Convergent evidence from mouse and human studies suggests the involvement of zinc finger protein 326 gene in antidepressant treatment response.
OBJECTIVE
The forced swim test (FST) is a commonly used model to predict antidepressant efficacy. Uncovering the genetic basis of the model may unravel the mechanism of antidepressant treatment.


METHODS
FVB/NJ (FVB) and C57BL/6J (B6) were first identified as the response and non-response strains to fluoxetine (a serotonin-specific reuptake inhibitor antidepressant) treatment in the mouse FST. Simple-interval (SIM) and composite-interval (CIM) mappings were applied to map the quantitative trait loci (QTLs) of the anti-immobility effect of fluoxetine in FST (FST(FLX)) in 865 male B6×FVB-F2 mice. The brain mRNA expressions of the gene with the maximum QTL-linkage signal for FST(FLX) after the FST were compared between B6 and FVB mice and also compared between fluoxetine and saline treatment. The association of the variants in the human homologue of the mouse FST(FLX)-QTL gene with major depressive disorder (MDD) and antidepressant response were investigated in 1080 human subjects (MDD/control = 582/498).


RESULTS
One linkage signal for FST(FLX)-QTL was detected at an intronic SNP (rs6215396) of the mouse Zfp326 gene (maximal CIM-LOD = 9.36). The Zfp326 mRNA expression in the FVB thalamus was significantly down-regulated by fluoxetine in the FST, and the higher FVB-to-B6 Zfp326 mRNA expressions in the frontal cortex, striatum and hypothalamus diminished after fluoxetine treatment. Two coding-synonymous SNPs (rs2816881 and rs10922744) in the human homologue of Zfp326, ZNF326, were significantly associated with the 8-week antidepressant treatment response in the MDD patients (Bonferroni-corrected p = 0.004-0.028).


CONCLUSIONS
The findings suggest the involvement of the Zfp326 and ZNF326 genes in antidepressant treatment response.
Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.
Ying-Jay
YJ
Liou
Chien-Hsiun
CH
Chen
Chih-Ya
CY
Cheng
Shiow-Yi
SY
Chen
Tai-Jui
TJ
Chen
Younger W-Y
YW
Yu
Fang-Shin
FS
Nian
Shih-Jen
SJ
Tsai
Chen-Jee
CJ
Hong
D000328:Adult; D000368:Aged; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013045:Species Specificity; D013550:Swimming; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
D000928:Antidepressive Agents; D004268:DNA-Binding Proteins; D005473:Fluoxetine; D009687:Nuclear Proteins; D012333:RNA, Messenger; D017367:Selective Serotonin Reuptake Inhibitors; D014157:Transcription Factors; C115511:Zfp326 protein, mouse