Gene-set analysis based on the pharmacological profiles of drugs to identify repurposing opportunities in schizophrenia

Simone De Jong, Lewis R. Vidler, Younes Mokrab, David A. Collier, Gerome Breen

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Genome-wide association studies (GWAS) have identified thousands of novel genetic associations for complex genetic disorders, leading to the identification of potential pharmacological targets for novel drug development. In schizophrenia, 108 conservatively defined loci that meet genome-wide significance have been identified and hundreds of additional sub-threshold associations harbour information on the genetic aetiology of the disorder. In the present study, we used gene-set analysis based on the known binding targets of chemical compounds to identify the 'drug pathways' most strongly associated with schizophrenia-associated genes, with the aim of identifying potential drug repositioning opportunities and clues for novel treatment paradigms, especially in multi-target drug development. We compiled 9389 gene sets (2496 with unique gene content) and interrogated gene-based p-values from the PGC2-SCZ analysis. Although no single drug exceeded experiment wide significance (corrected p<0.05), highly ranked gene-sets reaching suggestive significance including the dopamine receptor antagonists metoclopramide and trifluoperazine and the tyrosine kinase inhibitor neratinib. This is a proof of principle analysis showing the potential utility of GWAS data of schizophrenia for the direct identification of candidate drugs and molecules that show polypharmacy.

Original languageEnglish
Pages (from-to)826-830
Number of pages5
JournalJournal of Psychopharmacology
Volume30
Issue number8
DOIs
Publication statusPublished - 1 Aug 2016

Fingerprint

Schizophrenia
Pharmacology
Pharmaceutical Preparations
Genes
Inborn Genetic Diseases
Genome-Wide Association Study
Drug Repositioning
Polypharmacy
Trifluoperazine
Metoclopramide
Dopamine Antagonists
Protein-Tyrosine Kinases
Genome
Therapeutics

Keywords

  • antipsychotics
  • drug repositioning
  • genetic pathways
  • genome-wide association studies
  • Schizophrenia

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)

Cite this

Gene-set analysis based on the pharmacological profiles of drugs to identify repurposing opportunities in schizophrenia. / De Jong, Simone; Vidler, Lewis R.; Mokrab, Younes; Collier, David A.; Breen, Gerome.

In: Journal of Psychopharmacology, Vol. 30, No. 8, 01.08.2016, p. 826-830.

Research output: Contribution to journalArticle

De Jong, Simone ; Vidler, Lewis R. ; Mokrab, Younes ; Collier, David A. ; Breen, Gerome. / Gene-set analysis based on the pharmacological profiles of drugs to identify repurposing opportunities in schizophrenia. In: Journal of Psychopharmacology. 2016 ; Vol. 30, No. 8. pp. 826-830.
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