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.

Fig. 1

Genome-wide scan heterogeneity LOD scores.

Fig. 2

(a) Maximized two-point LOD scores for genome-wide (in bold) and fine-mapping markers in chromosome 3. Candidate regions are indicated by black horizontal lines. (b) Microsatellite markers and genes on candidate regions 3p25 and 3p14. (1) Microsatellite markers with LOD scores >1; (2) differentially expressed genes after controlling for pH and PMI effects (p≤0.05) ; (3) physical location of the 114 (3p25) and 31 (3p14) genes included in brain expression analyses.

Fig. 3

Gene probe sets differentially expressed in various brain regions. (a) Chromosome 3p25; (b) chromosome 3p14. Brodmann areas (BA) are indicated as follows: BA 8/9, light blue; BA10, dark blue ; BA 44, violet ; BA 45, green; BA47, grey. Dotted lines indicate absolute fold change of 1.3. Genes selected for validation are in bold.

Fig. 4

(a) Maximized two-point LOD scores for genome-wide (in bold) and fine-mapping markers in chromosome 14. Candidate region is indicated by a black horizontal line. (b) Microsatellite markers and genes on candidate region 14q11. (1) Microsatellite markers with LOD scores >1; (2) differentially expressed genes after controlling for pH and PMI effects (p≤0.05) ; (3) physical location of the 286 genes included in brain expression analyses. (c) Gene probe sets differentially expressed in various brain regions. Brodmann areas (BA) are indicated as follows : BA 8/9, light blue ; BA10, dark blue ; BA 44, violet ; BA 45, green; BA 46, red; BA 47, grey. Dotted lines indicate absolute fold change of 1.3. Genes selected for validation are in bold.