Molecular analyses of circadian gene variants reveal sex-dependent links between depression and clocks

S. Q. Shi, M. J. White, H. M. Borsetti, J. S. Pendergast, A. Hida, C. M. Ciarleglio, P. A. De Verteuil, A. G. Cadar, C. Cala, D. G. McMahon, R. C. Shelton, S. M. Williams, C. H. Johnson

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


An extensive literature links circadian irregularities and/or sleep abnormalities to mood disorders. Despite the strong genetic component underlying many mood disorders, however, previous genetic associations between circadian clock gene variants and major depressive disorder (MDD) have been weak. We applied a combined molecular/functional and genetic association approach to circadian gene polymorphisms in sex-stratified populations of control subjects and case subjects suffering from MDD. This approach identified significant sex-dependent associations of common variants of the circadian clock genes hClock, hPer3 and hNpas2 with major depression and demonstrated functional effects of these polymorphisms on the expression or activity of the hCLOCK and hPER3 proteins, respectively. In addition, hCLOCK expression is affected by glucocorticoids, consistent with the sex-dependency of the genetic associations and the modulation of glucocorticoid-mediated stress response, providing a mechanism by which the circadian clock controls outputs that may affect psychiatric disorders. We conclude that genetic polymorphisms in circadian genes (especially hClock and hPer3, where functional assays could be tested) influence risk of developing depression in a sex- and stress-dependent manner. These studies support a genetic connection between circadian disruption and mood disorders, and confirm a key connection between circadian gene variation and major depression.

Original languageEnglish
Article numbere748
JournalTranslational Psychiatry
StatePublished - Mar 1 2016

Bibliographical note

Funding Information:
We thank the following for providing essential constructs or cell lines: Dr Malcolm von Schantz (PSV40::FLuc::3′UTR (ref. 33), Dr Joon-Kyu Lee (PCMV::hPer3), Dr Steven Reppert and David Weaver (Bmal1, mClock and PAvp::FLuc plasmids), Dr Quanyong Zhou (PPK2.8::FLuc), Dr Richard O''Brien for HepG2 cells and Dr Stephen Brandt for COS-1 cells. The human biomaterials (DNA samples) and clinical data for the depression and controls samples that were analyzed in this study were collected by the NIMH Center for Collaborative Genetic Studies on Mental Disorders through the Human Genetics Initiative (HGI), and the individuals who collected the biomaterials and clinical data for the Center for Collaborative Genetic Studies Mental Disorders/HGI are acknowledged in Supplementary Information. This research was supported by grants from the National Institutes of Health (R21 MH082258 from NIMH, P20 GM103534 from NIGMS and UL1 RR024975-01 from NCATS), and a Discovery Grant from Vanderbilt University. S-QS was partially supported by NARSAD Young Investigator Award #17623. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry


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