Large-scale genomic data-mining implicates dysregulated nuclear receptor-mediated signaling in mental illness

Abstract

Aim: Mental illness comprises a group of heterogeneous conditions attributable to a complex interplay between hereditary and environmental components. Acting at the interface between environmental stimuli and their genomic actions, nuclear receptors (NRs) appear uniquely suited to facilitate gene-environment interactions in the context of mental health. Genetic disruptions to the NR transcriptomic complex (NTC) give rise to neuropsychiatric pathologies, and epidemiological risks involving a steroid response are among the most replicated in psychiatry. Importantly, pharmacological targeting of NR-mediated signaling is clinically effective in the treatment of psychiatric disorders. Here, we systematically interrogated large-scale deposited data to provide a comprehensive evaluation of the genomic NTC risk burden in mental illness.Methods: Utilizing data from large, recent genome-, exome-, and methylome-wide association studies on psychiatric disorders, we assessed the representation of NTC genes among top associated loci and tested the gene set associations for NTC and NR target genes using GWAS summary statistics. Through data mining and transcriptomic profiling of NR-mediated signaling in the diseased and healthy human brain, we categorized psychiatry-relevant NTC gene networks.