Abstract
Knowledge of psychiatric disease genetics has advanced rapidly during the past decade with the advent of genome-wide association studies (GWAS). However, less progress has been made in harnessing these data to reveal new therapies. Here we propose a framework for drug repositioning by comparing transcriptomes imputed from GWAS data with drug-induced gene expression profiles from the Connectivity Map database and apply this approach to seven psychiatric disorders. We found a number of repositioning candidates, many supported by preclinical or clinical evidence. Repositioning candidates for a number of disorders were also significantly enriched for known psychiatric medications or therapies considered in clinical trials. For example, candidates for schizophrenia were enriched for antipsychotics, while those for bipolar disorder were enriched for both antipsychotics and antidepressants. These findings provide support for the usefulness of GWAS data in guiding drug discovery.
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Acknowledgements
We would like to thank C.-W. Chan and C.-F. Wong for assistance in drug annotations. We are grateful to S.K.W. Tsui and S.S.Y. Lui for discussions and to the Hong Kong Bioinformatics Centre for computing support. This study was partially supported by the Lo-Kwee Seong Biomedical Research Fund and a Direct Grant from the Chinese University of Hong Kong to H.-C.S.
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H.-C.S. conceived and designed the study. H.-C.S. and C.K.-L.C. performed data analyses. H.-C.S. interpreted the data. H.-C.S., C.K.-L.C., W.-T.C., K.-S.H., C.-P.L. and S.H.-Y.Y. performed drug annotations (here W.-T.C., K.-S.H., C.-P.L. and S.H.-Y.Y. are listed in alphabetical order). P.-C.S. provided advice on statistical and computational analyses. H.-C.S. wrote the manuscript and supervised the study. All authors approved the final version of the manuscript.
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Supplementary information
Supplementary Text and Figures
Supplementary Note and Supplementary Tables 1 and 10–12 (PDF 512 kb)
Supplementary Table 2
Manually curated lists of top 15 drug repositioning candidates for each brain region for schizophrenia (XLSX 44 kb)
Supplementary Table 3
Manually curated lists of top 15 drug repositioning candidates for each brain region for bipolar disorder (XLSX 40 kb)
Supplementary Table 4
Manually curated lists of top 15 drug repositioning candidates for each brain region for major depressive disorder with GWAS data from the Psychiatric Genomics Consortium (XLSX 42 kb)
Supplementary Table 5
Manually curated lists of top 15 drug repositioning candidates for each brain region for major depressive disorder with GWAS data from the CONVERGE Consortium (XLSX 41 kb)
Supplementary Table 6
Manually curated lists of top 15 drug repositioning candidates for each brain region for Alzheimer's disease (XLSX 44 kb)
Supplementary Table 7
Manually curated lists of top 15 drug repositioning candidates for each brain region for anxiety disorders (XLSX 40 kb)
Supplementary Table 8
Manually curated lists of top 15 drug repositioning candidates for each brain region for attention deficit hyperactivity disorder (XLSX 43 kb)
Supplementary Table 9
Manually curated lists of top 15 drug repositioning candidates for each brain region for autistic spectrum disorders (XLSX 43 kb)
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So, HC., Chau, CL., Chiu, WT. et al. Analysis of genome-wide association data highlights candidates for drug repositioning in psychiatry. Nat Neurosci 20, 1342–1349 (2017). https://doi.org/10.1038/nn.4618
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DOI: https://doi.org/10.1038/nn.4618
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