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

Abstract

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 CYP2D6, 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.

Figure 1.. Study Design.

Depicted 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, RNA = ribonucleic acid, XWAS = both transcriptome and proteome wide association studies, MR = Mendelian randomization, coloc = colocalization.

Figure 2.. Overlap of Enriched Drugs for Psychiatric Disorders.

A network plot depicting each of the enriched drugs (colored nodes) for each psychiatric disorder labelled central hubs. Each drug node is colored based on their level 1 anatomical therapeutic chemical classification. The thicker the edge (line connecting nodes to disorder), the larger the fold enrichment. ADHD = Attention deficit hyperactivity disorder, BIP = Bipolar disorder, DEP = Depression, SCZ = Schizophrenia, MULTIPLE = A drug with multiple classifications, NAN = No anatomical therapeutic chemical code.

Figure 3.. Transcriptome- and Proteome-Wide Association Study Results.

For each psychiatric disorder the results of transcriptome- and proteome-wide association studies are presented. Significantly associated molecular traits that are also a part of gene sets for enriched drugs are labelled. Labelled molecular traits that were also colocalized are represented with an asterisk. ADHD: attention deficit hyperactivity disorder, BIP: bipolar disorder, DEP: Depression, SCZ: schizophrenia, TWAS = Transcriptome wide association study, PWAS = Proteome wide association study, ns= not significant.

Figure 4.. Mendelian Randomization Results.

For each psychiatric disorder the results of the Mendelian Randomization (MR) analyses are presented. Panel A shows the MR results in the forward direction with the psychiatric disorders as the outcome traits. Panel B shows the MR results in the reverse direction with the psychiatric disorders as the exposure traits. Significantly associated molecular traits that are also a part of a drug gene set enriched for the disorder are labelled. Labelled molecular traits that were also colocalized are represented with an asterisk. ADHD: attention deficit hyperactivity disorder, BIP: bipolar disorder, DEP: Depression, SCZ: schizophrenia, eQTL = expression quantitative trait loci, pQTL = protein quantitative trait loci, ns=not significant.

Figure 5.. Prioritization of Candidate Drug Targets.

The list of prioritized potential drug targets for each psychiatric disorder after combining results of molecular trait analyses from transcriptome and proteome wide association studies, Mendelian randomization, and colocalization. ADHD: attention deficit hyperactivity disorder, BIP: bipolar disorder, DEP: Depression, SCZ: schizophrenia, TWAS = Transcriptome wide association study, PWAS = Proteome wide association study, MR = Mendelian randomization, eQTL = expression quantitative trait loci, pQTL = protein quantitative trait loci, ns= not significant.

Figure 6.. Prioritization of Drug Compounds.

The prioritized list of drug compounds (in bold) for each psychiatric disorder with molecular trait support for enriched drugs. In brackets next to each drug compound is the level 1 anatomical therapeutic chemical (ATC) classification code. Below each drug compound is a brief description. In most cases the description is based on the level 3 ATC classification. Drugs without an ATC code use descriptions from various other sources including: ClinicalTrials.gov (CTG; https://clinicaltrials.gov/), PubChem (PC; https://pubchem.ncbi.nlm.nih.gov/), Kyoto encyclopedia of genes and genomes (KEGG; https://www.genome.jp/kegg/kegg2.html), Therapeutic target database (TTD; https://idrblab.net/ttd/). For drug compounds with the same support score, priority went to those with an ATC code (prioritizing nervous system classification) or to drugs previously associated with psychiatric disorders. [C] = Cardiovasculat system drug, [G] = Genito urinary system and sex hormones, [N] = Nervous system drug, PKC inhib/immunosup. = Protein kinase C inhibitor and immunosuppressant, Neg. Cor. = Drug with negative correlation support between proteome wide association study effect estimate and drug induced gene expression.