Brief report
Increased DNA methylation status of the serotonin receptor 5HTR1A gene promoter in schizophrenia and bipolar disorder

https://doi.org/10.1016/j.jad.2011.03.018Get rights and content

Abstract

Background

Epigenetic changes may play a role in the etiology of psychotic diseases. It has been demonstrated that the serotonin receptor, 5HTR1A, is implicated in schizophrenia (SCZ) and bipolar disorder (BPD). The aim of this study was to investigate the methylation status of a promoter region of the 5HTR1A gene in BPD and SCZ patients.

Methods

Our study included 58 BPD and 40 SCZ (DSM-IV criteria) as well as 67 control subjects. DNA was extracted from blood leukocytes and high-resolution melt (HRM) method was used for analysis.

Results

Non-parametric analysis of variance (Kruskal–Wallis) within groups was significant: H = 67.6; p < 0.0001. The Mann–Whitney U-test showed increased methylation level in both BPD (Z =  7.4; p < 0.0001) and SCZ (Z = 4.2; p < 0.0001) compared to controls. No effect either of age or gender by own, was observed. ANCOVA revealed a modest effect of age/gender covariance (F = 3.99; p < 0.048).

Limitation

We used a peripheral tissue. The relationship between methylation of blood and brain DNA is not well known. Data need to be replicated in a brain tissue.

Conclusion

We observed increased DNA methylation in the promoter region of the 5HTR1A gene of SCZ and BPD. This could explain the reported decrease of the receptor expression. The current study supports the growing interest of DNA methylation in psychopathology.

Introduction

A great deal of evidence implicates the serotonin (5HT) system dysfunction in psychiatric diseases, particularly in the two major psychotic diseases, Schizophrenia (SCZ) and Bipolar disorders (BPD) (Lesch, 1998). 5HTR1A is an important subtype of 5HT receptors, widely distributed in the brain, especially in the cortico-limbic regions receiving serotoninergic input from the raphe nuclei (Lesch and Gutknecht, 2004). These receptors also serve as somato-dendritic autoreceptors controlling the firing rate of the 5HT neuron (Blier and de Montigny, 1987). Alteration of these receptors has been reported in both BPD and SCZ, mostly (but not always) with decrease in either binding levels of 5HTR1a in the cortex or in 5HTR1A mRNA levels (Gray et al., 2006, Lopez-Figueroa et al., 2004). Genetic studies have also reported association of the 5HTR1A gene variants in bipolar patients (Kishi et al., 2011). In particular, pharmacogenetic studies reported that one 5HTR1A gene variant (− 1019 C > G), was associated with drug treatment response in both SCZ (Mossner et al., 2009, Reynolds et al., 2006) and BPD (Benedetti et al., 2004). To diversify these studies, another approach for assessing 5HT receptors could be, for example, an epigenetic method of the 5HTR1A gene, such as DNA methylation of its gene promoter.

DNA methylation is a major epigenetic mechanism which occurs in the context of genome CpG islands by covalently linking CH3 groups to cytosine molecules, without changing DNA sequence (Gruenbaum et al., 1981). This chemical modification is conserved after cell division and inherited by descendant cells during the successive mitoses (Razin and Riggs, 1980). When present in the gene promoter, this covalent modification of DNA can affect gene transcription by altering the accessibility of RNA polymerase and transcription factors (Jaenisch and Bird, 2003). DNA methylation has been offered as an epigenetic explanation for the discordance of monozygote twins for schizophrenia (Petronis et al., 2003). In fact, DNA methylation is implicated in developmental processes such as cell differentiation and thus could contribute to the etiology of neurodevelopmental disorders (Scarano et al., 2005). Embryonic and fetal development is continuously exposed to maternal physiology including drugs and dietary components and some of these are known to affect DNA methylation, leading to recognizable syndromes and subtle deviations in neural development (Singh et al., 2003). It has been widely speculated that epigenetic changes may play a role in the etiology of psychotic illnesses such as schizophrenia (SCZ) and bipolar disorder (BPD) (Abdolmaleky et al., 2004).

Recently, studies showing that DNA methylation could be associated with SCZ and BPD, have dramatically raised (Grayson et al., 2006, Guidotti et al., 2000). Increasing number of genes with altered methylation status in psychotic diseases has been reported so far, and this interest is constantly growing (Pidsley and Mill, 2011).

Although epigenetic studies have been mostly conducted on DNA extracted from affected tissues, i.e. tumors or post-mortem brain tissues, blood cells have also proven to be good material for epimutation studies (Cui et al., 2003, Weksberg et al., 2002). Following recent studies, DNA from peripheral blood cells may be useful to reveal epigenetic changes resulting from early embryogenesis (Rosa et al., 2008).

Therefore, due to the importance of this receptor in the serotonin neurotransmission, the present study was aimed to explore the methylation status in the 5HTR1A gene promoter region in both SZP and BPD populations. By studying the two major psychotic disorders, we also searched for a common signature between BPD and SCZ, as both disorders were shown to share a number of genetic and neurobiological features (Craddock et al., 2005).

Section snippets

Subjects

The study was approved by the Ethics Committee of the Geneva University Hospitals, and all subjects provided written informed consent. The sample consisted of 165 subjects (58% male): 67 controls; 58 BPD and 40 SCZ. Table 1 summarizes the details of demographic and clinical data of the population.

Both BPD and SZP patients were recruited from consecutive admissions to the psychiatric unit of the University Hospitals of Geneva. All patients met the DSM-IV criteria and were descended from at least

Results

Results expressed in percentage of methylation (mean values ± standard deviation) are displayed in Fig. 1. Kruskal–Wallis yields H = 67.6; p < 0.0001. Mann–Whitney analysis indicated significant increases in methylation percentages between each diagnostic group versus controls: BPD vs controls (Z =  7.4; p < 0.0001); SCZ vs controls (Z =  4.2; p < 0.0001) and all combined cases vs controls (Z =  7.1; p < 0.0001). There was also a significant difference between SZP vs BPD (Z =  4.2; p < 0.0001). Effects of age and

Discussion

The aim of this study was to assess the methylation status of 5HTR1A promoter region in SCZ and BPD subjects compared with healthy controls. The study observed significant increase in DNA methylation status of SCZ and BPD patients, compared to healthy controls. This is the first time that such information on a major gene in psychiatry, namely the 5HTR1A, is reported in these two major psychotic disorders. As expressed above, previous studies have indeed reported changes in 5HT1A receptors

Role of funding source

This work was supported by the Swiss National Fund for Scientific Research (SNFSR), grant no. 31-120471. SNFSR 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

All authors declare that they have no conflict of interest.

Acknowledgment

The authors thank their colleagues working at the Geneva University Hospitals, Unit of Psychiatry Genetics.

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