sample; total n = 16,087 subjects

Replicated genome-wide significance for ADH1B, ADH1C

Novel genome-wide significant risk variant rs1437396 between

MTIF2 and CCDC88A

GWAS of alcohol consumption

Schumann et al.

[204], 2011

n.a. 26,316 individuals from 12 population-based

samples

Genome-wide significance for AUTS2 rs6943555

Nominal significant association with RASGRF2 rs26907

Baik et al.

[205], 2011

n.a. Initial sample: 1,721 males; replication sample:

1,113 males

Replicated genome-wide significance for SNPs on chromosome

12q24, including C12ORF51 rs2074356, C12orf51 in LD with

ALDH2, CCDC63, MYL2

Genome-wide significance, but no replication for SNPs in

CCDC63, OAS3, CUX2 and RPH3A

Takeuchi et al.

[164], 2011

n.a. Initial sample: 733 ever-drinkers, 729

nondrinkers; replication sample: 2,794 drinkers,

1,521 occasional drinkers, 1,351 nondrinkers

genome-wide significance for ALDH2 rs671 in both discovery

and replication sample

replicated nominal significance for ADH1B rs1229984

Chen et al.

[206], 2012

n.a. Initial sample: 904 Caucasians, 3 replication

samples (n = 1,972, 761, 2,955)

Genome-wide significance for SNP clusters in ANKRD7, CYTL1

Most significant SNPs ANKRD7 rs4295599, CYTL1 rs16836497

Heath et al.

[170], 2011

n.a. 8,754 individuals including 2,062 patients No genome-wide significance

Convergent evidence for association of ANKS1A rs2140418 and

TMEM108 rs10935045 with drinking severity

Kapoor et al.

[207], 2013

COGA, SAGE 2,322 subjects from 118 extended families;

2,593 subjects from a case-control study

No genome-wide significance

Meta-analysis suggests association of LMO1 and PLCL1 with

maximum number of drinks

Nominal association of AUTS2, INADL, C15ORF32 and HIP1

with measures of alcohol consumption in meta-analysis

Pan et al.

[208], 2013

COGA, SAGE 1,059 subjects from COGA study, 1,628 subjects

from SAGE study; replication in OZALC

sample

Genome-wide significant association of rs11128951 near SGOL1

with maximum number of drinks

Meta-analysis additionally shows association of rs17144687 near

DTWD2, rs12108602 near NDST4 and rs2128158 in KCNB2

with maximum number of drinks

GWAS of alcohol-related phenotypes

Wang et al.

[176], 2013

COGA 2,322 subjects from 118 extended families;

replication in SAGE and OZALC samples

Genome-wide significance for 3 SNPs in C15ORF53 gene with

alcohol dependence symptom count, albeit only nominally

significant after inflation correction

Wang et al.

[209], 2012

COGA 461 patients, 408 controls No genome-wide significance

4 SNPs nominally associated with alcohol withdrawal severity:

rs770182 (near EFNA5, chromosome 5q21); rs10975990,

rs10758821 and rs1407862 (KDM4C, 9p24.1)

Joslyn et al.

[179], 2010

n.a. 367 healthy individuals with positive family

history for alcohol dependence

Gene set enrichment analysis, not aimed at single genome-wide

significant loci

156 loci pointing to 173 genes, mostly in neuronal signaling

pathways, influence alcohol level of response

Zlojutro et al.

[177], 2011

COGA 1,192 patients, 692 controls; replication in 262

pedigrees (1,195 individuals)

No genome-wide significance, ARID5A rs4907240 and HTR7

rs7916403 nominally associated with novelty-related theta

oscillations

HTR7 rs7916403 nominally associated with diagnosis of alcohol

dependence

FDR = False discovery rate; n.a. = not available; SNP = single-nucleotide polymorphism; SAGE = Study of Addiction: Genetics and Environment;

FSCD = Family Study of Cocaine Dependence; COGEND = Collaborative Genetic Study of Nicotine Dependence; OZALC = Australian Twin-Family Study

of Alcohol Use Disorder; MGS2 = Molecular Genetics of Schizophrenia; GCD = GWAS discovery samples; LD = linkage disequilibrium.

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classified drinking behavior (nondrinkers vs. occasional

drinkers vs. drinkers) and level of alcohol consumption,

ALDH2 rs671 came out as the strongest predictor with

genome-wide significance. The most recent replication of

the prominent role for ALDH2 in the modulation of

drinking behavior in East Asians comes from a GWAS by

Quillen et al.

[165] , which was performed in an isolated

rural Chinese sample.

In addition to these highly expected findings, GWAS

have also helped to identify novel risk loci for alcohol de-

pendence and related phenotypes, albeit resulting in

more ambiguous results (see table 1 for a summary).

While some studies did not yield any genetic variations

with genome-wide significance, others identified several

candidate loci, many of which could, however, not be re-

liably replicated subsequently. A reason for the inconclu-

sive results of most GWAS might be insufficient statistical

power resulting from required corrections for multiple

testing. Means to circumvent this problem include meta-

analyses of the literature and reanalyses of pre-existing

original data, both of which increase statistical power. For

example, Wang et al.

[166, 167] combined data sets from

the SAGE, the COGA and the OZALC GWAS

[168–170]

and identified several gene loci not reported in the initial

publications ( table1 , first part). In a very recent GWAS,

Gelernter et al.

[171] included a total of 16,087 subjects,

both newly recruited and from pre-existing samples. The

study yielded strong genome-wide associations with vari-

ants in the ADH gene cluster and additionally identified

a putatively regulatory variant rs1437396, located be-

tween the MTIF2 and CCDC88A genes as a novel risk

variant with replicated genome-wide significance

[171] .

A further scientific challenge posed by GWAS is due

to the identification of numerous associations that have

been observed with genetic variants that are either extra-

genic or located in thus far poorly characterized genes. To

understand the biological processes that underlie the ob-

served associations, it is therefore necessary to further

characterize the impact of the identified variants at both

the molecular and system levels. At a molecular level, ex-

pression quantitative trait locus studies allow the identi-

fication of both cis and trans regulatory associations of

genetic variations with gene expression levels. Zuo et al.

[172, 173] combined the GWAS approach with expres-

sion quantitative trait locus in the analysis of data from

2,090 alcohol-dependent patients and 2,026 controls. The

observed associations of variants in PHD finger protein 3

gene ( PHF3), protein tyrosine phosphatase type IVA,

member 1 gene (PTP4A1) region [173] , and KIAA0040

[172] genes with alcohol dependents corresponded to re-

sults of transcriptome-wide expression analyses showing

that the transcripts of these genes were involved in regu-

latory mechanisms of other alcohol-related candidate

genes

[172, 173] .

At the system level, it has been suggested that the re-

lated endophenotypes are more directly related to the

molecular effect of a gene variant than the clinical pheno-

type

[174, 175] . A potential endophenotype solely based

on clinical criteria is the symptom count as a crude, but

straightforward measure of disease severity that can be

applied in both patients and healthy controls. In a GWAS

directed at alcohol dependence symptom count, Wang et

al.

[176] found converging evidence for a role of the thus

far poorly characterized C15ORF53 gene in the etiology

of alcohol dependence-related phenotypes. Other endo-

phenotypes show a weaker statistical association with the

clinical phenotype of interest, but might be more directly

related to the underlying pathophysiological mecha-

nisms. For example, novelty-related brain oscillations in

the theta band have previously been found to be linked to

alcohol dependence. Zlojutro et al.

[177] performed a

2-stage GWAS on event-related theta oscillations in 1,192

patients and 692 controls, using 262 pedigrees (1,095 in-

dividuals) as a replication sample. They identified ge-

netic variations in the ARID5A gene (rs4907240) and in

the gene coding for the serotonin receptor 7 ( HTR7 ,

rs7916403) to be associated with novelty-related theta ac-

tivity.

From Genes to Pathways

The genes associated with alcohol dependence in both

GWAS and replicated candidate-based association stud-

ies are, at first sight, a rather heterogeneous group, with

their products being involved in diverse biological func-

tions, including (peripheral) alcohol metabolism, neuro-

transmission, intracellular signaling, but also seemingly

unrelated processes like immune function. For example,

the KIAA0040 risk variant identified in a GWAS by Zuo

et al.

[172] and replicated in the meta-analysis by Wang

et al.

[167] , encodes an HLA1-DR11-restricted T cell epi-

tope with yet unknown function

[178] . However, expres-

sion quantitative trait locus analysis has demonstrated

that the expression of the KIAA0040 gene is associated

with the expression of multiple other genes involved in

neurotransmission, including several genes previously

implicated in alcohol dependence and other psychiatric

disorders, such as DRD2-TTC12, DRD3, HTR1B, GRM5

and OPRD1 [172] . Further evidence for a role of genes

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involved in neurotransmission and intracellular signaling

comes from a gene set enrichment analysis (GSEA) on

GWAS data performed by Joslyn et al.

[179] . GSEA is a

computational method that assesses differential distribu-

tion of a priori defined sets of genes between populations

of interest. Joslyn et al. observed that level of alcohol re-

sponse phenotypes (i.e. self-report on the effects of etha-

nol, subjective high assessment, body sway

[180] ) showed

a systematic distribution difference in 173 genes, includ-

ing CDH13 and XRCC5 , which had been identified as sus-

ceptibility genes for ethanol sensitivity and alcohol de-

pendence elsewhere

[161, 181, 182] . Multiple genes iden-

tified in the GSEA were related to glutamatergic signaling,

a finding well in line with previous results of animal stud-

ies and candidate gene analyses

[183, 184] . Additionally,

the muscarinic receptor (CHRM2) has been replicated in

2 GWAS

[185, 186] and several other well-replicated can-

didate genes (i.e. >10 studies), such as GABRA2 [168] ,

MAOA [166] , GRIN2B [179] and ANKK1 [186] , have

emerged in recent GWAS, further confirming the role of

the cholinergic, dopaminergic and GABAergic transmit-

ter systems. Many of these variants do not only affect the

risk for AUD, but also have an influence on other sub-

stance-related disorders (e.g. GABRA2, CHRM2, NFKB1)

[68, 106, 132, 135, 187] .

Summary and Future Perspectives

Considerable progress has been made in the research

of genetic contributions to alcohol dependence. For sev-

eral genetic variations, a prominent role in the risk for

developing alcohol-related disorders is largely undisput-

ed. Most prominently, several functional variations in

genes involved in alcohol metabolism, namely the ADH

and ALDH genes, play a major role in modulating alco-

hol-related behaviors and thereby affect the individual

risk for AUD. This is particularly true for the ALDH2 * 2

variant that strongly predicts drinking behavior in East

Asian populations, with effect sizes only comparable to

the robust association of APOE/TOMM40 with dementia

[188] . In populations of European ancestry, in which the

coding variations in ALDH are far less common, the

greatest proportion of the individual genetic risk is yet

unexplained and probably reflects the accumulating ef-

fects of multiple genes with minor individual impact.

However, the importance of alcohol-metabolizing en-

zymes becomes evident as most robust associations in Eu-

ropeans have been observed in the ADH gene cluster.

With recent advances in high-throughput genotyping

and bioinformatics, GWAS in large samples become fea-

sible that allow the robust detection of variants beyond

the metabolism-related genes

[171] . Additionally, rare

genetic variations that are insufficiently detected by

GWAS as well as gene-gene and GxE interactions

[189–

191] are likely to contribute heritability, phenomena that

are actually common to the genetics of most psychiatric

disorders

[192] .

A more comprehensive characterization of the genetic

susceptibility to AUD will most likely require (a) a more

refined characterization of alcohol-related phenotypes

(e.g. subtypes of alcohol dependence with higher vs. low-

er heritability) and (b) advanced analytic techniques that

make use of both array and next-generation sequencing

technologies

[193] . A comprehensive discussion of stud-

ies applying these approaches is beyond the scope of this

review, but we refer to recent review papers that cover

GWAS of alcohol dependence

[182, 186, 194–196] . A po-

tential future challenge might be posed by the change in

diagnostic criteria with the publication of DSM-V

[6] .

While merging the diagnostic criteria into a single entity

‘substance use disorders’ with varying degrees of severity

might ease the definition of endophenotypes or of semi-

quantitative approaches like symptom count

[176] , great

care must be taken when comparing studies based on

DSM-V with previously published DSM-IV-based work.

Also, GxE interactions must be considered

[189–191] , al-

though keeping in mind that the GxE approach is one of

the most challenging and complex of all conceptual

frameworks applied in the genetic investigation of AUDs

[197] .

From the statistical point of view, lack of power is a

weakness of most genetic investigations in psychiatry, a

problem that is actually shared by many disciplines with-

in neurosciences and contributes to poor replicability of

data

[198] ; very large samples are required to overcome

this essential limitation. Preliminary findings must be

confirmed in independent studies, and much work re-

mains to be done to elucidate the neural mechanisms un-

derlying the genetic associations. Nevertheless, owing to

the emergence of new technologies allowing to study even

larger sample sizes, progress will be swift. The future will

involve studies of epigenetic factors, copy number vari-

ants and other rare genetic variations, and gene expres-

sion data.

As we learn more about the genetic framework of

AUD, we find that different genetic variants lead to vary-

ing responses to treatment options, which might improve

our ability to design individualized therapy concepts

[135, 199] . One example for the potential pharmacoge-

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netic approaches is the association of the OPRM1 As-

n40Asp variation with the efficacy of the opioid antago-

nist naltrexone on relapse prevention

[117] , although it

remains to be established whether this association is of

clinical significance. Irrespective of the actual magnitude

of the effect of OPRM1 Asn40Asp, this observation

should stimulate large-scale studies investigating the role

of genetic markers in the response to pharmacotherapy,

with the possibility to perform GWAS on treatment out-

comes being a promising approach in the near future.

More generally, from a clinical perspective, distinct

phenotype characterization of a vast number of individu-

als including data on AUDs and alcohol-related pheno-

types, comorbid psychiatric and medical disorders as well

as therapy response is needed to facilitate the identifica-

tion of patients that might benefit from certain therapeu-

tic lines. The above considerations refer both to pharma-

cotherapeutic and to psychotherapeutic approaches. The

identification of reliable genetic markers predicting the

response to psychotherapy, medications and their com-

bination remains a great scientific challenge for the fu-

ture.

Acknowledgements

This work was supported by the Deutsche Forschungsgemein-

schaft (SFB 779, TP A8). We thank Claudia Hägele for her helpful

comments on the paper.

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Associações entre polimorfismos genéticos da álcool: desidrogenase e o transtorno por uso de álcool

Article

Mar 2020

Associações entre polimorfismos genéticos da enzima álcool desidrogenase e o transtorno por uso de álcool

Article

Full-text available

Mar 2020

O transtorno por uso de álcool (TUA) é influenciado pela genética, principalmente na metabolização do etanol. Os genes da álcool desidrogenase (ADH1B/ADH1C), enzima que transforma o etanol, apresentam SNPs (single nucleotide polymorphisms) que resultam em isoenzimas com diferentes taxas catalíticas. Estudos demonstraram que os SNPs Arg48His, Arg370Cys, Arg272Gln e Ile350Val contribuem para o TUA. Este artigo revisou os estudos que investigaram SNPs em ADH1B (Arg48His/Arg370Cys) e ADH1C (Arg272Gln/Ile350Val), bem como avaliou as variações nas frequências alélicas desses genes e a influência no TUA nas diferentes populações no mundo. As frequências alélicas dos polimorfismos nos genes ADH1B e ADH1C foram comparadas entre diferentes regiões do mundo. A revisão foi realizada através de plataformas eletrônicas como NCBI/PUBMED, Google Scholar, SciELO, Science Direct, MEDLINE, LILACS e Scopus. As coletas dos dados referentes as frequências dos polimorfismos nos genes ADH1B e ADH1C foram realizadas a partir do banco de dados Ensembl Genome Browser 92 com os seguintes descritores: rs1229984, rs2066702, rs1693482 e rs698. As frequências alélicas dos polimorfismos foram comparadas pelos testes qui-quadrado de Pearson e exato de Fisher, considerando um nível de significância pré-estabelecido para o erro alfa de 5% (p

GENETIC ASPECTS OF DEVIANT BEHAVIOR

Article

Sep 2019

Motivational learning biases are differentially modulated by genetic determinants of striatal and prefrontal dopamine function

Article

Full-text available

Nov 2021
J NEURAL TRANSM

Dopaminergic neurotransmission plays a pivotal role in appetitively motivated behavior in mammals, including humans. Notably, action and valence are not independent in motivated tasks, and it is particularly difficult for humans to learn the inhibition of an action to obtain a reward. We have previously observed that the carriers of the DRD2/ANKK1 TaqIA A1 allele, that has been associated with reduced striatal dopamine D2 receptor expression, showed a diminished learning performance when required to learn response inhibition to obtain rewards, a finding that was replicated in two independent cohorts. With our present study, we followed two aims: first, we aimed to replicate our finding on the DRD2/ANKK1 TaqIA polymorphism in a third independent cohort (N = 99) and to investigate the nature of the genetic effects more closely using trial-by-trial behavioral analysis and computational modeling in the combined dataset (N = 281). Second, we aimed to assess a potentially modulatory role of prefrontal dopamine availability, using the widely studied COMT Val108/158Met polymorphism as a proxy. We first report a replication of the above mentioned finding. Interestingly, after combining all three cohorts, exploratory analyses regarding the COMT Val108/158Met polymorphism suggest that homozygotes for the Met allele, which has been linked to higher prefrontal dopaminergic tone, show a lower learning bias. Our results corroborate the importance of genetic variability of the dopaminergic system in individual learning differences of action-valence interaction and, furthermore, suggest that motivational learning biases are differentially modulated by genetic determinants of striatal and prefrontal dopamine function.

Understanding the neurobiological effects of drug abuse: Lessons from zebrafish models

Article

Full-text available

Jan 2020

Drug abuse and brain disorders related to drug comsumption are public health problems with harmful individual and social consequences. The identification of therapeutic targets and precise pharmacological treatments to these neuropsychiatric conditions associated with drug abuse are urgently needed. Understanding the link between neurobiological mechanisms and behavior is a key aspect of elucidating drug abuse-related targets. Due to various molecular, biochemical, pharmacological, and physiological features, the zebrafish (Danio rerio) has been considered a suitable vertebrate for modeling complex processes involved in drug abuse responses. In this review, we discuss how the zebrafish has been successfully used for modeling neurobehavioral phenotypes related to drug abuse and review the effects of opioids, cannabinoids, alcohol, nicotine, and psychedelic drugs on the central nervous system (CNS). Moreover, we summarize recent advances in zebrafish-based studies and outline potential advantages and limitations of the existing zebrafish models to explore the neurochemical bases of drug abuse and addiction. Finally, we discuss how the use of zebrafish models may present fruitful approaches to provide valuable clinically translatable data.

Associations of BRAP polymorphisms with the risk of alcohol dependence and scores on the Alcohol Use Disorders Identification Test

Article

Full-text available

Dec 2018

Background Alcohol dependence (AD) is a common disorder that is influenced by genetic as well as environmental factors. A previous genome-wide association study (GWAS) of the Korean population performed by our research group identified a number of genes, including BRCA1-associated protein (BRAP) and protein arginine methyltransferase 8 (PRMT8), as novel genetic markers of AD. Methods The present investigation was a fine-mapping follow-up study of 459 AD and 455 non-AD subjects of Korean descent to determine the associations between BRAP and PRMT8 polymorphisms and AD. The Alcohol Use Disorders Identification Test (AUDIT) was administered to screen for the degree of AD risk in the subjects and 58 genetic variants, 5 for BRAP and 53 for PRMT8, were genotyped for subsequent association analyses. Results In the present case–control analysis, BRAP rs3782886 showed the most significant association signal with a risk of AD (P=1.29×10⁻¹⁶, Pcorr =7.74×10⁻¹⁶, OR =0.19). There were also significant differences in the overall and subcategory scores for the BRAP genetic variants, including rs3782886 (P=9.94×10⁻³¹, Pcorr =5.96×10⁻³⁰ at rs3782886 for the overall AUDIT score). However, the genetic effects of PRMT8 polymorphisms observed in our previous GWAS were not replicated in the present study (minimum P=0.0005, Pcorr >0.05, OR =0.30 at rs4766139 in the recessive model). Furthermore, the single-nucleotide polymorphisms of PRMT8 were not associated with the overall and subcategory AUDIT scores. Conclusion The present findings suggest that the genetic variants of BRAP may contribute to a predisposition for an alcohol use disorder.

Evaluation of previous substance dependence genome-wide significant findings in a Spanish sample

Article

Apr 2018
DRUG ALCOHOL DEPEN

Background: Substance dependence is a chronic and relapsing disorder explained by genetic and environmental risk factors. The aim of our study is to replicate previous genome-wide significant (GWS) hits identified in substance dependence in general or in cocaine dependence in particular using an independent sample from Spain. Methods: We evaluated, in a Spanish sample of 1711 subjects with substance dependence (1011 of them cocaine dependent) and 1719 control individuals, three SNPs identified as GWS in previous studies: rs1868152 and rs2952621 (located near LINC02052 and LINC01854, respectively), associated with substance dependence, and rs2629540 (in the first intron of FAM53B), associated with cocaine dependence. Results: We replicated the association between rs2952621 and substance dependence under the dominant model (P = 0.020), with the risk allele (T) being the same in our sample and in those two reported previously. We then performed a meta-analysis of the two samples used in the original study that reported the association of rs2952621 with substance dependence (Collaborative Studies on Genetics of Alcoholism (COGA) and Study of Addiction: Genetics and Environment (SAGE)) together with our Spanish sample. The meta-analysis of 3747 cases and 4043 controls confirmed the association (OR = 1.26, 95% CI = 1.15-1.39). Conclusions: The rs2952621 variant, located downstream from the yet uncharacterized gene LINC01854, is associated with substance dependence in our Spanish sample. Further research is needed to understand its contribution to the susceptibility to substance dependence.

The changes in retinal nerve fiber layer and macular thickness in Chinese patients with alcohol dependency

Article

Oct 2021
DRUG ALCOHOL DEPEN

Objectives This study examined the changes in the retinal nerve fiber layer (RNFL) thickness and the macular thickness in Chinese patients with alcohol dependency and ascertaining the influence of optic cup volume on cognitive functioning. Methods A total of 26 alcohol-dependent patients and 53 age- and gender-matched healthy controls were enrolled in the study. All subjects underwent Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) measurement and were scanned via spectral-domain optical coherence tomography (OCT). Results Compared with the healthy controls, the alcohol-dependent patients returned lower scores across all subscales and total RBANS scores. The total thickness of the RNFL of the left eye, temporal and nasal RNFLthickness of both eyes were thinner in the alcohol-dependent patients (all p < 0.05). In terms of macular thickness, eight macular regions and the average thickness of the right eye and three of the left eye were thinner in the alcohol-dependent patients than in the healthy controls. The linear regression analysis indicated that a higher alcohol consumption was associated with thinner RNFL and macular thickness especially in temporal and inferior quadrant region after controlling for smoker status, age, BMI, cholesterol level and AKT level. Conclusions A higher alcohol consumption was significantly associated with thinner RNFL and macular thickness, indicating that alcohol is a potential risk factor affecting RNFL thickness and macular thickness. Meanwhile, the increase in optic cup volume was associated with the reduced cognitive functioning of the alcohol-dependent patients.

Обзор генетических основ формирования девиантного поведения

Article

Jan 2021

Calcium/calmodulin-dependent protein kinase IV gene polymorphisms in Korean alcohol-dependent patients

Article

Jul 2017

Introduction: A relationship between alcohol dependence (AD) and calcium/calmodulin-dependent protein kinase IV (CAMKIV) has been reported in a whole genome study of Korean AD patients. The purpose of the present study is to compare the frequency of CAMKIV genotypes and alleles between AD and control subjects in Korea. Methods: The present study includes 281 AD patients and 139 control subjects. Seven single nucleotide polymorphism of CAMKIV gene known to show significant separation ratio in Asians were searched in SNP database and previous studies related to CAMKIV gene. Polymerase chain reaction and restriction fragment length polymorphism techniques were used to analyze genotype of CAMKIV gene SNPs. Results: Major TT genotype and T allele frequencies of rs 25917 in AD patients were significantly higher than those of control subjects (genotype frequency, p=0.002; allele frequency, p=0.001). Major CC genotype and C allele frequencies of rs 117590959 in AD patients were also significantly higher than those of control subjects (genotype frequency, p<0.001; allele frequency, p=0.001). Major genotypes of rs25917 (p=0.002, odd ratio: 3.13, 95% CI: 1.54-6.38) and rs11790959 (p=0.002, odd ratio: 3.22, 95% CI: 1.52-6.81) showed significantly higher odds ratios associated with AD than minor genotypes in logistic regression. Discussion: These results suggest that CAMKIV might be a candidate AD gene. Further research is needed to determine the precise relationship between CAMKIV and AD and the function of each SNP.

Quantitative Trait Loci Involved in Genetic Predisposition to Acute Alcohol Withdrawal in Mice

Article

Full-text available

May 1997

Alcohol dependence (alcoholism) is accompanied by evidence of tolerance, withdrawal (physiological dependence), or compulsive behavior related to alcohol use. Studies of strain and individual differences using animal models for acute physiological dependence liability are useful means to identify potential genetic determinants of liability in humans. Behavioral and quantitative trait analyses were conducted using animal models for high risk versus resistance to acute physiological dependence. Using a two-step genetic mapping strategy, loci on mouse chromosomes 1, 4, and 11 were mapped that contain genes that influence alcohol withdrawal severity. In the aggregate, these three risk markers accounted for 68% of the genetic variability in alcohol withdrawal. Candidate genes in proximity to the chromosome 11 locus include genes encoding the α 1 , α 6 , and γ 2 subunits of type-A receptors for the inhibitory neurotransmitter, GABA. In addition, suggestive linkage is indicated for two loci on mouse chromosome 2, one near Gad1 encoding glutamic acid decarboxylase, and the other near the El2 locus which influences the seizure phenotype in the neurological mutant strain El. The present analyses detect and map some of the loci that increase risk to develop physiological dependence and may facilitate identification of genes related to the development of alcoholism. Syntenic conservation between human and mouse chromosomes suggests that human homologs of genes that increase risk for physiological dependence may localize to 1q21–q32, 2q24–q37/11p13, 9p21–p23/1p32–p22.1, and 5q32–q35.

Genome-wide association study of theta band event-related oscillations identifies serotonin receptor gene HTR7 influencing risk of alcohol dependence

Article

Full-text available

Jan 2011

Lack of an Allelic Association Between Polymorphisms of the Dopamine D2 Receptor Gene and Alcohol Dependence in the German Population

Article

Apr 1999

Genome-wide significant association signals in IPO11-HTR1A region specific for alcohol and nicotine co-dependence.

Article

Jan 2013
ALCOHOL CLIN EXP RES

A Genomewide Association Study of Nicotine and Alcohol Dependence in Australian and Dutch Populations

Article

Feb 2010
TWIN RES HUM GENET

Persistent tobacco use and excessive alcohol consumption are major public health concerns worldwide. Both alcohol and nicotine dependence (AD, ND) are genetically influenced complex disorders that exhibit a high degree of comorbidity. To identify gene variants contributing to one or both of these addictions, we first conducted a pooling-based genomewide association study (GWAS) in an Australian population, using Illumina Infinium 1M arrays. Allele frequency differences were compared between pooled DNA from case and control groups for: (1) AD, 1224 cases and 1162 controls; (2) ND, 1273 cases and 1113 controls; and (3) comorbid AD and ND, 599 cases and 488 controls. Secondly, we carried out a GWAS in independent samples from the Netherlands for AD and for ND. Thirdly, we performed a meta-analysis of the 10, 000 most significant AD- and ND-related SNPs from the Australian and Dutch samples. In the Australian GWAS, one SNP achieved genomewide significance (p < 5 x 10 -8 ) for ND (rs964170 in ARHGAPlOon chromosome 4, p = 4.43 x 10” 8 ) and three others for comorbid AD/ND (rs7530302 near MARK1 on chromosome 1 ( p = 1.90 x 10 -9 ), rs1784300 near DDX6 on chromosome 11 (p = 2.60 x 10 -9 ) and rs12882384 in KIAA1409 on chromosome 14 (p = 4.86 x 10 -8 )). None of the SNPs achieved genomewide significance in the Australian/Dutch meta-analysis, but a gene network diagram based on the top-results revealed overrepre-sentation of genes coding for ion-channels and cell adhesion molecules. Further studies will be requirec before the detailed causes of comorbidity between AC and ND are understood.

Co-occurrence of 12-month alcohol and drug use disorders and personality disorders in the United States - Results from the National Epidemiologic Survey on Alcohol and Related Conditions (reprinted from Archives of General Psychiatry, vol 61, pg 361, 2004)

Article

Jan 2006
ALCOHOL RES HEALTH

Background: Very little information is available on the co-occurrence of different personality disorders (PDs) and alcohol and drug use disorders in the U.S. population. Objective: To present national data on sex differences in the co-occurrence of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) alcohol and drug use disorders and 7 of the 10 DSM-IV PDs. Design: Face-to-lace interviews conducted in the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (N = 43,093). Setting: The United States and the District of Columbia, including Alaska and Hawaii. Participants: Household and group-quarters residents, age 18 and older. Results: Among individuals with a current alcohol use disorder, 28.6 percent (95 percent confidence interval [CI], 26.7-30.6) had at least one PD, whereas 47.7 percent (95 percent CI, 43.9-51.6) of those with a current drug use disorder had at least one PD. Further, 16.4 percent (95 percent CI, 15.1-17.6) of individuals with at least one PD had a current alcohol use disorder, and 6.5 percent (95 percent CI, 5.7-7.3) had a current drug use disorder. Associations between PDs and alcohol and drug use disorders were overwhelmingly positive and significant (P <.05). Overall, alcohol use disorders were most strongly related to antisocial (odds ratio [OR], 4.8; 95 percent CI, 4.1-5.6), histrionic (OR, 4.7; 95 percent CI 3.&-5.8), and dependent (OR, 3.0; 95 percent CI, 1.9-4.8) PDs. Drug use disorders also were more highly associated with antisocial (OR, 11.8; 95 percent CI, 9.7-14.3), histrionic (OR, 8.0; 95 percent CI, 6.0-10.7), and dependent (OR, 11.6; 95 percent CI, 7.1-19. 1) PDs. Associations between obsessive-compulsive, histrionic, schizoid, and antisocial PDs and specific alcohol and drug use disorders were significantly stronger (P <.04) among women than men, whereas the association between dependent PD and drug dependence was significantly greater (P <.04) among men than women. Conclusions: The co-occurrence of PDs with alcohol and drug use disorders is pervasive in the U.S. population. Results highlight the need for further research on the underlying structure of these disorders and the treatment implications of these disorders when comorbid.

Ethanol consumption and resistance are inversely relted to neuropeptide Y levels

Article

Nov 1998

Genetic linkage analysis of rats that were selectively bred for alcohol preference identified a chromosomal region that includes the neuropeptide Y (NPY) gene. Alcohol-preferring rats have lower levels of NPY in several brain regions compared with alcohol-non-preferring rats. We therefore studied alcohol consumption by mice that completely lack NPY as a result of targeted gene disruption. Here we report that NPY-deficient mice show increased consumption, compared with wild-type-mice, of solutions containing 65, 10% and 20% (v/v) ethanol. NPY-deficient mice are also less sensitive to the sedative/hypnotic effects of ethanol, as shown by more rapid recovery from ethanol-induced sleep, even though plasma ethanol concentrations do not differ significantly from those of controls. In contrast, transgenic mice that overexpress a marked NPY gene in neurons that usually express it have a lower preference for ethanol and are more sensitive to the sedative/hypnotic effects of this drug than controls. These data are direct evidence that alcohol consumption and resistance are inversely related to NPY levels in the brain.

The 12-month prevalence and trends in DSM-IV alcohol abuse and dependence: United States, 1991-1992 and 2001-2002

Article

Jan 2004
DRUG ALCOHOL DEPEN

Genome-wide association study identifies novel breast cancer susceptibility loci

Article

Jan 2007

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r(2) > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10(-7)). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.

Genome‐wide search for genes affecting the risk for alcohol dependence

Article

May 1998
Am J Med Genet

Alcohol dependence is a leading cause of morbidity and premature death. Several lines of evidence suggest a substantial genetic component to the risk for alcoholism: sibs of alcoholic probands have a 3–8 fold increased risk of also developing alcoholism, and twin heritability estimates of 50–60% are reported by contemporary studies of twins. We report on the results of a six-center collaborative study to identify susceptibility loci for alcohol dependence. A genome-wide screen examined 291 markers in 987 individuals from 105 families. Two-point and multipoint nonparametric linkage analyses were performed to detect susceptibility loci for alcohol dependence. 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. In addition, there was suggestive evidence for a protective locus on chromosome 4 near the alcohol dehydrogenase genes, for which protective effects have been reported in Asian populations. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:207–215, 1998.