A functional variant in the serotonin receptor 7 gene (HTR7), rs7905446, is associated with good response to SSRIs in bipolar and unipolar depression

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DOI

  • Ya Bin Wei, Karolinska University Hospital og Karolinska Institute
  • ,
  • Michael McCarthy, University of California, San Diego
  • ,
  • Hongyan Ren, Sichuan University, University of Alberta
  • ,
  • Tania Carrillo-Roa, Max Planck Institute of Psychiatry
  • ,
  • Tatyana Shekhtman, University of California, San Diego
  • ,
  • Anna DeModena, University of California San Diego
  • ,
  • Jia Jia Liu, Peking University
  • ,
  • Susan G Leckband, Karolinska University Hospital, VA San Diego Healthcare System
  • ,
  • Ole Mors
  • Marcella Rietschel, Medical Faculty Mannheim, Heidelberg University, Mannheim
  • ,
  • Neven Henigsberg, University of Zagreb
  • ,
  • Annamaria Cattaneo, IRCCS
  • ,
  • Elisabeth B Binder, Max Planck Institute of Psychiatry, Emery University
  • ,
  • Katherine J Aitchison, University of Alberta
  • ,
  • John R Kelsoe, University of California, San Diego

Predicting antidepressant response has been a clinical challenge for mood disorder. Although several genome-wide association studies have suggested a number of genetic variants to be associated with antidepressant response, the sample sizes are small and the results are difficult to replicate. Previous animal studies have shown that knockout of the serotonin receptor 7 gene (HTR7) resulted in an antidepressant-like phenotype, suggesting it was important to antidepressant action. In this report, in the first stage, we used a cost-effective pooled-sequencing strategy to sequence the entire HTR7 gene and its regulatory regions to investigate the association of common variants in HTR7 and clinical response to four selective serotonin reuptake inhibitors (SSRIs: citalopram, paroxetine, fluoxetine and sertraline) in a retrospective cohort mainly consisting of subjects with bipolar disorder (n = 359). We found 80 single-nucleotide polymorphisms (SNPs) with false discovery rate < 0.05 associated with response to paroxetine. Among the significant SNPs, rs7905446 (T/G), which is located at the promoter region, also showed nominal significance (P < 0.05) in fluoxetine group. GG/TG genotypes for rs7905446 and female gender were associated with better response to two SSRIs (paroxetine and fluoxetine). In the second stage, we replicated this association in two independent prospective samples of SSRI-treated patients with major depressive disorder: the MARS (n = 253, P = 0.0169) and GENDEP studies (n = 432, P = 0.008). The GG/TG genotypes were consistently associated with response in all three samples. Functional study of rs7905446 showed greater activity of the G allele in regulating expression of HTR7. The G allele displayed higher luciferase activity in two neuronal-related cell lines, and estrogen treatment decreased the activity of only the G allele. Electrophoretic mobility shift assay suggested that the G allele interacted with CCAAT/enhancer-binding protein beta transcription factor (TF), while the T allele did not show any interaction with any TFs. Our results provided novel pharmacogenomic evidence to support the role of HTR7 in association with antidepressant response.

OriginalsprogEngelsk
TidsskriftMolecular Psychiatry
Vol/bind25
Sider (fra-til)1312-1322
ISSN1359-4184
DOI
StatusUdgivet - 2020

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