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

Abstract

Recent studies have suggested an important role of de novo mutations (DNMs) in neuropsychiatric disorders. As DNMs are not subject to elimination due to evolutionary pressure, they are likely to have greater disruptions on biological functions. While a number of sequencing studies have been performed on neuropsychiatric disorders, the implications of DNMs for drug discovery remain to be explored.In this study, we employed a gene-set analysis approach to address this issue. Four neuropsychiatric disorders were studied, including schizophrenia (SCZ), autistic spectrum disorders (ASD), intellectual disability (ID) and epilepsy. We first identified gene-sets associated with different drugs, and analyzed whether the gene-set pertaining to each drug overlaps with DNMs more than expected by chance. We also assessed which medication classes are enriched among the prioritized drugs. We discovered that neuropsychiatric drug classes were indeed significantly enriched for DNMs of all four disorders; in particular, antipsychotics and antiepileptics were the most strongly enriched drug classes for SCZ and epilepsy respectively. Interestingly, we revealed enrichment of several unexpected drug classes, such as lipid-lowering agents for SCZ and anti-neoplastic agents. By inspecting individual hits, we also uncovered other interesting drug candidates or mechanisms (e.g. histone deacetylase inhibition and retinoid signaling) that might warrant further investigations.Taken together, this study provided evidence for the usefulness of DNMs in guiding drug discovery or repositioning.

The role of the retinoids in schizophrenia: genomic and clinical perspectives

“…Exome sequencing of schizophrenia probands and their unaffected parents has uncovered de novo rare variation (spontaneously occurring in the proband) mapped to retinoid genes which could be clinically significant for that individual [99]. Genes enriched for predicted deleterious de novo rare variation in schizophrenia were also overrepresented for genes which interact with at-RA [100]. Whole genome sequencing (WGS) provides an opportunity to more accurately assess the impact of rare variants in schizophrenia.…”

Turning genome-wide association study findings into opportunities for drug repositioning

“…Also, while the focus of this review is on repositioning using GWAS data, the pathway-based approach can be readily extended to handle other types of human genomic data. For example, a recent study showed by pathway analysis that de novo mutations may be used to guide drug discoveries for neuro-psychiatric disorders [64]. Readers may also refer to [65] for further discussions on the potential of GWAS data in drug discovery for neuro-psychiatric disorders.…”