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Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project

The Pharmacogenomics Journal volume 12, pages 68–77 (2012)Cite this article

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Abstract

Suicidal thoughts during antidepressant treatment have been the focus of several candidate gene association studies. The aim of the present genome-wide association study was to identify additional genetic variants involved in increasing suicidal ideation during escitalopram and nortriptyline treatment. A total of 706 adult participants of European ancestry, treated for major depression with escitalopram or nortriptyline over 12 weeks in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study were genotyped with Illumina Human 610-Quad Beadchips (Illumina, San Diego, CA, USA). A total of 244 subjects experienced an increase in suicidal ideation during follow-up. The genetic marker most significantly associated with increasing suicidality (8.28 × 10−7) was a single-nucleotide polymorphism (SNP; rs11143230) located 30 kb downstream of a gene encoding guanine deaminase (GDA) on chromosome 9q21.13. Two suggestive drug-specific associations within KCNIP4 (Kv channel-interacting protein 4; chromosome 4p15.31) and near ELP3 (elongation protein 3 homolog; chromosome 8p21.1) were found in subjects treated with escitalopram. Suggestive drug by gene interactions for two SNPs near structural variants on chromosome 4q12, one SNP in the apolipoprotein O (APOO) gene on chromosome Xp22.11 and one on chromosome 11q24.3 were found. The most significant association within a set of 33 candidate genes was in the neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene. Finally, we also found trend for an association within genes previously associated with psychiatric phenotypes indirectly linked to suicidal behavior, that is, GRIP1, NXPH1 and ANK3. The results suggest novel pathways involved in increasing suicidal ideation during antidepressant treatment and should help to target treatment to reduce the risk of this dramatic adverse event. Limited power precludes definitive conclusions and replication in larger sample is warranted.

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Acknowledgements

We acknowledge the contribution of Maja Bajs, Mara Barreto, Cristian Bonvicini, Desmond Campbell, Elzbieta Cegielska, Monika Dmitrzak-Weglarz, Amanda Elkin, Caterina Giovannini, Joanna M Gray, Cerisse Gunasinghe, Bhanu Gupta, Sudhir Kumar, Susanne Höfels, Petra Kalember, Paweł Kapelski, Zrnka Kovacic, Dejan Kozel, Anna Leszczynska-Rodziewicz, Sylvie Linotte, Andrej Marusic, Julien Mendlewicz, Metka Paragi, Laura Pedrini, Jorge Perez, Ute Pfeiffer, Aleksandra Rajewska-Rager, Luciana Rillosi, Christine Schmäl, Anna Schuhmacher, Maria Skibiñska, Rebecca Smith, Farzana Hoda, Jana Strohmaier, Jerneja Sveticic, Aleksandra Szczepankiewicz, Alenka Tancic, Sandra Weber, Thomas Schulze, Piotr Czerski and Richard J Williamson. The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref: LSHB-CT-2003-503428. Lundbeck provided both nortriptyline and escitalopram free of charge for the GENDEP study. 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. The genotyping was funded by joint grant from the Medical Research Council, UK and GlaxoSmithKline (G0701420). The fund providers had no role in the design and conduct of the study, in data collection, analysis, interpretation or writing the report.

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Authors and Affiliations

  1. MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK

    N Perroud, R Uher, M Y M Ng, A Farmer, G Breen, K J Aitchison, C M Lewis, I W Craig & P McGuffin

  2. Department of Psychiatry, University of Geneva Medical School, Geneva, Switzerland

    N Perroud & M Guipponi

  3. University Hospitals of Geneva, Geneva, Switzerland

    N Perroud & M Guipponi

  4. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland

    M Guipponi

  5. Department of Psychiatry, Laboratory of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan, Poland

    J Hauser

  6. Croatian Institute for Brain Research, Medical School, University of Zagreb, Zagreb, Croatia

    N Henigsberg

  7. Department of Psychiatry, University of Bonn, Bonn, Germany

    W Maier

  8. Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark

    O Mors

  9. Biological Psychiatry Unit and Dual Diagnosis ward IRCCS, Centro San Giovanni di Dio, FBF, Brescia, Italy

    M Gennarelli

  10. Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany

    M Rietschel

  11. Laboratoire de Psychologie Médicale, Université Libre de Bruxelles and Psy Pluriel—Centre Européen de Psychologie Médicale, Brussels, Belgium

    D Souery

  12. Institute of Public Health of the Republic of Slovenia, Ljubljana, Slovenia

    M Z Dernovsek

  13. Regionspsykiatrien Silkeborg, Aarhus University Hospital, Aarhus, Denmark

    A S Stamp

  14. Centre National de Génotypage, Evry Cedex, France

    M Lathrop

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  1. N Perroud
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Correspondence to N Perroud.

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Competing interests

Perroud, Uher, Ng, Hauser, Guipponi, Maier, Mors, Gennarelli, Rietschel, Dernovsek, Stamp, Lathrop, Breen, Craig and Lewis declare no competing interests. Henigsberg and Souery participated in clinical trials sponsored by pharmaceutical companies including GlaxoSmithKline and Lundbeck. Henigsberg has received honoraria for participating in expert panels for pharmaceutical companies. Aitchison, Farmer and McGuffin have received consultancy fees and honoraria for participating in expert panels for pharmaceutical companies including Lundbeck and GlaxoSmithKline.

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Perroud, N., Uher, R., Ng, M. et al. Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project. Pharmacogenomics J 12, 68–77 (2012). https://doi.org/10.1038/tpj.2010.70

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