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Translating genome-wide association findings into new therapeutics for psychiatry

Nature Neuroscience volume 19, pages 1392–1396 (2016)Cite this article

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Abstract

Genome-wide association studies (GWAS) in psychiatry, once they reach sufficient sample size and power, have been enormously successful. The Psychiatric Genomics Consortium (PGC) aims for mega-analyses with sample sizes that will grow to >1 million individuals in the next 5 years. This should lead to hundreds of new findings for common genetic variants across nine psychiatric disorders studied by the PGC. The new targets discovered by GWAS have the potential to restart largely stalled psychiatric drug development pipelines, and the translation of GWAS findings into the clinic is a key aim of the recently funded phase 3 of the PGC. This is not without considerable technical challenges. These approaches complement the other main aim of GWAS studies, risk prediction approaches for improving detection, differential diagnosis, and clinical trial design. This paper outlines the motivations, technical and analytical issues, and the plans for translating PGC phase 3 findings into new therapeutics.

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Figure 1: PGC GWAS drug target analysis strategy: utilizing diverse information sources for drug target discovery.

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Author information

Authors and Affiliations

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

    Gerome Breen, Paul F O'Reilly, Héléna A Gaspar, Christopher Huebel & David A Collier

  2. UK National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health, South London and Maudsley Hospital, London, UK

    Gerome Breen, Héléna A Gaspar, Christopher Huebel & David A Collier

  3. Neuroscience Therapeutic Area, Janssen Research & Development, LLC, Titusville, New Jersey, USA

    Qingqin Li & Husseini Manji

  4. Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Bryan L Roth

  5. National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Bryan L Roth

  6. Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Bryan L Roth

  7. Neuroscience Research Unit, Pfizer Inc, Cambridge, Massachusetts, USA

    Patricio O'Donnell

  8. H. Lundbeck A/S, Synaptic Transmission, Neuroscience Research DK, Valby, Denmark

    Michael Didriksen

  9. Department of Neuroscience, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA

    Ricardo Dolmetsch

  10. Department of Psychiatry, University of California San Diego, and Veterans Affairs San Diego Healthcare System, La Jolla, California, USA

    John R Kelsoe

  11. Neuroscience Discovery and Translational Area, Pharma Research & Early Development, F. Hoffmann - La Roche, Basel, Switzerland

    Dheeraj Malhotra

  12. Department of Basic Medical Science, Institute of Psychiatry, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy

    Alessandro Bertolino

  13. Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research/VU University Amsterdam, Amsterdam, the Netherlands

    Danielle Posthuma

  14. Department of Clinical Genetics, VU University Medical Centre Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands

    Danielle Posthuma

  15. Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Pamela Sklar

  16. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Pamela Sklar

  17. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Pamela Sklar

  18. Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK

    Shitij Kapur

  19. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Patrick F Sullivan

  20. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Patrick F Sullivan

  21. Discovery Neuroscience Research, Eli Lilly and Company Ltd, Windlesham, Surrey, UK

    David A Collier

  22. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Howard J Edenberg

  23. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Howard J Edenberg

Authors
  1. Gerome Breen
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  2. Qingqin Li
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  3. Bryan L Roth
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  4. Patricio O'Donnell
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  5. Michael Didriksen
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  6. Ricardo Dolmetsch
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  7. Paul F O'Reilly
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  8. Héléna A Gaspar
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  9. Husseini Manji
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  10. Christopher Huebel
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  11. John R Kelsoe
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  12. Dheeraj Malhotra
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  13. Alessandro Bertolino
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  14. Danielle Posthuma
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  15. Pamela Sklar
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  16. Shitij Kapur
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  17. Patrick F Sullivan
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  18. David A Collier
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  19. Howard J Edenberg
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Corresponding author

Correspondence to Gerome Breen.

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Competing interests

Many of the authors work for pharmaceutical companies and/or have grants from them.

Supplementary information

Supplementary Table 1

Current and recent trials in psychiatry, including the nine disorders studied in the PGC phase 3 (XLSX 1844 kb)

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Breen, G., Li, Q., Roth, B. et al. Translating genome-wide association findings into new therapeutics for psychiatry. Nat Neurosci 19, 1392–1396 (2016). https://doi.org/10.1038/nn.4411

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