The DRD2 gene and the risk for alcohol dependence in bipolar patients

Eur Psychiatry 2000 ; 15 : 103-8 © 2000 Éditions scientifiques et médicales Elsevier SAS. All rights reserved S0924933800002054/FLA

ORIGINAL ARTICLE

The DRD2 gene and the risk for alcohol dependence in bipolar patients P. Gorwood1,2*, F. Bellivier3,4, J. Adès1,2, M. Leboyer3,4 Hospital Louis Mourier (Service de Psychiatrie adulte du Professeur Adès). Colombes 92700; 2 CNRS UMR 7593 (Laboratoire ‘Personnalité et conduites adaptatives’ du Professeur Jouvent), Paris; 3 Hôpital Albert Chenevier et Henri Mondor, AP-HP (Service de psychiatrie adulte du Professeur Rouillon) Créteil 94000; 4 INSERM U 513 (Laboratoire neurobiologie et Psychiatrie), Créteil 94000, France

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Summary – The high co-morbidity between bipolar disorder and alcohol dependence may have different explanations, one of them being the existence of common genetic factors for the two disorders. Several candidate genes may be involved but the genes acting in the dopaminergic pathway may be more specifically involved. We have thus tested the role of the gene encoding the D2 dopamine receptor (TaqI A1 allele) in the potentially shared vulnerability to alcohol dependence and bipolar disorder. One hundred and twenty-two French (for at least two generations) patients were recruited on the basis of hospital or outpatient files and were interviewed with the DIGS. The A1 allele frequencies were compared between four groups, namely, with bipolar patients and co-morbid alcohol dependence (N = 21), with bipolar patients without alcohol morbidity (N = 31), with alcohol dependence without mood disorder (N = 35) and unaffected controls (N = 35). The Hardy Weinberg equilibrium for the DRD2 Taq1 A1 genotypes was respected for the sample as a whole, and for each subsample. We observed that 42.9% of control subjects have at least one A1 allele, a frequency which is not significantly different from the one observed in the affected sample as a whole (39.1%), neither from patients with alcohol dependence (37.1%), patients with bipolar disorder (48.4%) nor patients with alcohol dependence and bipolar disorder (28.6%). The regression analysis based on the three variables (bipolar disorder, alcohol dependence and interaction between these two disorders) does not explain the presence of the A1 allele of the DRD2 gene. We thus found no evidence for a significant role of the A1 allele of the D2 dopamine receptor gene in the specific association between bipolar disorder and alcohol dependence in our sample. © 2000 Éditions scientifiques et médicales Elsevier SAS alcoholism / co-morbidity / genetics / mood disorder

INTRODUCTION Alcohol-dependent subjects have a twofold increased risk for depressive disorders, the lifetime prevalence of alcohol abuse or dependence for major unipolar depres-

sion being 16.5% [40]. The co-morbidity between bipolar disorder and alcohol dependence is especially high; the odds ratio between mania and alcohol dependence is 4.6 in the Epidemiological Catchment Area study and 4.9 in the National Comorbidity Study [26].

* Correspondence and reprints: Philip Gorwood, M.D., Ph.D., Service de Psychiatrie, Hôpital Louis Mourier 178, rue des Renouillers, 92701 Colombes cedex, France

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The lifetime prevalence of alcohol abuse or dependence in bipolar disorder is 43.6%, and over 60% for bipolar I [43]. It is thus bipolar disorder rather than global mood disorder which may have an important comorbidity [1]. The existence of such a high co-morbidity may have different explanations, one of them being false comorbidity. In this view, Schuckit [46] has described five factors that may contribute to the confusion between alcoholism and affective disorders: 1) dysphoric symptoms can be caused by alcohol in most people; 2) serious but temporary depression can follow prolonged drinking; 3) during mania, drinking may escalate (rather than be initiated); 4) a third co-morbid psychiatric disorder may coexist; and 5) alcoholism and affective disorder may coexist independently in a small proportion of patients. These confouding factors may be partly relevant for bipolar disorders as they are at greater risk for increased alcohol intake during the manic phase of their illness [44] and during the hypomanic phase of cyclothymia [56]. However, the high co-morbidity between bipolar disorder and alcoholism might be explained by genetic factors common for the two disorders. Co-transmission of bipolar disorder and alcoholism in families has been shown [31]. Relatives of early onset bipolar patients have a prevalence of alcoholism two to three times higher than that reported in controls [42, 51]. Cotransmission could be particularly, but not exclusively, observed in subgroups of patients with familial comorbidity [30, 57], the excess of alcoholism in bipolar relatives being especially present in probands with comorbid alcoholism [58]. However, this familial co-transmission could be either familial or genetic. Two adoption studies are in favour of the genetic hypothesis. Ingraham showed that substance abuse was more common in the biological relatives of affectively ill adoptees than in controls’ relatives [23], and Cadoret showed that, on the basis of his adoptions studies, the depressive spectrum disease might represent a gene environment interaction involving the genetic diathesis for alcoholism [6]. If the co-transmission of manic depressive illness and alcoholism is partly genetics, some genes are more prone to be involved in the shared vulnerability of these two disorders. Several candidate genes may be involved, but the genes acting in the dopaminergic pathway may be more specifically implicated in this common vulnerability [14]. Different arguments show that dopamine may be involved in mood disorders, and especially in

manic depressive illness. For example, dopamine precursor (L Dopa) almost uniformly produces hypomania in bipolar patients [18, 33, 54]. Amphetamine can precipitate hypomania in bipolar patients and induce a hypomania-like state in normal subjects [24]. The direct dopamine agonists, bromocriptine and piribedil, seem to be effective antidepressants in some bipolar patients and able to precipitate mania [17, 47, 48]. Neuroleptics that selectively block dopamine receptors (such as pimozide) are effective against severe mania. Chronic administration of classic antidepressants decreases presynaptic dopamine autoreceptor sensitivity, and presumably reduces negative feedback on dopamine turnover [7]. Furthermore, dopamine could also be involved in the vulnerability to alcohol dependence [19]. A number of substances that share the potential for abuse by humans also share the ability to enhance dopaminergic activity in mesolimbic mesocortical circuits thought to be important for reward and reinforcement behaviour [15, 28, 59]. Dopaminergic cell bodies in the midbrain receive inputs from several sources and then project impulses to the forebrain, thereby possibly acting as a final common pathway for behavioural activation [45, 50, 60]. Furthermore, alcohol-preferring rats have low basal dopamine concentrations in the cortex and nucleus accumbens, and show greater locomotor activation and greater increases in dopamine turnover after low doses of alcohol than alcohol non-preferring rats [34, 55]. Genes encoding for dopamine receptors and enzymes implicated in dopamine transmission can thus be considered as potentially involved in both disorders. The genes coding for dopamine receptors have nearly all been studied in both disorders. The gene encoding for the D2 receptor has been extensively studied because of its location on chromosome 11q22, thus close to the gene coding for tyrosine hydroxylase, a highly studied candidate gene in bipolar disorder [28]. Furthermore, the Taq1 DRD2 allele A1 was associated [2, 8, 20, 36, 37, 40, 49, 53] or linked [9] to alcohol dependence in numerous studies, although the results are heterogenous [20] Discrepancies in the results may have different explanations, but phenotypic and genetic heterogeneity are generally regarded as very likely. We have thus tested the role of the gene encoding the D2 dopamine receptor (TaqI A1 allele) in the potentially shared vulnerability to alcohol dependence and bipolar disorder. To detect the specific role of the D2 gene, we recruited four Eur Psychiatry 2000 ; 15 : 103–8

DRD2 gene, bipolar disorder and alcoholism

samples in order to measure interaction between bipolar disorder and alcoholism (alcoholic bipolar patients, alcohol-dependent patients, bipolar patients and controls), all of them French for at least two generations. According to the potential confounding effect of gender in our study (dependence is more frequent in males and mood disorders affect females preferentially), the control sample was limited to one sex, namely males. MATERIAL AND METHOD Twenty-one bipolar patients with co-morbid alcohol dependence were recruited in two settings, the Hospital Pitié Salpétrière in Paris (N = 18) and the Hospital Louis Mourier in Colombes (N = 3). The age at interview was 45.8 years old (standard deviation = 9.45), with seven females and 14 males. The age at onset of the bipolar disorder was on average 27 years (standard deviation = 11.5), and 17 of them were bipolar I (81%). Thirty-one bipolar patients without alcoholism comorbidity were also recruited from the Hospital Pitié Salpétrière. The age at interview was 53.4 years old (standard deviation = 10.7), with 16 females and 15 males. The age at onset is on average 29.8 years (standard deviation = 10.9), and 26 of them were bipolar I (83.9%). Thirty-five alcohol-dependent patients without bipolar disorder were selected from a previous collection of patients at the Hospital Louis Mourier [20]. The age at interview was on average 46.2 years old (standard deviation = 9.8), all male; the average age at onset of alcohol dependence was 33.3 years (standard deviation = 7.4). Thirty-five healthy controls were also recruited in Hospital Louis Mourier, without alcohol abuse or dependence, nor substance abuse, and without any mood disorder. They were all males, with an age at interview of 43.5 years (standard deviation = 6.5). The 122 patients were recruited on the basis of hospital or outpatient files. All patients and controls gave their written informed consent, a consent which was previously submitted to and approved by the ethic committee of the university. Lifetime clinical investigation for patients and controls were based on face-to-face interviews conducted by one of the two trained cliniciens (PG and FB) with the French version of the DIGS (Diagnostic Interview for Genetic Studies) [39], a semi-structured interview that is based on both DSMEur Psychiatry 2000 ; 15 : 103–8

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III-R and RDC criteria. The DSM-III-R criteria were used in this study (for psychiatric and addictive disorders) DNA was extracted from peripheral leukocytes [29]. The polymerase chain reaction (PCR) amplifying the Taq1 polymorphism of the DRD2 gene was carried out using a previously described method [21]. A v2 test was used to compare allelic frequencies in patients and controls within each sample, and observed genotype frequencies compared with those expected according to the Hardy Weinberg equilibrium. The interaction between phenotypes were assessed with a logistic regression analysis with qualitative variables, the independent variable being the existence of allele A1, and the dependent variables the existence of bipolar disorder and of alcohol dependence. The significance of the interaction between these two disorders was tested in the model. RESULTS The Hardy Weinberg equilibrium for the DRD2 taq1A1 genotypes was respected for the sample as a whole (χ2 = 0.83; df = 1; P = 0.36) and for each subsample (χ2 < 1.2; df = 1; P > 0.22). We observed that 42.9% of control subjects have at least one A1 allele, a frequency which is not significantly different from the one observed in the affected sample as a whole (39.1%) (χ2 = 0.15; df = 1; P = 0.70), neither from the different subsamples, namely patients with alcohol dependence (37.1%) (χ2 = 0.24; df = 1; P = 0.63), patients with bipolar disorder (48.4%) (χ2 = 0.20; df = 1; P = 0.65) or patients with alcohol dependence and bipolar disorder (28.6%) (χ2 = 1.14; df = 1; P = 0.29). The theoretical distribution of the A1 allele on the basis of chance alone is not significantly different from the one which is really observed (χ2 = 0.42; df = 1; P = 0.52) (table I). The regression analysis based on the three variables (bipolar disorder, alcohol dependence and interaction between these two disorders) does not explain the independent variable (presence of the A1 allele of the DRD2 gene) (χ2 = 2.32; df = 3; P = 0.51). The odds ratio of the three dependent variables are given in table II. DISCUSSION We found no evidence of a significant role for the A1 allele of the D2 dopamine receptor gene in the specific

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Table I. Frequency of A1 allele (Taq1 A1 DRD2 polymorphism) in four samples according to presence or absence of bipolar disorder and alcohol dependence. Bipolar disorder

Alcohol dependence

Yes No Total

Yes

No

Total

6/21 (28.6%) 13/35 (37.1%) 19/56 (33.9%)

15/31 (48.4%) 15/35 (42.9%) 30/66 (45.5%)

21/52 (40.4%) 28/70 (40.0%) 39/122 (32.0%)

association between bipolar disorder and alcohol dependence in our sample. In fact, the role of the DRD2 on alcoholism remain controversial [20], and the linkage studies in bipolar disorder are mainly in favour of a strict exclusion [11, 16, 22, 32, 35]; some association studies were also negative [10, 38, 56]. Nevertheless, some studies were in favour of a minor role of the DRD2, contributing to susceptibility to bipolar disorder [41]. Furthermore, phenotypic heterogeneity is a limitation raised in the vast majority of these studies. The possibility that the gene is involved in the hypothetic common genetic vulnerability of bipolar disorder and alcohol dependence thus cannot be ruled out on the basis of the negative linkage studies based exclusively on manic-depressive illness. In our sample with the four forms of possible interaction between bipolar disorder and alcohol dependence, we found no different frequency of the A1 allele. However, the present study has several limitations. Firstly, although the main sample represents more than 120 patients, different subsamples are of limited size, thus decreasing the possibility of observing moderate effects. Secondly, as these analyses are based on a casecontrol association study, the results are not protected from a stratification bias. Although we selectively recruited patients with Caucasian and French origins for at least two generations, there is no way to exclude a hypothetical bias except to perform family case-control studies. Thirdly, choosing specific subsamples (here co-morbid manic depressive disorders in males) does not exclude a role of the DRD2 gene tested on other aspects of manic depresive illness, such as early onset, Table II. Odds ratio of the two phenotypes (bipolar disorder and alcohol dependence) and their interaction regarding A1 allele frequency (Taq1 A1 DRD2 polymorphism). Phenotypes

Odds ratio

Significance

Alcohol dependence (1) Bipolar disorder (2) Interaction (1)*(2)

0.79 1.25 0.54

0.63 0.65 0.40

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