American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 116B:55–59 (2003) Association Between the Dopamine Receptor D4 (DRD4) Gene and Obsessive-Compulsive Disorder Bruno Millet, 1 * Nadia Chabane, 2 Richard Delorme, 3 Marion Leboyer, 3 Sophie Leroy, 1 Marie-France Poirier, 1 Marie-Chantal Bourdel, 1 Marie-Christine Mouren-Simeoni, 2 Fre ´ deric Rouillon, 3 Henri Loo, 1 and Marie-Odile Krebs 1 1 INSERM E0117 Paris V, University Department of Psychiatry, Sainte-Anne Hospital, Paris, France 2 Psychiatric Department of Child Psychiatry, AP-HP, Ho ˆpital Robert Debre´, Paris, France 3 Ho ˆpital Albert Chenevier et Henri Mondor, Department of Psychiatry, AP-HP, Cre´teil, France Obsessive-compulsive disorder (OCD) is a frequent and disabling anxiety disorder. Dopamine (DA) might be involved in its pathophysiology, therefore DA receptors are candidate genes in OCD. A 48-base pairs (bp) polymorphism located in the third exon of the dopamine receptor type 4 (DRD4) gene has been described. Previous case control studies, however, have report- ed inconclusive results in OCD. The aim of the study was to study this polymorphism in a family-based association study of 55 trios. Extended transmission-disequilibrium test (ETDT) for preferential allele transmission in this group showed an absence of transmis- sion of the allele 2 for the 48 bp repeat polymorphism of the DRD4 gene (P ¼ 0.005). Moreover, in a population-based associa- tion study, we found a significantly lower frequency of the allele 2 in patients suffer- ing from OCD compared to ethnically- matched controls (P ¼ 0.02). We found no association of DRD4 48 bp polymorphism with OCD in the subgroup of patients with comorbid tics. This study is the first to report on a significant association of vari- ants of the DRD4 gene in OCD, found on both family- and population-based studies. The results suggest that the 2 allele or a nearby genetic variation could have a pro- tective effect against OCD symptoms. ß 2003 Wiley-Liss, Inc. KEY WORDS: dopamine; DRD4 gene; obsessive-compulsive disor- der; tics; family-based asso- ciation studies INTRODUCTION Obsessive-compulsive disorder (OCD) is a frequent and disabling anxiety disorder with a lifetime preval- ence rate ranging from 2–3% [Karno et al., 1988; Weissman et al., 1994]. Although the etiology remains largely unknown, converging lines of evidence from twin studies [Inouye, 1965; Carey and Gottesman, 1981; Torgersen, 1983; Rasmussen et al., 1986; Andrews et al., 1990], family genetic studies [Carey et al., 1981; Lenane et al., 1990; Bellodi et al., 1992; Black et al., 1992; Leonard et al., 1992; Nicolini et al., 1993; Pauls et al., 1995, Nestadt et al. 2000] and segregation analyses [Nicolini et al., 1991; Alsobrook et al., 1999; Cavallini et al., 1999] support the idea that OCD has a strong genetic component. Recent efforts in the search for genes relevant to the etiology of OCD have used the candidate genes approach [Catalano et al., 1994; Nicolini et al., 1996; Billett et al., 1997; Cruz et al., 1997; Billett et al., 1998; Cavallini et al., 1998]. For instance, family-based association studies found positive association of OCD with COMT [Schindler et al., 2000] and 5HT1Db [Mundo et al., 2000] gene variants. Apart from the main hypothesis suggesting serotonin abnormalities, some authors propose that dopamine (DA) could participate in the pathophysiology of the disorder [Goodman, 1994]. Indeed, DA modulates caudate nucleus activity and anti-dopaminergic agents have showed some efficacy on treatment-resistant OCD with [McDougle et al., 1994] or without comorbid tics [McDougle et al., 2000]. In addition, the emergence of obsessive-compulsive symptoms during treatment with clozapine, a DRD4 antagonist, has been reported [Baker et al., 1992]. Genes coding for DA receptors, especially DRD4, might thus be candidate genes in OCD. A poly- morphic 48 base-pair (bp) repeat has been described in the region coding for the third exon of the DRD4 gene Grant sponsor: INSERM; Grant sponsor: Pfizer France. *Correspondence to: Bruno Millet, Sainte Anne Hospital, University Department of Psychiatry, 7 rue Cabanis, Paris, France. E-mail: millet@chsa.broca.inserm.fr Received 9 October 2001; Accepted 12 June 2002 DOI 10.1002/ajmg.b.10034 ß 2003 Wiley-Liss, Inc.