Gene-set analysis based on the pharmacological profiles of drugs to identify repurposing opportunities in schizophrenia.
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.
MRC Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health, King's College London, London, UK sdejongwork@gmail.com.
Simone
S
de Jong
Discovery Neuroscience Research, Eli Lilly and Company Ltd, Windlesham, Surrey, UK.
Lewis R
LR
Vidler
Sidra Medical Research Center, Doha, Qatar.
Younes
Y
Mokrab
MRC Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK Discovery Neuroscience Research, Eli Lilly and Company Ltd, Windlesham, Surrey, UK.
David A
DA
Collier
MRC Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health, King's College London, London, UK.
Gerome
G
Breen
D014150:Antipsychotic Agents / Q000494:pharmacology*; D015195:Drug Design; D058492:Drug Repositioning / Q000379:methods; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008787:Metoclopramide / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics*; D014268:Trifluoperazine / Q000494:pharmacology
D014150:Antipsychotic Agents; D011804:Quinolines; D014268:Trifluoperazine; C487932:neratinib; D008787:Metoclopramide
Schizophrenia; antipsychotics; drug repositioning; genetic pathways; genome-wide association studies