Molecular Psychiatry (2001) 6, 570–578  2001 Nature Publishing Group All rights reserved 1359-4184/01 $15.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium G Turecki 1 , P Grof 2 , E Grof 2 , V D’Souza 1 , L Lebuis 1 , C Marineau 1 , P Cavazzoni 2 , A Duffy 2 , C Be ´tard 3 , P Zvolsky ´ 5 , C Robertson 6 , C Brewer 3 , TJ Hudson 3 , GA Rouleau 1 and M Alda 2,4 1 Douglas Hospital Research Institute, Douglas Hospital, and the Center for Research in Neuroscience, McGill University Health Centre, Montreal, Canada; 2 Department of Psychiatry, University of Ottawa, Canada; 3 Montreal Genome Centre, McGill University Health Centre, Montreal, Canada; 4 Department of Psychiatry, Dalhousie University, Halifax, Canada; 5 Charles University, Prague, Czech Republic; 6 Royal Ottawa Hospital, Ottawa, Canada Genetic mapping studies in bipolar disorder (BD) have been hampered by the unclear bound- aries of the phenotypic spectrum, and possibly, by the complexity of the underlying genetic mechanisms, and heterogeneity. Among the suggested approaches to circumvent these prob- lems, a pharmacogenetic strategy has been increasingly proposed. Several studies have indi- cated that patients with BD who respond well to lithium prophylaxis constitute a biologically distinct subgroup. In this study we have conducted a complete genome scan using 378 mark- ers spaced at an average distance of 10 cM in 31 families ascertained through excellent lithium responders. Response to lithium was evaluated prospectively with an average follow-up of 12 years. Evidence for linkage was found with a locus on chromosome 15q14 (ACTC, lod score = 3.46, locus-specific P-value = 0.000014) and suggestive results were observed for another marker on chromosome 7q11.2 (D7S1816, lod score = 2.68, locus-specific P-value = 0.00011). Other interesting findings were obtained with markers on chromosomes 6 and 22, namely D6S1050 (lod score = 2.0, locus-specific P-value = 0.00004) and D22S420 (lod score = 1.91). Nonparametric linkage analysis provided additional support for the role of these loci. Further analyses of these results suggested that the locus on chromosome 15q14 may be implicated in the etiology of BD, whereas the 7q11.2 locus may be relevant for lithium response. In conclusion, our results provide original evidence suggesting that loci on 15q14 and 7q11.2 may be implicated in the pathogenesis of BD responsive to lithium. Molecular Psy- chiatry (2001) 6, 570–578. Keywords: lithium response; bipolar disorder; genome-scan; linkage analysis; chromosome 15; chro- mosome 7 Introduction Since the late 1950s, researchers have been aware of a relationship between drug response and genetic vari- ation. 1 Genes make humans more or less likely to respond to a given pharmacological treatment and/or to present a certain side-effect profile. 2–4 Thus, selecting research subjects based on common patterns of response or non-response to a given pharmacological treatment may be useful to define genetically more homogeneous subgroups. We have been using such an approach, focusing on bipolar patients who present an excellent response to lithium prophylaxis. After five decades of use in mood disorders, lithium remains the first-choice therapy for preventing recur- Correspondence: M Alda MD, Department of Psychiatry, Dalhou- sie University, Abbie J Lane Building, 5909 Jubilee Road, Halifax, Nova Scotia, B3H 2E2, Canada. E-mail: maldais.dal.ca Received 30 October 2000; revised 22 January 2001; accepted 24 January 2001 rences. Although some authors have questioned its effectiveness, lithium is the best-studied and clearly effective mood stabilizer currently available. 5 How- ever, its effectiveness tends to vary depending on the clinical presentation. It is more effective in forms of BD characterized by typical symptomatology, absence of comorbidity and a specific family history of bipolar disorder. 6–8 There is also evidence that responders and nonresponders to lithium treatment differ in certain neuroendocrine responses involving the serotonergic and endorphin systems. 9 Over the last 20 years, several studies have suggested that lithium-responsive patients are more likely to have relatives affected with BD than lithium nonresponders. 10–15 Moreover, segregation analysis in this population indicates a major gene effect consistent with an autosomal recessive mode of inheritance. 16,17 Taken together, these findings suggest that response to lithium prophylaxis may help define a distinct bipolar phenotype with less genetic hetero- geneity and stronger genetic effect. Therefore, we col- lected a sample of subjects and their families prospec-