Association analysis of ATF4 and ATF5, genes for interacting-proteins of DISC1, in bipolar disorder.
Disrupted in schizophrenia 1 (DISC1) and its molecular cascade are implicated in the pathophysiology of schizophrenia and bipolar disorder. As interacting-proteins with DISC1, Nudel, ATF4, ATF5, LIS1, alpha-tubulin, PDE4B, eIF3, FEZ1, Kendrin, MAP1A and MIPT3 were identified. We previously showed the down-regulation of ATF5 in the lymphoblastoid cells derived from affected co-twin of monozygotic twins discordant for bipolar disorder. We also suggested the contribution of endoplasmic reticulum stress response pathway to the illness, and ATF4 is one of major components in the pathway. Truncated mutant DISC1 reportedly cannot interact with ATF4 and ATF5. These findings suggest the role of these genes in the pathophysiology of bipolar disorder. In this study, we tested genetic association of ATF4 and ATF5 genes with bipolar disorder by a case-control study in Japanese population (438 patients and 532 controls) and transmission disequilibrium test in 237 trio samples from NIMH Genetics Initiative Pedigrees. We also performed gene expression analysis in lymphoblastoid cells. We did not find any significant association in both genetic study and expression analysis. By the exploratory haplotype analysis, nominal association of ATF4 with bipolar II patients was observed, but it was not significant after correction of multiple testing. Contribution of common variations of ATF4 and ATF5 to the pathophysiology of bipolar disorder may be minimal if any.
Kakiuchi
Chihiro
C
Laboratory for Molecular Dynamics of Mental Disorders, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Ishiwata
Mizuho
M
Nanko
Shinichiro
S
Kunugi
Hiroshi
H
Minabe
Yoshio
Y
Nakamura
Kazuhiko
K
Mori
Norio
N
Fujii
Kumiko
K
Yamada
Kazuo
K
Yoshikawa
Takeo
T
Kato
Tadafumi
T
D051701:Activating Transcription Factor 4 / Q000235:genetics*; D051696:Activating Transcription Factors / Q000235:genetics*; D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics; D016022:Case-Control Studies; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism*
C497109:ATF4 protein, human; C507532:ATF5 protein, human; D051696:Activating Transcription Factors; C412476:DISC1 protein, human; D005819:Genetic Markers; D009419:Nerve Tissue Proteins; D051701:Activating Transcription Factor 4