Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Translating genome-wide association findings into new therapeutics for psychiatry

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

Subjects

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

Buy

All prices are NET prices.

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

References

  1. Fibiger, H.C. Schizophr. Bull. 38, 649–650 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Rizzo, S.J., Edgerton, J.R., Hughes, Z.A. & Brandon, N.J. J. Biomol. Screen. 18, 509–521 (2013).

    Article  PubMed  Google Scholar 

  3. Papassotiropoulos, A. & de Quervain, D.J. Trends Cogn. Sci. 19, 183–187 (2015).

    Article  PubMed  Google Scholar 

  4. Jones, H.J. et al. JAMA Psychiatry 73, 221–228 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  5. O'Donnell, P. & Ehlers, M.D. JAMA Psychiatry 72, 1067–1068 (2015).

    Article  PubMed  Google Scholar 

  6. Shorter, E. Can. J. Psychiatry 56, 193–197 (2011).

    Article  PubMed  Google Scholar 

  7. Fitzgerald, K. et al. Lancet 383, 60–68 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Pearson, E. Nat. Genet. 46, 323–324 (2014).

    Article  CAS  PubMed  Google Scholar 

  9. Lu, W. et al. Hum. Mol. Genet. 24, 2390–2400 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Nature 511, 421–427 (2014).

  11. Purcell, S.M. et al. Nature 506, 185–190 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Fromer, M. et al. Nature 506, 179–184 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Okada, Y. Clin. Genet. 86, 432–440 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. Teslovich, T.M. et al. Nature 466, 707–713 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Manolio, T.A. et al. Genet. Med. 15, 258–267 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Sanseau, P. et al. Nat. Biotechnol. 30, 317–320 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Nelson, M.R. et al. Nat. Genet. 47, 856–860 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Ripke, S. et al. Nat. Genet. 45, 1150–1159 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mangravite, L.M. et al. Arterioscler. Thromb. Vasc. Biol. 30, 1485–1492 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sekar, A. et al. Nature 530, 177–183 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Akbarian, S. et al. Nat. Neurosci. 18, 1707–1712 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fromer, M. et al. Nat. Neurosci. 19, 1442–1453 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gusev, A. et al. Nat. Genet. 48, 245–252 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gamazon, E.R. et al. Nat. Genet. 47, 1091–1098 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. BrainSeq: A Human Brain Genomics Consortium. Neuron 88, 1078–1083 (2015).

  26. Gandal, M.J., Leppa, V., Won, H., Parikshak, N.N. & Geschwind, D.H. Nat. Neurosci. 19, 1463–1476 (2016).

    Article  Google Scholar 

  27. Cao, C. & Moult, J. BMC Genomics 15 (suppl. 4), S5 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Segrè, A.V., Wei, N., Altshuler, D. & Florez, J.C. Diabetes 64, 1470–1483 (2015).

    Article  PubMed  Google Scholar 

  29. Lee, S.H. et al. Nat. Genet. 45, 984–994 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Schubert, C.R., Xi, H.S., Wendland, J.R. & O'Donnell, P. Neuron 84, 537–541 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Sun, Y. & Dolmetsch, R.E. Swiss Med. Wkly. 146, w14241 (2016).

    PubMed  Google Scholar 

  32. Chatterjee, N., Shi, J. & García-Closas, M. Nat. Rev. Genet. 17, 392–406 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wray, N.R., Goddard, M.E. & Visscher, P.M. Genome Res. 17, 1520–1528 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dima, D. & Breen, G. J. Psychopharmacol. 29, 867–871 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. Hu, Y. et al. Am. J. Hum. Genet. 92, 547–557 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Agerbo, E. et al. JAMA Psychiatry 72, 635–641 (2015).

    Article  PubMed  Google Scholar 

  37. Vassos, E. et al. Biol. Psychiatry http://dx.doi.org/10.1016/j.biopsych.2016.06.028 (2016).

  38. de Leeuw, C.A., Mooij, J.M., Heskes, T. & Posthuma, D. PLOS Comput. Biol. 11, e1004219 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  39. De Jong, S., Vidler, L., Mokrab, Y., Collier, D.A. & Breen, G.D. J. Psychopharmacol. 30, 826–830 (2016).

    Article  CAS  PubMed  Google Scholar 

  40. Stefansson, H. et al. Nature 505, 361–366 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Wellcome Trust Case Control Consortium. Nature 464, 713–720 (2010).

  42. Rucker, J.J. et al. Mol. Psychiatry 18, 183–189 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Network & Pathway Analysis Subgroup of Psychiatric Genomics Consortium. Nat. Neurosci. 18, 199–209 (2015).

  44. Prathipati, P. & Mizuguchi, K. Curr. Top. Med. Chem. 16, 1009–1025 (2016).

    Article  CAS  PubMed  Google Scholar 

  45. Greene, C.S. et al. Nat. Genet. 47, 569–576 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qingqin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bryan L Roth
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Patricio O'Donnell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael Didriksen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ricardo Dolmetsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paul F O'Reilly
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Héléna A Gaspar
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Husseini Manji
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Christopher Huebel
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. John R Kelsoe
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dheeraj Malhotra
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Alessandro Bertolino
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Danielle Posthuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Pamela Sklar
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Shitij Kapur
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Patrick F Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. David A Collier
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Howard J Edenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gerome Breen.

Ethics declarations

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)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.4411

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing