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

doi:10.1038/tp.2016.9

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 journal › Article › peer-review

55 Scopus citations

Abstract

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 language	English
Article number	e748
Journal	Translational Psychiatry
Volume	6
DOIs	https://doi.org/10.1038/tp.2016.9
State	Published - 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.

Funding

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.

Funders	Funder number
Human Genetics Initiative
National Institutes of Health (NIH)	P20 GM103534, R21 MH082258
National Institutes of Health (NIH)
National Institute of Mental Health
National Heart, Lung, and Blood Institute (NHLBI)	T32HL007411
National Heart, Lung, and Blood Institute (NHLBI)
National Institute of General Medical Sciences	UL1 RR024975-01
National Institute of General Medical Sciences
National Center for Advancing Translational Sciences (NCATS)
Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center
National Alliance for Research on Schizophrenia and Depression	17623
National Alliance for Research on Schizophrenia and Depression

ASJC Scopus subject areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Biological Psychiatry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/tp.2016.9

Cite this

Shi, S. Q., White, M. J., Borsetti, H. M., Pendergast, J. S., Hida, A., Ciarleglio, C. M., De Verteuil, P. A., Cadar, A. G., Cala, C., McMahon, D. G., Shelton, R. C., Williams, S. M., & Johnson, C. H. (2016). Molecular analyses of circadian gene variants reveal sex-dependent links between depression and clocks. Translational Psychiatry, 6, Article e748. https://doi.org/10.1038/tp.2016.9

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abstract = "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.",

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

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.",

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AU - Shi, S. Q.

AU - White, M. J.

AU - Borsetti, H. M.

AU - Pendergast, J. S.

AU - Hida, A.

AU - Ciarleglio, C. M.

AU - De Verteuil, P. A.

AU - Cadar, A. G.

AU - Cala, C.

AU - McMahon, D. G.

AU - Shelton, R. C.

AU - Williams, S. M.

AU - Johnson, C. H.

N1 - 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.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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