Prospects for epigenetic research within cohort studies of psychological disorder: A pilot investigation of a peripheral cell marker of epigenetic risk for depression

doi:10.1016/j.biopsycho.2009.12.003

Biological Psychology

Volume 83, Issue 2, February 2010, Pages 159-165

https://doi.org/10.1016/j.biopsycho.2009.12.003 Get rights and content

Abstract

Cohort studies have considerable prima facie value for investigating epigenetic processes in psychological disorder; however, the future prospects for such studies will depend on valid peripheral markers. The purpose of this pilot study was to investigate association between buccal cell methylation and risk for depression. Epigenotyping was limited to promoter methylation of the serotonin transporter gene (5HTT). A transcription limiting VNTR in the 5HTT promoter (5HTTLPR) was also genotyped. A nested sample of 25 depressed and 125 non-depressed adolescents was drawn from an established longitudinal study of adolescent health. There was no association between depressive symptoms and either buccal cell 5HTT methylation or 5HTTLPR. However, depressive symptoms were more common among those with elevated buccal cell 5HTT methylation who carried 5HTTLPR short-allele (OR 4.9, CI 1.9–13, p = 0.001). Both complete and partial (as little as 10%) methylation of a 5HTT reporter gene in an expressing cell line reduced 5HTT activity. Replication is needed.

Section snippets

Participants and design

Adolescent participants (N = 150, 83 male), with and without a history of depression, were sampled from an established life course study of adolescent health and development (Victorian Adolescent Health Cohort Study, VAHCS). The VAHCS is a population representative sample of 2032 young Australians living in the state of Victoria who have been followed across 8 waves since 1992. The cohort was initially defined with a two-stage cluster sample in which we selected two Year 9 classes at random from

Results

The average methylation level across the entire CpG Island was 6.3% (95% confidence interval (CI) 5.8–6.8, range 2.9–22%). Table 1 shows methylation levels for each of the 36 CpG units assayed among those reporting no depressive symptoms and those reporting persistent depressive symptoms during adolescence.

Principal factor analysis (PFA) was used to explore possible sub-regions within the 5HTT CpG Island defined by co-variation in methylation levels between CpG units. PFA identified eight

Discussion

Depressive symptoms during adolescence were not associated with buccal cell methylation of the entire 5HTT promoter or within sub-regions of the promoter defined by Factor Analysis. Depressive symptoms were likewise not associated with 5HTTLPR genotypes. Carriers of the 5HTTLPR s-allele who had the highest level of 5HTT buccal cell methylation within one sub-region of the promoter (denoted F1) did have an elevated risk for depression. However, until replicated in appropriately powered studies,

Acknowledgements

The authors would like to thank Prof. Glenn Bowes, Prof. Robert Williamson, Menrnoush Lotfi, Philip Greenwood, and Dr. Sue Forrest for their valuable contributions to this research. We acknowledge contributions of Drs. Richard Saffery and Jeffrey Craig as joint senior authors. This work is supported by the following Australian scientific funding organizations: (1) the Victorian Health Promotion; the National Health and Medical Research Council, and; The Colonial Foundation.

We report no

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The serotonergic (5-HTergic) system is closely involved in the pathophysiology of mood and anxiety disorders and the responsibility of this system may differ for each symptom. In this study, we examined the relationship between the dysfunction of the 5-HTergic system and abnormal behaviors in the social defeat stress model, an animal model of mood and anxiety disorders and in mice with knockdown of Slc6a4, the gene encoding SERT. Monoamine content, serotonin (5-HT) release, 5-HT uptake, 5-HT transporter (SERT) protein levels, and behaviors were investigated in mice subjected to chronic social defeat stress and in mice with knockdown of Slc6a4, in 5-HTergic neurons projecting to the prefrontal cortex (PFC). Furthermore, DNA methylation of Slc6a4 was examined in mice subjected to chronic social defeat stress. Increased turnover, increased extracellular basal levels, decreased release and decreased uptake of 5-HT, and decreased SERT protein levels were observed in the PFC of the stressed mice. The decreased 5-HT uptake correlated with anxiety-like behavior characterized by decreased time spent in the open arms of the elevated plus maze. DNA methylation was increased in the CpG island of Slc6a4 in 5-HTergic neurons projecting to the PFC of the stressed mice. Similar to the stressed mice, mice with Slc6a4 knockdown in 5-HTergic neurons projecting to the PFC also showed decreased release and uptake of 5-HT in the PFC and increased anxiety-like behavior. Chronic stress may induce anxiety due to dysfunction in the prefrontal 5-HTergic system via decreased SERT expression in the PFC.
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Growing evidence suggests that epigenetic modification is vital in biological processes of depression. Findings from studies exploring the associations between DNA methylation and depression have been inconsistent.
A systematical search of EMBASE, PubMed, Web of Science, and PsycINFO databases was conducted to include studies focusing on the associations between DNA methylation and depression (up to November 1st 2021) according to PRISMA guidelines with registration in PROSPERO (CRD42021288664).
A total of 47 studies met inclusion criteria and 31 studies were included in the meta-analysis. This meta-analysis found that genes hypermethylation, including BDNF (OR: 1.15, 95%CI: 1.01–1.32, I² = 90 %), and NR3C1 (OR: 1.43, 95%CI: 1.09–1.87, I² = 88 %) was associated with increased risk of depression. Significant association of SLC6A4 hypermethylation with depression was only found in the subgroup of using original data (OR: 1.09, 95%CI: 1.01–1.19, I² = 52 %). BDNF hypermethylation could increase the risk of depression only in the Asian population (OR: 1.18, 95%CI: 1.01–1.40, I² = 91 %), and significant associations of NR3C1 hypermethylation with depression were found in the group for depressive symptoms (OR: 1.34, 95%CI: 1.08–1.67, I² = 85 %), but not for depressive disorder (OR: 1.89, 95%CI: 0.54–6.55, I² = 94 %).
More studies are needed to explore the factors that might influence the estimates owing to the contextual heterogeneity of the pooling of included studies.
It is noted that DNA hypermethylation, namely BDNF and NR3C1, is associated with increased risk of depression. The findings in this study could provide some material evidence for preventing and diagnosing of depression.
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The etiology of major depressive disorder (MDD) is complex, with both genetic susceptibility and exposure to stressful life events being contributing factors. Stressors can change epigenetic marks, sometimes enduringly, and these changes may play an important role in the development of MDD. Because stress is so closely related to the development of MDD, we review here both the epigenetics of stress and the epigenetics of depression. Although candidate genes have been interrogated frequently in epigenetic studies, there has been little consistency in MDD association, with the one exception being BDNF, where increased methylation has been repeatedly found. There have now been 20 unbiased studies investigating DNA methylation changes across the genome in MDD, and while their top findings have differed, the possibility of convergence across these studies requires further attention. While much remains to be learned about the role of epigenetics in the pathogenesis of MDD, a summary methylation risk score in MDD patients might provide an opportunity for clinical applications of epigenetic data.
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Suicide is a problem resulting from the interaction between several factors. Among these, early-life adversity, characterized by child sexual, physical abuse or parental neglect, is one of the strongest risk factors for depression and suicidal behaviors. While it is clear that child abuse increases the risk for depression and suicide, the mechanisms mediating these effects are still under deep investigation. A growing body of literature suggests that epigenetic mechanisms may be involved in mediating the effects of early-life adversity (ELA) on behavior. In both human and animal models, ELA has been shown to alter DNA methylation in genes regulatory regions which, in turn, has been associated with changes in gene expression and behavioral modifications. However, although epigenetic modifications have been found in several genes, the extent of epigenetic changes induced by ELA is still unknown, and their impact on increasing suicide risk are unclear. This chapter aims at identifying and describing the molecular mechanisms by which ELA induces behavioral changes conferring vulnerability toward mood disorders and suicidal behaviors.
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Epigenetic modifications can alter gene expression through mechanisms that are heritable, but do not involve direct changes in the nucleotide sequence of the genome. Recent findings have suggested that epigenetic modifications are associated with several psychiatric disorders. As such, this chapter will introduce the general principles of epigenetics and molecular mechanisms, and discuss the implications they have on major depressive disorder. We first begin with DNA methylation, as it is the most widely studied epigenetic modification. The importance of DNA methylation is outlined by monozygotic twin studies of major depressive disorder, and the role it plays in each of the three theories of depression. Afterward, we present two additional epigenetic modifications—histone modifications and noncoding RNAs—and their role in depression. In each section, we will also briefly touch on the therapeutic impact on patient diagnosis and care.
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To investigate whether the serotonin transporter (5-HTT or SERT or SLC6A4) mRNA level could be used as a biomarker of treatment response in patients with major depression treated with different antidepressants while controlling related factors.
One hundred and nineteen patients with major depression were recruited; all genotyped for the 5-HTT polymorphism concerning 5-HTTLPR, rs25531, and STin2 VNTR, provided demographic data and completed relevant questionnaires. Duloxetine and paroxetine were administered over 32 weeks to these patients. The Hamilton depression rating scale (HDRS) and 5-HTT mRNA level were evaluated at baseline (Week 0), and at 8, 16, 24 and 32 weeks.
Improvement in depressive symptoms (HDRS score declined) and increasing in 5-HTT mRNA level were found with longer duration of antidepressant treatment in patients with major depression. Patients with more 5-HTTPR long-form alleles and STin2.12 alleles had poor antidepressant treatment response. Duloxetine may give a better treatment response than paroxetine. Using structural equation modeling (SEM), the 5-HTTLPR long-form had a direct positive association with the 5-HTT mRNA level and an indirect adverse relationship with the 5-HTT mRNA level through neuroticism and previous suicide attempts.
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Prospects for epigenetic research within cohort studies of psychological disorder: A pilot investigation of a peripheral cell marker of epigenetic risk for depression

Abstract

Section snippets

Participants and design

Results

Discussion

Acknowledgements

Cell

Child & Adolescent Psychiatric Clinics of North America

Journal of Biological Chemistry

Lancet

The relationship of serotonin transporter gene polymorphisms and haplotypes to mrna transcription

American Journal of Medical Genetics

Heterochromatin—many flavours, common themes

Bioessays

Prospects for epigenetic epidemiology

American Journal of Epidemiology

Epigenetic differences arise during the lifetime of monozygotic twins

Proceedings of the National Academy of Sciences of the United States of America

Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and linkage disequilibria in African- and European-American and Japanese populations and in alcohol-dependent subjects

Human Genetics

Heritable rather than age-related environmental and stochastic factors dominate variation in DNA methylation of the human IGF2/H19 locus

Human Molecular Genetics

Allelic variation of human serotonin transporter gene expression

Journal of Neurochemistry

Stage-specific and cell type-specific aspects of genomic imprinting effects in mammals

Differentiation