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Pharmacogenomics of selective serotonin reuptake inhibitor treatment for major depressive disorder: genome-wide associations and functional genomics

The Pharmacogenomics Journal volume 13, pages 456–463 (2013)Cite this article

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Abstract

A genome-wide association (GWA) study of treatment outcomes (response and remission) of selective serotonin reuptake inhibitors (SSRIs) was conducted using 529 subjects with major depressive disorder. While no SNP associations reached the genome-wide level of significance, 14 SNPs of interest were identified for functional analysis. The rs11144870 SNP in the riboflavin kinase (RFK) gene on chromosome 9 was associated with 8-week treatment response (odds ratio (OR)=0.42, P=1.04 × 10−6). The rs915120 SNP in the G protein-coupled receptor kinase 5 (GRK5) gene on chromosome 10 was associated with 8-week remission (OR=0.50, P=1.15 × 10−5). Both SNPs were shown to influence transcription by a reporter gene assay and to alter nuclear protein binding using an electrophoretic mobility shift assay. This report represents an example of joining functional genomics with traditional GWA study results derived from a GWA analysis of SSRI treatment outcomes. The goal of this analytical strategy is to provide insights into the potential relevance of biologically plausible observed associations.

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Acknowledgements

This research was supported, in part, by NIH grants RO1 GM28157, U19 GM61388 (The Pharmacogenomics Research Network), P20 1P20AA017830-01 (The Mayo Clinic Center for Individualized Treatment of Alcohol Dependence), and a PhRMA Foundation Center of Excellence in Clinical Pharmacology Award. Dr Yuan Ji’s work was supported by a KL2 Mentored Career Development Award (NIH/NCRR/NCATS KL2 TR000136) and a Gerstner Family Mayo Career Development Award in Individualized Medicine. This publication was supported by NIH/NCRR/NCATS CTSA Grant Number UL1 RR024150. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. We thank the staff of the Mayo Clinic Rochester Department of Psychiatry and Psychology for their effort in recruiting the patients to the Mayo PGRN-AMPS, Dr Ryan Abo for his assistance in gene annotation, and Lori Solmonson for her assistance with the preparation of the paper. The authors also wish to thank the STAR*D investigators for both their effort and generosity in sharing the clinical data and DNA samples.

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  1. Y Ji and J M Biernacka: These authors contributed equally to this work

Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA

    Y Ji, S Hebbring, Y Chai & R M Weinshilboum

  2. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

    J M Biernacka, G D Jenkins, A Batzler & D Schaid

  3. Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA

    K A Snyder & D A Mrazek

  4. Department of Information Technology, Mayo Clinic, Rochester, MN, USA

    M S Drews

  5. Department of Medicine, Indiana University, Indianapolis West Lafayette, IN, USA

    Z Desta & D Flockhart

  6. RIKEN Center for Genomic Medicine, Yokohama, Japan

    T Mushiroda, M Kubo, Y Nakamura & N Kamatani

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Correspondence to D A Mrazek.

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Competing interests

Dr Mrazek has developed intellectual property that has been licensed by AssureRx Health, which has been subsequently incorporated into a physician decision support software product. He has also received research funding from AssureRx Health to create and maintain a bibliographic system designed to monitor the scientific literature related to studies addressing psychiatric pharmacogenomic relationships. No other author has any potential conflict of interest to report.

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Ji, Y., Biernacka, J., Hebbring, S. et al. Pharmacogenomics of selective serotonin reuptake inhibitor treatment for major depressive disorder: genome-wide associations and functional genomics. Pharmacogenomics J 13, 456–463 (2013). https://doi.org/10.1038/tpj.2012.32

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