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

Genetics can inform biologically relevant drug development and repurposing which may improve patient care. Here, we leverage the genetics of psychiatric disorders to prioritize potential drug targets and compounds. We used the genome-wide association studies of four psychiatric disorders [attention deficit hyperactivity disorder (ADHD), bipolar disorder, depression, and schizophrenia] and genes encoding drug targets. We conducted drug enrichment analyses incorporating the novel and biologically specific GSA-MiXeR tool. We conducted multiple 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. We reveal candidate drug targets associated with a single or multiple disorders and that implicate glutamate signalling. Drug prioritization indicated genetic support for psychotropic medications including several top ranked antipsychotics for schizophrenia. We also observed genetic support for commonly used psychotropics for psychiatric treatment (e.g., clozapine, duloxetine, and lithium). Revealed opportunities for drug repurposing included cholinergic drugs for ADHD, estrogen modulators for depression, and matrix metalloproteinases for ADHD and depression. Our findings indicate the genetic liability to schizophrenia is associated with reduced brain and blood expression of CYP2D6, a gene encoding a metabolizer of drugs and neurotransmitters, suggesting a genetic risk for poor drug response and altered neurotransmission. Our extensive analyses highlight the utility of genetics for informing drug development and repurposing for psychiatric disorders providing novel opportunities for improving patient outcomes. Graphical AbstractDepicted is the series of analyses conducted to generate a list of prioritized drug targets and compounds. First pairings of genome-wide association study (GWAS) traits with drugs are generated using enrichment analyses. Next a series of molecular trait analyses are conducted to generate and rank list of potential drug targets for each GWAS trait. Finally, enrichment and molecular trait results are combined to generate a ranked list of prioritized drugs for each GWAS trait based on supporting genetic evidence. ADHD = Attention deficit hyperactivity disorder, BIP = Bipolar disorder, DEP = Depression, SCZ = Schizophrenia, DBP = Diastolic blood pressure, T2D = Type 2 diabetes, RNA = ribonucleic acid, XWAS = both transcriptome and proteome wide association studies, MR = Mendelian randomization, coloc = colocalization. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/24314069v2_ufig1.gif" ALT="Figure 1"> View larger version (78K): org.highwire.dtl.DTLVardef@45c61dorg.highwire.dtl.DTLVardef@d1c003org.highwire.dtl.DTLVardef@951aeborg.highwire.dtl.DTLVardef@11a5338_HPS_FORMAT_FIGEXP M_FIG C_FIG