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Donskov et al. J Transl Genet Genom 2021;5:136-62 Journal of Translational
DOI: 10.20517/jtgg.2021.12
Genetics and Genomics

Original Article Open Access

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

mental illness

1,4
Julie G. Donskov 1,2,3,4 , Anna Starnawska 1,2,3,4 , Jonatan Pallesen 1,2,3,4 , Jakob Grove 1,2,3,4 , Anders D. Børglum ,
Per Qvist 1,2,3,4
1
Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark.
2
iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus 8000, Denmark.
3
Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus 8000, Denmark.
4
Centre for Genomics and Personalized Medicine, CGPM, Aarhus University, Aarhus 8000, Denmark.
Correspondence to: Dr. Per Qvist, Department of Biomedicine, Aarhus University, Høegh-Guldbergs Gade 10, Aarhus 8000,
Denmark. E-mail: per.q@biomed.au.dk
How to cite this article: Donskov JG, Starnawska A, Pallesen J, Grove J, Børglum AD, Qvist P. Large-scale genomic data-mining
implicates dysregulated nuclear receptor-mediated signaling in mental illness. J Transl Genet Genom 2021;5:136-62.
https://dx.doi.org/10.20517/jtgg.2021.12
Received: 8 Mar 2021 First Decision: 16 Apr 2021 Revised: 7 May 2021 Accepted: 20 May 2021 First online: 28 May 2021

Academic Editor: Richard E. Frye Copy Editor: Xi-Jun Chen Production Editor: Xi-Jun Chen

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.

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing,
adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as
long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and
indicate if changes were made.

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