title: Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium.
abstract: Genetic mapping studies in bipolar disorder (BD) have been hampered by the unclear boundaries of the phenotypic spectrum, and possibly, by the complexity of the underlying genetic mechanisms, and heterogeneity. Among the suggested approaches to circumvent these problems, a pharmacogenetic strategy has been increasingly proposed. Several studies have indicated 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 markers 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.
authors.affiliation: Douglas Hospital Research Institute, McGill University Health Centre, Montreal, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Turecki
authors.forename: P
authors.initials: P
authors.lastname: Grof
authors.forename: E
authors.initials: E
authors.lastname: Grof
authors.forename: V
authors.initials: V
authors.lastname: D'Souza
authors.forename: L
authors.initials: L
authors.lastname: Lebuis
authors.forename: C
authors.initials: C
authors.lastname: Marineau
authors.forename: P
authors.initials: P
authors.lastname: Cavazzoni
authors.forename: A
authors.initials: A
authors.lastname: Duffy
authors.forename: C
authors.initials: C
authors.lastname: Bétard
authors.forename: P
authors.initials: P
authors.lastname: Zvolský
authors.forename: C
authors.initials: C
authors.lastname: Robertson
authors.forename: C
authors.initials: C
authors.lastname: Brewer
authors.forename: T J
authors.initials: TJ
authors.lastname: Hudson
authors.forename: G A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: M
authors.initials: M
authors.lastname: Alda
mesh_terms: D000328:Adult; D017668:Age of Onset; D018692:Antimanic Agents / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000235:genetics*; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15; D002897:Chromosomes, Human, Pair 7; D005260:Female; D005500:Follow-Up Studies; D005799:Genes, Dominant; D005808:Genes, Recessive; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D008094:Lithium / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D015233:Models, Statistical; D012984:Software; D013997:Time Factors
chemical_list: D018692:Antimanic Agents; D005819:Genetic Markers; D008094:Lithium