Alcohol 43 (2009) 271e275

RAPID COMMUNICATION

The TaqI A DRD2 polymorphism in type II alcohol dependence: a markerof age at onset or of a familial disease?

Emmanuel Pintoa,*, Jean Reggersa, Philip Gorwoodb, Claudette Bonib, Gabrielle Scantamburloa,William Pitchota, Marc Ansseaua

aDepartment of Psychiatry, University of Liege, CHU Sart Tilman B35, B-4000 Liege, BelgiumbINSERM U675, University Paris VII, Faculte Xavier Bichat, 75870 Paris Cedex 18, France

Received 11 September 2008; received in revised form 28 December 2008; accepted 24 February 2009

Abstract

Cloninger’s type II is a severe, early-onset, male-limited, and genetically influenced, impulsive form of alcoholism. Significant associ-ation has been reported between the A1 allele of the D2 dopamine receptor (DRD2) gene, substance misuse and personality traits of impul-sivity and novelty seeking. We assessed the association between the TaqI A DRD2 gene polymorphism with Cloninger’s typology andfamily history of alcohol abuse, which is thought to be more frequent in type II alcoholics. Fifty-one male alcohol-dependent patients werediscriminated between type I and type II according to age at onset of alcohol-related problems and interviewed about family history ofalcoholism. The associations between DRD2 (A1 or A2 alleles), family history, and typology were assessed by Pearson’s chi-square test.Although typology was not associated with the studied polymorphism, a higher rate of general family history of alcohol abuse was stillobserved in type II patients (c2

1 5 4.53; P 5 .033). Furthermore, the A1 allele of the DRD2 was significantly associated with paternal historyof alcoholism (c2

1 5 4.66; P 5 .031) and male, first-degree, collateral history of alcoholism (c21 5 4.40; P 5 .036). Age at onset of alcohol-

related problems as main discriminator between type I and type II alcohol dependence does not seem to be associated by the TaqI A DRD2polymorphism. However, the A1 allele of the DRD2 may be a marker of male familial alcoholism, which has been associated with type IIalcohol dependence. � 2009 Elsevier Inc. All rights reserved.

Keywords: Alcohol; Dependence; Typology; DRD2; TaqI A polymorphism; A1 allele; family history

Introduction

Alcohol dependence is a very common, complexdisorder, which affects lifelong up to 20% of the adult pop-ulation in the United States (Alcoholism, 2000) and in mostdeveloped countries. Family, twin, and adoption studieshave demonstrated that genes play a major role in the devel-opment of alcohol dependence (Heath, 1995). Heritabilityestimates range from 50 to 60% for both men and women(Prescott et al., 1999). Moreover, it has been demonstratedthat vulnerability to alcohol dependence and variability ofits course among individuals result from interactionsbetween genetic and environmental factors (Crabbe,2002). Numerous molecular studies have established a plau-sible biological link between the A1 allele of TaqI restric-tion fragment length polymorphism in the D2 dopaminereceptor gene (DRD2) and alcohol dependence (Munafoet al., 2007; Noble, 2003). The presence of this allele on

* Corresponding author. Tel.:þ32-4-366-79-60; fax:þ32-4-366-72-83.

E-mail address: epinto@chu.ulg.ac.be (E. Pinto).

0741-8329/09/$ e see front matter � 2009 Elsevier Inc. All rights reserved.

doi: 10.1016/j.alcohol.2009.02.006

chromosome 11q22-23 is associated with lower D2receptor density and reduced central nervous system dopa-minergic function, which is thought to potentiate the incen-tive salience of triggers for addictive behaviors that mayincrease dopamine levels (Young et al., 2004).

Many studies, however, have failed to replicate an asso-ciation between DRD2 and alcohol dependence, probablybecause of population stratification (differences in variablesother than disease status, ethnicity, e.g.,) and differences inseverity of alcoholism across studies. It has been suggestedthat this association might be male-limited (Limosin et al.,2002) or limited to severe alcoholics (Noble, 2000). Amongthe severity subtypes that have been most widely examined,comorbid antisocial personality disorder has beenfrequently associated with the A1 allele of the DRD2 inalcohol-dependent patients (Matsushita et al., 2001; Ponceet al., 2003; Ponce et al., 2008). Along with this observa-tion, it has been suggested that risk factors for alcoholdependence, such as impulsivity or deficient behavioralinhibition, may partly be mediated by the DRD2 gene (Hillet al., 1999; Ishiguro et al., 1999; Limosin et al., 2003),

272 E. Pinto et al. / Alcohol 43 (2009) 271e275

whereas temperaments such as novelty seeking were likelyto be associated with this gene (Berman et al., 2002; Suharaet al., 2001). In this perspective, Cloninger’s typology(Cloninger, 1987), which discriminates milieu-limited,late-onset, male and female type I alcoholism from severe,early-onset, male-limited, genetically influenced, impulsiveand antisocial type II alcoholism, could be a good pheno-typical basis for candidate gene studies in alcohol depen-dence. However, whether the DRD2 gene should partlyinfluence type II alcoholism remains controversial.

We therefore tested the hypothesis that male type I alco-holics would differ from type II according to their DRD2A1 allelic status, expecting type II to be more frequentlyassociated with the A1 allele. Furthermore, we examinedthe possible association of the DRD2 A1 allele with specifictypological features, such as family history of alcoholismand impulsivity.

Table 1

Clinical and demographic data according to typology

Variable

Type I Type II

F PN 5 22 N 5 29

Age at the time

of the study

(years 6 S.D.)

48.86 6 7.48 42.10 6 8.71 9.26 .004**

Duration of

dependence/age (%)

25.21 6 16.20 40.46 6 18.24 10.26 .002**

Daily number

of drinks (N 6 S.D.)

17.12 6 7.13 23.0 6 12.96 4.17 .046*

% in Type I % in Type I c21 P

Alcohol dependence

in any member

of the family

56.5 82.4 4.53 .033*

Alcohol dependence

in fathers

39.1 55.9 1.54 .215

Alcohol dependence

in brothers

21.7 47.1 3.78 .052

Abbreviation: S.D. 5 standard deviation; Type II patients differed

from type I in severity of alcohol dependence but not in family history

of male first-degree alcoholic relatives. *P ! .05; **P ! .01.

Materials and methods

To test the study hypothesis, 51 male alcohol-dependentpatients according to Diagnostic and Statistical Manual ofMental Disorders, Fourth Edition criteria were recruitedbefore hospitalization for withdrawal. Diagnosis was madeby the primary investigator (E.P.) and double-checked byanother investigator (G.S.). Patients were discriminatedbetween type I and type II according to von Knorring’scriteria of age at onset of alcohol-related problems (vonKnorring et al., 1985). Age at onset (after 25 years of agefor type I; before 25 for type II) appears indeed as a criticalclassification criterion between these categories (Lykouraset al., 2004; Modestin and Wurmle, 1997). Daily numberof drinks at the time of the study was recorded as an indi-cator of alcohol dependence severity and during the inclu-sion interview, patients were asked to report any familyhistory of alcoholism. Finally, impulsivity was assessedusing the Buss and Durkee Inventory (Buss and Durkee,1957).

Participants were all of Caucasian descent and had to beat least 18 years old. They had to report no other depen-dence or substance abuse except for alcohol or nicotine.Patients presenting with any other present psychiatric disor-ders were excluded as well. The Ethical Committee of theUniversity of Liege Medical School approved the protocoland all participants provided informed consent beforeparticipation in the study.

Patients donated 3 mL of blood for genotyping.Genomic DNA was extracted from peripheral leukocytesusing the QIAmp DNA Mini Kit (QIAGEN Inc., Valencia,CA). The evaluated locus was genotyped by previouslydescribed PCR methodologies using published primersequences (Grandy et al., 1993). Amplification of theDRD2 gene was performed in 10 mL using 0.05 mL of thefollowing primers: 50-CCG TCG ACG GCT GGC CAAGTT GTC TA-30 and 50-CCG TCG ACC CTT CCT GAGTGT CAT CA-30 and 2 mL of DNA, 0.08 mL of 25 mM

dNTP, 0.4 mL of 50 mM MgCl2 and 0.5 mL of Taq EurobioPolymerase. After 5 min at 95�C and 30 s at 60�C, forty30-s cycles were performed at 72�C and terminated at72�C for 8 min and at 25�C for 10 min. The final productwas then digested for 2 h at 65�C with 0.5 mL of TaqI.Finally, the fragments were resolved by electrophoresis in3% agarose gels and the restriction pattern was A1 al-leled304 bp and A2 alleled178 and 125 bp.

We assessed the possible influence of genotype ontypology and on family history using nonparametric Pear-son’s chi-square test, whereas the associations betweenthe DRD2 A1 allele, daily number of drinks, or impulsivityscores were assessed through univariate analysis of vari-ance. As reported in the literature (Munafo et al., 2007),DRD2 A1 þ allelic status is the principal variable as faras this polymorphism is concerned. We therefore pooledA1 þ homo- and heterozygous patients in our analysis.

Results

The mean age of the sample was 44 6 8.8 years. Partic-ipants had drunk for an average of 15.0 6 9.8 years. Theyhad undergone an average of 1.9 6 2.5 alcohol detoxifica-tions before this evaluation and had 19.1 6 9.2 drinks perday at the time of the study.

Among the 51 patients of the sample, 22 (43.14%) re-ported an onset of alcohol-related problems after 25 yearsof age (mean age at onset 5 29.31 6 3.93) and were catego-rized as type I alcoholics, whereas 29 (56.86%) were classi-fied as type II (mean age at onset 5 18.09 6 5.43). Type IIalcoholics were younger than type I at the time of the study,but the ratio between age and duration of the dependence washigher in type II (Table 1) who reported a higher daily numberof drinks (P 5 .046). These differences were still observed

Table 2

Genotype frequencies

Variable A1A1 A1A2 A2A2 Total

Type I 2 5 15 22

Frequency among

type I (%)

9.1 22.72 68.18 100

Type II 3 5 21 29

Frequency among

type II (%)

10.34 17.24 72.42 100

Type I and type II 5 10 36 51

Frequency (%) 9.8 19.6 70.6 100

Frequencies for the TaqI A polymorphism of the D2 dopamine receptor

gene did not demonstrate HardyeWeinberg equilibrium (c21 5 7.280;

P ! .006) in the whole sample. However, HardyeWeinberg equilibrium

was found in type I (c21 5 2.001; P ! .157), but not in type II

(c21 5 5.590; P ! .018).

273E. Pinto et al. / Alcohol 43 (2009) 271e275

between the two groups when each parameter was entered asa covariate. Family history of alcohol dependence was morefrequent in type II patients, but this was not related to higherrates of alcoholism in male, first-degree relatives. Finally, nodifference in Beck Depression Inventory (BDI) total andsubscales scores was observed between early- and late-onsetalcoholics.

Frequencies for the TaqI A polymorphism of the DRD2did not demonstrate HardyeWeinberg equilibrium(c2

1 5 7.280; P ! .006), meaning that there was an excessof A1 allele in our sample (Table 2). However, whenobserved within the two subgroups, genotype frequenciesdid not deviate significantly from HardyeWeinberg equi-librium in type I patients (c2

1 5 2.001; P ! .157), whereasthey did in type II (c2

1 5 5.590; P ! .018).Still, allelic status did not discriminate type I from type

II (Table 3) and the DRD2 A1 allele was neither associatedwith a longer duration of alcohol dependence nor withhigher amounts of alcohol drinking. Furthermore, impul-sivity, as measured through BDI total and subscales scores,was not associated with the presence of the A1 allele.However, there was a significant association between theA1 allele and alcoholism in patients’ male, first-degree rela-tives (P 5 .031 in fathers; P 5 .036 in brothers).

Table 3

Clinical and demographic data according to allelic status

Variable A1A1 or A

Age at the time of the study (years 6 S.D.) 19.4 6 7.3

Duration of dependence/age (%) 35.74 6 23

Daily number of drinks (N 6 S.D.) 19.33 6 11

A1A1 or A

Typology: % of type I 31.82

Typology: % of type II 27.58

In A1A1 o

Alcohol dependence in any member of the family (%) 86.7

Alcohol dependence in fathers (%) 73.3

Alcohol dependence in brothers (%) 60.0

Abbreviation: S.D. 5 standard deviation. The A1 allele of D2 dopamine re

alcohol dependence in male, first-degree relatives. *P ! .05.

Discussion

The main result of this study was the association wefound between the A1 allele of the DRD2 and alcohol depen-dence in male, first-degree relatives. Indeed, our datasuggest that subjects carrying this genotype belong to fami-lies in which men (fathers or brothers to our patients) sufferfrom alcohol dependence. This is in line with previousstudies showing the implication of this polymorphism inthe genetic loading of alcoholism (Noble, 2003). Althoughchildren of alcoholics are clearly at risk for substance relatedproblems (Conway et al., 2003; Hoffman and Cerbone,2002), the specific association between D2 dopaminergicfunction and familial forms of alcohol dependence has oftenbeen debated. However, this hypothesis benefits fromconvincing findings. In a neuroendocrine study, Wiesbecket al. (1995) demonstrated that patients coming from fami-lies in which some members were alcohol-dependentpresented a blunted response in growth hormone after anapomorphine challenge, suggesting that hypo-D2 func-tioning could be a heritable trait marker of alcoholism. Morerecently, a significant association between the A1 allele anda family history of alcohol dependence was found in malealcohol-dependent patients (Ponce et al., 2003). However,the authors of this study did not specify whether the alco-holic relatives of the tested patients were male. On the otherhand, it has been showed (Conner et al., 2005) that, ina sample of sons of alcoholic not older than 16, those whocarried the A1 allele of the DRD2 were at higher risk ofdeveloping a substance use disorder (alcohol, nicotine, andcannabis). These results tend to confirm our observationsand suggest that carrying the TaqI A polymorphism of theDRD2 may be a risk factor for alcohol and other drug-related problems in subjects with a family history of malealcohol dependence.

However, this polymorphism did not discriminate type Ifrom type II alcoholics in our sample, meaning that the A1allele of the DRD2 may not be associated with early onsetof alcohol-related problems. This is in line with a recent

1A2 A2A2 F P

8 22.36 6 10.84 0.933 .339

.26 34.43 6 17.85 0.045 .829

.34 19.08 6 8.38 0.008 .931

1A2 A2A2 c21 P

68.18

0.108 .985

72.41

r A1A2 carriers In A2A2 carriers c21 P

68.6 1.78 .181

40.0 4.66 .031*

28.6 4.40 .036*

ceptor gene does not discriminate type I from type II but is associated with

274 E. Pinto et al. / Alcohol 43 (2009) 271e275

study by Sakai et al., 2007 where no evidence of associationbetween the TaqI A polymorphism and early onset ofalcohol-related problem was found, but in contradictionwith previous results in a Japanese sample (Kono et al.,1997). Furthermore, although type II patients exhibited asexpected clear factors of severe alcohol dependence (higherdaily number of drinks, longer duration of alcohol depen-dence in spite of their being younger compared with typeI patients), these features were not associated with a specificgenotype. Moreover, impulsivity, which has been associ-ated with type II alcoholism, was associated neither toallelic status nor to typology in our sample.

Therefore, the A1 allele of the DRD2 does not seem toinfluence all the criteria usually associated with type IIalcoholism. Indeed, this genotype does not seem to be asso-ciated with a specific subtype of patients characterized bya severe form of dependence, a high level of impulsivity,and more specifically, an early onset of alcohol-relatedproblems. Although it was showed through various studiesthat this polymorphism might be associated with antisocialpersonality in alcohol-dependent patients (Lu et al., 2001;Ponce et al., 2003; Ponce et al., 2008) our results, alongwith other negative findings (Lee et al., 1999; Parsianet al., 2000), suggest that the genetic loading in type IIalcohol dependence, when formally defined by age at onsetof alcohol-related problems, may be associated to othergenetic factors. The TaqI A DRD2 polymorphism seemsto be associated with a male-limited familial form ofalcohol dependence but not with all the characteristics ofCloninger’s type II alcoholism.

Clear limitations in our study have to be pointed out andimply that these results should be considered as prelimi-nary. First, it is probably underpowered as the size of oursample is quite small. Our results will therefore have tobe replicated in larger samples of patients and comparedwith a control group. Another concern is the excess ofDRD2 A1 allele in our sample. Genotypes usually meetcriteria for HardyeWeinberg equilibrium, which is notthe case for the TaqI A polymorphism in this study andmay reflect a recruitment bias. This allele has been indeedassociated with severe alcohol dependence (Noble, 2003)and many of the participating patients in this study were re-cruited in a psychiatric hospital well known for the severityof its hospitalized alcoholics. This may account for theexcess of A1 allele in our sample (particularly in the typeII subgroup, although, as previously mentioned, this differ-ence is not significant when compared with type I) and leadto underevaluate the impact of this allele on some of theobserved phenotypes. Finally, we cannot formally rule outthe possibility that the studied polymorphism is linkagedisequilibrium with other genotypes and not underlie by it-self the observed association with male familial alcoholism.It has been shown indeed that the TaqI A polymorphism islocalized close to a gene coding for a protein kinase (ankyr-in repeat and kinase domain containing 1 [ANNKK1])implicated in transduction processes (Dick et al., 2007).

Associated with the A1 allele of the DRD2, a variant of thisgene may confer susceptibility to severe alcohol depen-dence and antisocial personality traits (Dick and Bierut,2006).

In spite of their limitations, our results confirm theimplication of the DRD2 TaqI A polymorphism in alcoholdependence but suggest that its influence may be limitedto a male, familial form of the disease.

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