title: Implication of synapse-related genes in bipolar disorder by linkage and gene expression analyses.
abstract: Several chromosomal regions have been linked to bipolar disorder (BD). However, the search for specific genes has been hampered by inconsistent findings, partly due to genetic and phenotypic heterogeneity. We focused on lithium-responsive bipolar patients, a subgroup thought to be more homogeneous and conducted a multistage study including an initial linkage study followed up by fine mapping and gene expression. Our sample consisted of 36 families (275 genotyped individuals, 132 affected) recruited through probands who were responders to long-term lithium treatment. We conducted a genome-wide scan with 811 microsatellite markers followed by fine mapping. Gene expression studies of candidate regions were conducted on six post-mortem prefrontal brain regions of 20 individuals (8 BD and 12 controls). We identified regions 3p25, 3p14 and 14q11 as showing the highest genome-wide linkage signal (LOD 2.53, 2.04 and 3.19, respectively). Fine mapping provided further support for 3p25, while only modest support was found in the other two regions. We identified a group of synaptic, mitochondrial and apoptotic genes with altered expression patterns in BD. Analysis of an independent microarray dataset supported the implication of synapse-related and mitochondrial genes in BD. In conclusion, using two complementary strategies, we found evidence of linkage to lithium-responsive BD on 3p25, 3p14 and 14q11 as well as significantly dysregulated genes on these regions suggesting altered synaptic and mitochondrial function in BD. Further studies are warranted to demonstrate the functional role of these genes in BD.
authors.affiliation: Department of Psychiatry, McGill University, Montreal, QC, Canada.
authors.forename: Catalina
authors.initials: C
authors.lastname: Lopez de Lara
authors.forename: Iris
authors.initials: I
authors.lastname: Jaitovich-Groisman
authors.forename: Cristiana
authors.initials: C
authors.lastname: Cruceanu
authors.forename: Firoza
authors.initials: F
authors.lastname: Mamdani
authors.forename: Véronique
authors.initials: V
authors.lastname: Lebel
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Yerko
authors.forename: Angus
authors.initials: A
authors.lastname: Beck
authors.forename: L Trevor
authors.initials: LT
authors.lastname: Young
authors.forename: Guy
authors.initials: G
authors.lastname: Rouleau
authors.forename: Paul
authors.initials: P
authors.lastname: Grof
authors.forename: Martin
authors.initials: M
authors.lastname: Alda
authors.forename: Gustavo
authors.initials: G
authors.lastname: Turecki
mesh_terms: D000328:Adult; D018692:Antimanic Agents / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D002874:Chromosome Mapping; D005260:Female; D015870:Gene Expression; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008094:Lithium / Q000627:therapeutic use; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D013569:Synapses / Q000235:genetics*
chemical_list: D018692:Antimanic Agents; D008094:Lithium