title: Analysis of microsatellite markers and single nucleotide polymorphisms in candidate genes for susceptibility to bipolar affective disorder in the chromosome 12Q24.31 region.
abstract: Previous results from our genetic analyses using pedigrees from a French Canadian population suggested that the interval delimited by markers D12S86 and D12S378 on chromosome 12 was the most probable genomic region to contain a susceptibility gene for affective disorders. Here we present a more detailed genetic analysis of a 7.7 Mb genomic region located on 12q24.31. This region was saturated with 20 microsatellite markers to refine the candidate region and linkage analysis performed in 41 families from the Saguenay-Lac-St-Jean (SLSJ) region of Quebec. The results of two point parametric analysis using MFLINK supported the presence of a susceptibility locus on chromosome 12q24.31. Association studies with microsatellite markers using a case/control sample from the same population (n = 401) and analyzed with CLUMP revealed significant allelic associations between the bipolar phenotype and markers NBG6 (P = 0.008) and NBG12 (P < 10(-3)). According to these results, we investigated candidate genes in the NBG12 area. We analyzed 32 genes for the presence of polymorphisms in coding sequences and intron/exon junctions and genotyped 22 non-synonymous SNPs in the SLSJ case/control sample. Two uncommon polymorphisms (minor allele frequency < or = 0.03) found in KIAA1595 and FLJ22471 genes, gave P-values below 0.05 with the T1 statistic. Moreover, using haplotype analysis, a nearly significant haplotypic association was observed at the HM74 gene. These results do not give strong support for a role in the susceptibility to bipolar disorder of any of these genes analyzed. However, the significance of rare polymorphisms should be explored by further analyses.
authors.affiliation: Neuroscience, CHUL Research Center and Laval University, CHUQ Pavillon CHUL, Ste-Foy, Québec, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Shink
authors.forename: Mario
authors.initials: M
authors.lastname: Harvey
authors.forename: Monique
authors.initials: M
authors.lastname: Tremblay
authors.forename: Bernard
authors.initials: B
authors.lastname: Gagné
authors.forename: Pascal
authors.initials: P
authors.lastname: Belleau
authors.forename: Catherine
authors.initials: C
authors.lastname: Raymond
authors.forename: Michel
authors.initials: M
authors.lastname: Labbé
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Lafrenière
authors.forename: Nicholas
authors.initials: N
authors.lastname: Barden
mesh_terms: D000483:Alleles; D001714:Bipolar Disorder / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D004247:DNA