Psychiatric genome-wide association study enrichment shows promise for future psychopharmaceutical discoveries

Abstract

Abstract Background Innovation in psychiatric therapeutics has stagnated on known mechanisms. Psychiatric genome-wide association studies (GWAS) have identified hundreds of genome-wide significant (GWS) loci that have rapidly advanced our understanding of disease etiology. However, whether these results can be leveraged to improve clinical treatment for specific psychiatric disorders remains poorly understood. Methods In this proof-of-principal evaluation of GWAS clinical utility, we test whether the targets of drugs used to treat Attention Deficit Hyperactivity Disorder (ADHD), Bipolar Disorder (BiP), Generalized Anxiety Disorder (GAD), Major Depressive Disorder (MDD), Post-Traumatic Stress Disorder (PTSD), Schizophrenia (SCZ), Substance Use Disorders (SUDs), and insomnia (INS), are enriched for GWAS meta-analysis findings. Results The genes coding for treatment targets of medications used to SCZ, BiP, MDD, and SUDs (but not ADHD, PTSD, GAD, or INSOM) are enriched for GWS loci identified in their respective GWAS (ORs: 2.78-27.63; all ps <1.15e-3). Enrichment is largely driven by the presence of a GWS locus or loci within a gene coding for a drug target (i.e., proximity matching). Broadly, additional annotation (i.e., functional: Combined Annotation Dependent Depletion [CADD] scores, regulomeDB scores, eQTL, chromatin loop, and gene region; statistical: effect size of genome-wide significant SNPs; Z-score of SNPs; number of drug targets implicated by GWAS), with the exception of weighting by the largest SNP effect size, does not further improve enrichment across disorders. Evaluation of prior smaller GWAS reveal that more recent larger GWAS improve enrichment. Conclusions GWAS results may assist in the prioritization of medications for future psychopharmaceutical research.