Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder.
The pathophysiology of bipolar disorder is still unclear, although family, twin and linkage studies implicate genetic factors. Here we identified XBP1, a pivotal gene in the endoplasmic reticulum (ER) stress response, as contributing to the genetic risk factor for bipolar disorder. Using DNA microarray analysis of lymphoblastoid cells derived from two pairs of twins discordant with respect to the illness, we found downregulated expression of genes related to ER stress response in both affected twins. A polymorphism (-116C-->G) in the promoter region of XBP1, affecting the putative binding site of XBP1, was significantly more common in Japanese patients (odds ratio = 4.6) and overtransmitted to affected offspring in trio samples of the NIMH Bipolar Disorder Genetics Initiative. XBP1-dependent transcription activity of the -116G allele was lower than that of the -116C allele, and in the cells with the G allele, induction of XBP1 expression after ER stress was markedly reduced. Valproate, one of three mood stabilizers, rescued the impaired response by inducing ATF6, the gene upstream of XBP1. These results indicate that the -116C-->G polymorphism in XBP1 causes an impairment of its positive feedback system and increases the risk of bipolar disorder.
Kakiuchi
Chihiro
C
Laboratory for Molecular Dynamics of Mental Disorders, Brain Science Institute, RIKEN, Wako-shi, Saitama 351-0198, Japan.
Iwamoto
Kazuya
K
Ishiwata
Mizuho
M
Bundo
Miki
M
Kasahara
Takaoki
T
Kusumi
Ichiro
I
Tsujita
Takahiro
T
Okazaki
Yuji
Y
Nanko
Shinichiro
S
Kunugi
Hiroshi
H
Sasaki
Tsukasa
T
Kato
Tadafumi
T
D001483:Base Sequence; D001714:Bipolar Disorder / Q000235:genetics*; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D010940:Plant Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics
D004268:DNA-Binding Proteins; D010940:Plant Proteins; C097991:SBP1 protein, Antirrhinum majus; D014157:Transcription Factors; D004247:DNA