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Comparative genomic evidence for the involvement of schizophrenia risk genes in antipsychotic effects

Molecular Psychiatry volume 23, pages 708–712 (2018)Cite this article

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Abstract

Genome-wide association studies (GWAS) for schizophrenia have identified over 100 loci encoding >500 genes. It is unclear whether any of these genes, other than dopamine receptor D2, are immediately relevant to antipsychotic effects or represent novel antipsychotic targets. We applied an in vivo molecular approach to this question by performing RNA sequencing of brain tissue from mice chronically treated with the antipsychotic haloperidol or vehicle. We observed significant enrichments of haloperidol-regulated genes in schizophrenia GWAS loci and in schizophrenia-associated biological pathways. Our findings provide empirical support for overlap between genetic variation underlying the pathophysiology of schizophrenia and the molecular effects of a prototypical antipsychotic.

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Acknowledgements

This work was partially funded by the NIMH/NHGRI Center of Excellence for Genome Sciences grant (P50MH090338, P50HG006582, PIs Dr Fernando Pardo-Manuel de Villena and Dr Patrick F Sullivan).

Author contributions

PFS, YK, PG-R, FP-MdV and JJC designed the experiments. RJN, PG-R, AKR and CRQ performed the experiments. PFS, YK, PG-R, JJC, MDI-U, FP-MdV and PHL analyzed the data. JJC, PFS, YK and PG-R wrote the manuscript. All of the authors critically read and contributed comments to the final version of the manuscript.

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Author notes

  1. Y Kim, P Giusti-Rodriguez and J J Crowley: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Psychiatric Genomics, University of North Carolina, Chapel Hill, NC, USA

    Y Kim, P Giusti-Rodriguez, J J Crowley, R J Nonneman, A K Ryan, C R Quackenbush, M D Iglesias-Ussel & P F Sullivan

  2. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    Y Kim, P Giusti-Rodriguez, J J Crowley, R J Nonneman, A K Ryan, C R Quackenbush, M D Iglesias-Ussel, W Sun, F P-M de Villena & P F Sullivan

  3. Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    J J Crowley & P F Sullivan

  4. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    J J Crowley

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

    J Bryois & P F Sullivan

  6. Psychiatric and Neurodevelopmental Genetics Unit, Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA

    P H Lee

  7. Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA

    W Sun

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Correspondence to P F Sullivan.

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Competing interests

PFS is a consultant to Pfizer. The remaining authors declare no conflict of interest.

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Kim, Y., Giusti-Rodriguez, P., Crowley, J. et al. Comparative genomic evidence for the involvement of schizophrenia risk genes in antipsychotic effects. Mol Psychiatry 23, 708–712 (2018). https://doi.org/10.1038/mp.2017.111

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