Translating genome-wide association findings into new therapeutics for psychiatry

Gerome Breen^{1

2}, Qingqin Li³, Bryan L Roth^{4

5

6}, Patricio O'Donnell⁷, Michael Didriksen⁸, Ricardo Dolmetsch⁹, Paul F O'Reilly¹, Héléna A Gaspar^{1

2}, Husseini Manji³, Christopher Huebel^{1

2}, John R Kelsoe¹⁰, Dheeraj Malhotra¹¹, Alessandro Bertolino¹², Danielle Posthuma^{13

14}, Pamela Sklar^{15

16

17}, Shitij Kapur¹⁸, Patrick F Sullivan^{19

20}, David A Collier^{1

2

21}, Howard J Edenberg^{22

23}

Affiliations

¹ MRC Social, Genetic &Developmental Psychiatry Centre, Institute of Psychiatry, Psychology &Neuroscience, King's College London, London, UK.
² UK National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health, South London and Maudsley Hospital, London, UK.
³ Neuroscience Therapeutic Area, Janssen Research &Development, LLC, Titusville, New Jersey, USA.
⁴ Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
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.
⁶ Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁷ Neuroscience Research Unit, Pfizer Inc, Cambridge, Massachusetts, USA.
⁸ H. Lundbeck A/S, Synaptic Transmission, Neuroscience Research DK, Valby, Denmark.
⁹ Department of Neuroscience, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
¹⁰ Department of Psychiatry, University of California San Diego, and Veterans Affairs San Diego Healthcare System, La Jolla, California, USA.
¹¹ Neuroscience Discovery and Translational Area, Pharma Research &Early Development, F. Hoffmann - La Roche, Basel, Switzerland.
¹² Institute of Psychiatry, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
¹³ Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research/VU University Amsterdam, Amsterdam, the Netherlands.
¹⁴ Department of Clinical Genetics, VU University Medical Centre Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
¹⁵ Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁶ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁷ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁸ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
¹⁹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁰ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
²¹ Discovery Neuroscience Research, Eli Lilly and Company Ltd, Windlesham, Surrey, UK.
²² Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
²³ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

PMID: 27786187
PMCID: PMC5676453
DOI: 10.1038/nn.4411

Review

Translating genome-wide association findings into new therapeutics for psychiatry

Gerome Breen et al. Nat Neurosci. 2016.

. 2016 Oct 26;19(11):1392-1396.

doi: 10.1038/nn.4411.

Authors

Affiliations

¹ MRC Social, Genetic &Developmental Psychiatry Centre, Institute of Psychiatry, Psychology &Neuroscience, King's College London, London, UK.
² UK National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health, South London and Maudsley Hospital, London, UK.
³ Neuroscience Therapeutic Area, Janssen Research &Development, LLC, Titusville, New Jersey, USA.
⁴ Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
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.
⁶ Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁷ Neuroscience Research Unit, Pfizer Inc, Cambridge, Massachusetts, USA.
⁸ H. Lundbeck A/S, Synaptic Transmission, Neuroscience Research DK, Valby, Denmark.
⁹ Department of Neuroscience, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
¹⁰ Department of Psychiatry, University of California San Diego, and Veterans Affairs San Diego Healthcare System, La Jolla, California, USA.
¹¹ Neuroscience Discovery and Translational Area, Pharma Research &Early Development, F. Hoffmann - La Roche, Basel, Switzerland.
¹² Institute of Psychiatry, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
¹³ Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research/VU University Amsterdam, Amsterdam, the Netherlands.
¹⁴ Department of Clinical Genetics, VU University Medical Centre Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
¹⁵ Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁶ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁷ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁸ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
¹⁹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁰ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
²¹ Discovery Neuroscience Research, Eli Lilly and Company Ltd, Windlesham, Surrey, UK.
²² Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
²³ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

PMID: 27786187
PMCID: PMC5676453
DOI: 10.1038/nn.4411

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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Figures

**Figure 1**
PGC GWAS Drug Target Analysis Strategy: utilising diverse information sources for drug target discovery.

See this image and copyright information in PMC

References

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Translating genome-wide association findings into new therapeutics for psychiatry

Affiliations

Translating genome-wide association findings into new therapeutics for psychiatry

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

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Medical