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. Results: We found that NTC genes are significantly overrepresented in genome-, methylome-, and exome-wide associated loci and that the NTC, as well as NR target gene sets, is overall associated with mental illness. Accordingly, we identified transcriptomic NTC signatures in patient brain samples. In line with a key role for orchestrated NR-mediated signaling in the developing brain, particularly NTC co-expression networks with prenatal peak expression are enriched with differentially methylated, sex-biased, and psychiatry-associated risk variants. Conclusion: Here, we provide multilevel evidence that supports genomic NR-mediated signaling as a common and core molecular mechanism in mental illness, and we highlight specific NR-signaling pathways with putative diagnostic and pharmacological intervention potential in psychiatry.