Research report
Altered expression of circadian rhythm genes among individuals with a history of depression

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Abstract

Background

Depression has been associated with several circadian rhythm perturbations, suggesting a disruption of the circadian clock system in affective disorders. The interaction of several circadian clock genes generates these daily circadian rhythms.

Methods

This cross-sectional study evaluated whether circadian gene expression differed between individuals with a history of depression and participants without a similar history. The participants were 60 healthy older adults. Half of the participants had a history of depression. Real-time quantitative polymerase chain reaction was used to measure the circadian gene Clock, BMAL1, Period1, and Period2 messenger RNA levels in peripheral blood leukocytes.

Results

Individuals with a history of depression had higher Clock, Period1, and Bmal1 mRNA levels, compared to non-depressed participants.

Limitations

Although circadian gene expression fluctuates throughout the day, clock gene mRNA levels were evaluated only in the morning.

Conclusions

These results suggest that disruptions of the molecular mechanisms underlying the circadian clock system may be associated with depression.

Introduction

Depression has been associated with several circadian rhythm perturbations (Wirz-Justice, 2006). Insomnia and a shorter REM stage latency after sleep onset are frequently observed among depressed patients (Kupfer and Foster, 1972, Riemann et al., 2001). Depression has also been related to greater nocturnal elevation in body temperature (Rausch et al., 2003). Moreover, depressed patients display an earlier morning cortisol spike and have higher overall cortisol output than non-depressed patients (Yehuda et al., 1996). Furthermore, some studies have reported lower blood concentrations of melatonin, and delayed melatonin release in depressed patients, compared to controls (Parry and Newton, 2001). Collectively, these results suggest a disruption of the circadian clock system related to major depression (Monteleone and Maj, 2008).

The suprachiasmatic nucleus (SCN) of the hypothalamus is the internal clock entraining several physiological systems to a cycle of about 24 h (Hastings, 1997). The interaction of several circadian clock genes is thought to be responsible for the circadian fluctuation in protein expression (Zheng and Sehgal, 2008). These circadian genes have been found not only in the SCN, but also in several central and peripheral tissues such as extra-SCN brain regions, eye, heart, kidney, lung, liver, skeletal muscle, oral mucosa, and peripheral blood leukocytes (PBLs), indicating the presence of peripheral circadian oscillators throughout the body (Buijs and Kalsbeek, 2001).

Altered circadian gene expression may represent a vulnerability factor associated with increased risk for depression (Mendlewicz, 2009, Turek, 2007). The generation of circadian rhythms is instantiated by the transcriptional and translational feedback loops of several clock genes (Shearman et al., 2000). Perturbations in one or several of these genes may disrupt the circadian fluctuation in mRNA and protein expression and possibly also increase risk for depression (Turek, 2007, Zheng and Sehgal, 2008).

Clock gene polymorphisms have been associated with increased risk of recurrence of bipolar depression (Benedetti et al., 2003), but this result has not been replicated in all studies (Desan et al., 2000, Johansson et al., 2003). However, several other circadian gene polymorphisms have been related to risk for affective illness. Furthermore, the interaction of several clock gene polymorphisms may be necessary to disrupt circadian gene function (Kripke et al., 2009, Lavebratt et al., 2009). Indeed, the interaction of 3 clock gene polymorphisms predicted bipolar affective disorder (Shi et al., 2008). The current study therefore evaluated differences in four circadian gene mRNAs expressed in PBLs of individuals with and without a history of depression.

Section snippets

Participants

Participants were part of a larger study of caregiving stress and health. The 60 participants were recruited via notices placed in community and university newspapers, senior citizen centers, the Alzheimer's Disease Association, and from neurologists' referrals. Caregivers (n = 25) were providing at least 5 h of care per week for a family member with a progressive dementia. Noncaregiving controls (n = 35) were demographically similar to caregivers but without caregiving responsibilities. Subjects

Sociodemographic and clinical characteristics of study participants

Participants' mean age was 71.02 (SD = 10.11). The sample was comprised of 46 women and 14 men. Fifty-four participants were Caucasian and 6 were African-American. About one-third of the sample had a high school education and 68.3% of the participants were college graduate. Twenty-five participants were caring for a relative with dementia.

Thirty participants had a lifetime history of depression, and 30 were never clinically depressed. Among the 30 participants with a history of depression, 16 had

Discussion

Individuals with a history of depression displayed a different pattern of circadian gene expression than individuals without a history of unipolar affective disorder. Specifically, the presence of a history of depression was associated with higher Clock, Bmal1, and Period1 mRNA expression. When the circadian gene variables were analyzed as a set, only Clock mRNA levels independently predicted history of depression.

This over-expression of circadian genes mRNA may represent a biomarker of

Role of funding source

Funding for this study was provided by NIH Grants AG025732, AI059089, and K23-NS43222, General Clinical Research Center Grant MO1-RR0034, Comprehensive Cancer Center Grant CA16058, and a Fonds de la Recherche en Santé du Québec (FRSQ) Doctoral Training Award; the NIH and FRSQ had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Conflict of interest

Dr. Beversdorf reported speaking for Novartis, Eisai, and Pfizer within the past year on topics unrelated to the content of this manuscript. None of the other authors reported biomedical financial interests or potential conflicts of interest.

Acknowledgements

We thank Ms Liisa Hantsoo, who assisted with the preparation and proof-reading of the manuscript, and Ms. Carrie Houts, who provided advice for the statistical analysis of the data.

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