Abstract

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.

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Acknowledgements

This work was supported by grants to JRK from the NIMH (U01 MH92758) and the Department of Veterans Affairs and UCSD CTRI Pilot Project Grant (to MM and JRK). YBW was supported by the Swedish Research Council (Reg no. 2015–06372). HR was supported by the Alberta Centennial Addiction and Mental Health Research Chair held by KJA. GENDEP was funded by a European Commission Framework 6 grant (Contract Ref: LSHB-CT-2003503428). Lundbeck provided both nortriptyline and escitalopram free of charge. GlaxoSmithKline, the Medical Research Council and the Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King’s College London and South London and Maudsley NHS Foundation Trust (funded by the National Institute for Health Research, Department of Health, UK) contributed by funding add-on projects in the London center. A joint grant from the Medical Research Council, UK, and GlaxoSmithKline (G0701420) provided additional funding for the array genotyping. The funders had no role in the design and conduct of the study, in data collection, analysis, interpretation or writing the report. MARS samples were supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e: Med Programme (grant 01ZX1314J to EBB).

Author information

Affiliations

  1. Center for Molecular Medicine, Karolinska University Hospital, 17176, Stockholm, Sweden

    • Ya Bin Wei
    •  & Susan G. Leckband
  2. Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176, Stockholm, Sweden

    • Ya Bin Wei
  3. Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA

    • Ya Bin Wei
    • , Michael McCarthy
    • , Tatyana Shekhtman
    • , Anna DeModena
    •  & John R. Kelsoe
  4. Psychiatry Service, VA San Diego Healthcare System, San Diego, CA, 92161, USA

    • Michael McCarthy
    • , Tatyana Shekhtman
    • , Anna DeModena
    • , Susan G. Leckband
    •  & John R. Kelsoe
  5. Psychiatric Laboratory and Mental Health Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China

    • Hongyan Ren
  6. Department of Psychiatry and Medical Genetics, University of Alberta, Edmonton, AB, Canada

    • Hongyan Ren
    •  & Katherine J. Aitchison
  7. Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804, Munich, Germany

    • Tania Carrillo-Roa
    •  & Elisabeth B. Binder
  8. National Institute on Drug Dependence, Peking University, 100191, Beijing, China

    • Jia Jia Liu
  9. Institute of Mental Health, National Clinical Research Center for Mental Disorders, Key Laboratory of Mental Health and Peking University Sixth Hospita, Peking University, 100191, Beijing, China

    • Jia Jia Liu
  10. Psychosis Research Unit, Aarhus University Hospital, Aarhus, Denmark

    • Ole Mors
  11. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim Heidelberg University, Mannheim, Germany

    • Marcella Rietschel
  12. Croatian Institute for Brain Research, Center of Research Excellence for Basic, Clinical and Translational Neuroscience, University of Zagreb School of Medicine, Zagreb, Croatia

    • Neven Henigsberg
  13. Biological Psychiatry Unit, IRCCS, Brescia, Italy

    • Annamaria Cattaneo
  14. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA

    • Elisabeth B. Binder
  15. Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, 92093, USA

    • John R. Kelsoe

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Conflict of interest

KJA has been a member of various advisory boards, received consultancy fees and honoraria, and received research grants from companies including Johnson and Johnson Pharmaceuticals Research and Development, Bristol-Myers Squibb Pharmaceuticals Limited, and Janssen Inc., Canada. MM serves as scientific consultant to Janssen Pharmaceuticals. EBB receives a research grant from Böhringer Ingelheim.

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Correspondence to John R. Kelsoe.

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https://doi.org/10.1038/s41380-019-0397-1