Translating GWAS Findings Into Therapies For Depression And Anxiety Disorders: Drug Repositioning Using Gene-Set Analyses Reveals Enrichment Of Psychiatric Drug Classes

Abstract

Depression and anxiety disorders are the first and sixth leading cause of disability worldwide according to latest reports from the World Health Organization. Despite their high prevalence and the significant disability resulted, there are limited advances in new drug development. On the other hand, the advent of genome-wide association studies (GWAS) has greatly improved our understanding of the genetic basis underlying psychiatric disorders.In this work we employed gene-set analyses of GWAS summary statistics for drug repositioning. We explored five related GWAS datasets, including two on major depressive disorder (MDD-PGC and MDD-CONVERGE, with the latter focusing on severe melancholic depression), one on anxiety disorders, and two on depressive symptoms and neuroticism in the population. We extracted gene-sets associated with each drug from DSigDB and examined their association with each GWAS phenotype. We also performed repositioning analyses on meta-analyzed GWAS data, integrating evidence from all related phenotypes.Importantly, we showed that the repositioning hits are generally enriched for known psychiatric medications or those considered in clinical trials, except for MDD-PGC.Enrichment was seen for antidepressants and anxiolytics but also for antipsychotics. We also revealed new candidates or drug classes for repositioning, some of which were supported by experimental or clinical studies. For example, the top repositioning hit using meta-analyzed p-values was fendiline, which was shown to produce antidepressant-like effects in mouse models by inhibition of acid sphingomyelinase and reducing ceramide levels. Taken together, our findings suggest that human genomic data such as GWAS are useful in guiding drug discoveries for depression and anxiety disorders.

Metanalysis of genome-wide association studies for panic disorder suggest pathways and mechanisms of pathogenesis

“…The current results do not provide sufficient evidence for the 410 association of these drugs and their effects on the PF-ranked genes found for PD; in fact, no gene-411 drug association was found either at the individual drug level, or at the drug class level. Differently 412 from previous reports (So, 2017;So et al, 2016), which support drug repositioning from genes 413 extracted from GWAS for anxiety and mood disorders, our findings do not support such proposals. 414 Extensive methodological differences are probably responsible for this discrepancy.…”

Using genetic drug-target networks to develop new drug hypotheses for major depressive disorder

“…The enrichment of calcium channels confirms that calcium channel blockers such as verapamil may provide repurposing opportunities for MDD, 26 although their effects on blood pressure may prove problematic. 27 Pregabalin and gabapentin, both calcium channel modulators, are also top ranked repurposing candidates. Pregabalin has been shown to be an effective adjunctive treatment for MDD 28 and treatment-resistant bipolar disorder, 29 and gabapentin is used off-label for bipolar disorder.…”

Implications of de novo mutations in guiding drug discovery: A study of four neuropsychiatric disorders

“…Another study by Gasper et al 55 reported that as sample size increases, SCZ GWAS results were increasingly enriched for known psychiatric medications. We also recently revealed that GWAS results of depression and anxiety disorders (and related phenotypes) were enriched for psychiatric drug classes including antidepressants 56 . Taken together, the current study adds to the mounting evidence that data from human genomic studies are useful in guiding drug development in neuropsychiatry.…”