Leveraging the Genetics of Psychiatric Disorders to Prioritize Potential Drug Targets and Compounds.

Background: Genetics has the potential to inform biologically relevant drug treatment and repurposing which may ultimately improve patient care. In this study, we combine methods which leverage the genetics of psychiatric disorders to prioritize potential drug targets and compounds.

Methods: We used the largest available genome-wide association studies, in European ancestry, of four psychiatric disorders [i.e., attention deficit hyperactivity disorder (ADHD), bipolar disorder, depression, and schizophrenia] along with genes encoding drug targets. With this data, we conducted drug enrichment analyses incorporating the novel and biologically specific GSA-MiXeR tool. We then conducted a series of molecular trait analyses using large-scale transcriptomic and proteomic datasets sampled from brain and blood tissue. This included the novel use of the UK Biobank proteomic data for a proteome-wide association study of psychiatric disorders. With the accumulated evidence, we prioritize potential drug targets and compounds for each disorder.

Findings: We reveal candidate drug targets shared across multiple disorders as well as disorder-specific targets. Drug prioritization indicated genetic support for several currently used psychotropic medications including the antipsychotic paliperidone as the top ranked drug for schizophrenia. We also observed genetic support for other commonly used psychotropics (e.g., clozapine, risperidone, duloxetine, lithium, and valproic acid). Opportunities for drug repurposing were revealed such as cholinergic drugs for ADHD, estrogens for depression, and gabapentin enacarbil for schizophrenia. Our findings also indicate the genetic liability to schizophrenia is associated with reduced brain and blood expression of , a gene encoding a metabolizer of drugs and neurotransmitters, suggesting a genetic risk for poor drug response and altered neurotransmission.

Interpretation: Here we present a series of complimentary and comprehensive analyses that highlight the utility of genetics for informing drug development and repurposing for psychiatric disorders. Our findings present novel opportunities for refining psychiatric treatment.