The MAOA, COMT, MTHFR and ESR1 gene polymorphisms are associated with the risk of depression in menopausal women
Introduction
Epidemiologic studies indicate that the incidence of first onset or recurrent episodes of clinical depression in women during midlife ranges from 20 to 30% [1]. The potential relationship between depressive disorders and menopausal stages has been the object of intense controversy. Some studies have reported a higher likelihood of depressive symptoms as women progress through the menopausal transition [1], [2], [3], [4], [5], while others have reported an increased likelihood in the postmenopausal period [6], [7]. The prevalent findings suggest that incidence or severity of depressive symptoms is greatly increased in women during the transition to and after menopause, and hormonal changes occurring in these periods are thought to play an important role in this process [1], [2], [3], [4], [5], [6], [7]. Moreover, there are some studies clearly indicating that psychosocial factors may influence the risk for depressive symptoms in middle-aged women [8], [9]. Psychological, as well as vasomotor, symptoms including irritability, agitation, attention deficit, distrust of family members and partners, sleep disorders, lack of libido, hyperactivity and quarrelsomeness, is a common clinical disorder in menopausal women; however, little is known about the risk and protective factors that influence the occurrence and course of depression in women during midlife. In particular, the role of family history of depression in the development of incident and recurrent depression in middle-aged women is unknown [10]. Similarly, very few attempts to correlate menopausal depressive traits with gene polymorphisms have been made to date [11], [12], [13], [14], [15], [16], [17].
It has been reported that mood changes, including depression, may be linked to genes related to the monoamine neurotransmitter system. Well-studied components of this system are the serotonin (5-HT) receptor 2A (5HTR2A), 1B (5HTR1B), and 2C (5HTR2C) genes, and the rate-limiting enzyme in the biosynthesis of 5-HT, tryptophan hydroxylase 1 and 2 (TPH1 and TPH2). Genetic associations with depressive disorders have been reported for the 5HTR2A c.102C > T, 5HTR1B c.861G > C, 5HTR2C c.68G > C, TPH1 218C > A, and TPH2 c.1077G > A polymorphisms [18], [19], [20], [21], [22]. After acting at its receptor, 5-HT is metabolized by monoamine oxidase A (MAO-A), which also exhibits a high affinity for norepinephrine (NE), epinephrine and dopamine (DA, which is equally deaminated by MAO-A and MAO-B), and therefore MAO activity plays a critical role in the regulation of the monoaminergic system [23]. Indeed, several studies indicate that the gene coding for MAO-A (MAOA), mapped to the short arm of the X chromosome, may also be involved in the pathogenesis of depression [11], [24], [25], [26], [27], [28], [29], [30] (Table 1). Alterations in monoamine transmitter function and processing in men and women have been described, and differential sex effects potentially account for the higher female prevalence of mood disorders [27]. Functional analyses of the MAOA c.1460C > T genetic variation (SNP 1137070) have revealed the existence of the high activity T allele and the low activity C allele of this polymorphism [23]. Another regulatory polymorphism, a 30-bp variable number tandem repeat (VNTR) in the MAOA gene promoter (MAOA-uVNTR) has been demonstrated to affect the transcriptional efficiency of this gene [31]. It has been reported that women with a high activity MAOA genotype differ from men and from women with a low activity genotype, which suggests that previously reported gender differences in serotoninergic mechanisms may be driven in some women by the variability, either high or low, in activity of the MAOA genotype [27]. Our previous study [11] substantiates the genetic contribution of the MAOA c.1460 T high activity variant in postmenopausal depression and indicates that estradiol (E2) fluctuations are also associated with this polymorphism (Table 1).
The major enzymatic degradation pathways of catecholamine neurotransmitters and catechol derivatives of estrogen include the action of catechol-O-methyltransferase (COMT). COMT catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) on the catechol-O-hydroxyl group in the presence of magnesium ions [32]. The demethylated SAM is then immediately converted to S-adenosyl-l-homocysteine (SAH), which is subsequently deadenosylated to form homocysteine (Hcy). The COMT gene, which is mapped on chromosome 22, codes for an enzyme mainly involved in the deactivation of DA, although it is also potentially capable of degrading NE. A common functional polymorphism in COMT, which is the result of a G to A mutation (c.472G > A) that translates into a valine to methionine substitution at codon 158 (Val158Met), has been linked to a 3–4–fold decrease of the methylation activity of the enzyme [33], and also has been shown to account for a 40% decrease in enzyme activity in the human brain [34]. Studies have indicated that the Met 158 COMT allele influences pre-frontal cortex and limbic activity in response to aversive or emotionally-negative stimuli and to the endocrine response to stress [35], [36]. A large number of evidence suggests that this polymorphism is associated with major depressive disorder (MDD) and bipolar depression [37], [38], [39], [40], [41], [42], [43], [44], [45] (Table 1).
It has been reported that disturbances in the folate-dependent one-carbon metabolism may contribute to some congenital, neurological, and movement disorders, such as neural tube defects, non-syndromic cleft lip and palate, epilepsy, cognitive impairment in later life, Alzheimer's disease (AD), primary dystonia, Huntington’s disease, and Parkinson’s disease (PD) [46], [47], [48], [49], [50]. The reactions performed by the key enzymes of the methyl cycle, 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and NADP-dependent trifunctional enzyme MTHFD1, use cofactors of folate, vitamins B12 and B6 as donors of methyl groups, which are necessary for the synthesis of proteins, DNA, RNA, phospholipids, myelin, and catecholamines. The MTHFR c.677C > T (Ala222Val) polymorphism reduces the activity of MTHFR by 50% [30], which is associated with an elevation of blood plasma Hcy and a low SAM concentration. Other studies have also reported suggestive associations between decreased formation of SAM and the MTR c.2756A > G (Asp919Gly) or MTHFD1 c.1958G > A (Arg653Gln) polymorphic variants [49], [50]. Diminished activity of MTHFR, a rate-limiting enzyme for a cofactor for catecholamine synthesis, has previously been linked to psychiatric conditions such as mental retardation, schizophrenia, affective disorders, and depression [51], [52], [53], [54]. Our findings [12] also indicate a significant role of the MTHFR c.677C > T polymorphic variant in the development of depression in postmenopausal women (Table 1).
E2 likely promotes serotoninergic and norepinephrinergic neurotransmission by influencing synthesis, release, metabolism, or reuptake of 5-HT and NE [55]. In large part, E2 exerts these biological effects through intracellular activation of its principal receptors, estrogen receptor α (ESR1) and estrogen receptor β (ESR2) [56], which have been identified in region-specific areas of the brain. Of the two estrogen receptor subtypes, ESR1 is more predominantly expressed in brain areas that mediate affective and motivational processing, including the amygdala and hypothalamus [57]. The most frequently studied ESR1 polymorphisms are ESR1 454−351 A>G (SNP 9340799) and ESR1 454−397 C > T (SNP 2234693), otherwise known as XbaI and PvuII due to the creation of the aforementioned restriction sites. They are located at position 351 and 397 of intron 1, respectively, and are in strong linkage disequilibrium (LD). There is some evidence to indicate a significant association of the common ESR1 variants with more severe depressive symptoms in menopausal women [14], [15], [16], [17]. Currently, there is no definitive evidence concerning the functionality of these polymorphisms or the biological pathways they affect; however, some findings support the hypothesis that these SNPs impact estrogen activity, as they may alter ESR1 gene expression by influencing transcription factor binding [13], [58], [59]. Moreover, since ESR1 acts as a ligand-activated transcription factor affecting hundreds of genes, including regulating the synthesis and metabolism of various neurotransmitters in the brain, the exact mechanisms by which ESR1 variants could influence depression are complex [55], [56], [57], [58], [59], [60], [61], [62], [63] (Table 1). Since estrogens also exert an influence on multiple neurotransmitter receptors, such as inhibition of the GABA receptors [60], they may act on large areas of the nervous system causing a cascade of effects that are associated with mood improvement.
Emerging evidence suggests that the COMT polymorphic effects can be modified by epistatic interactions with genes in concurrent molecular pathways [64], [65]. For example, the effects of the COMT high activity Val158 allele on disease risk have been shown to be augmented by a low activity variant of the MTHFR gene, which regulates the bioavailability of SAH, a strong, noncompetitive inhibitor of COMT [66], [67], [68], [69]. Thus, we hypothesize that polymorphisms in COMT and functionally related genes implicated in depression, including ESR1 and MTHFR, interact in a concerted manner to influence COMT enzymatic activity and depression. In order to test this hypothesis, the present study seeks to estimate the relationship between SNPs located in these genes and depressive disorder in menopausal women. Since relatively little information is available that evaluates genetic association with menopausal depression, the aim of this study was also the assessment of a possible relation between polymorphic variants of the candidate genes participating in the etiology of some neurological and psychiatric disorders and the risk of depression in perimenopausal and postmenopausal women. The following genes were selected for the study: genes of receptors and enzymes of the serotoninergic system (5HTR2A, 5HTR1B, 5HTR2C, TPH1, TPH2, MAOA), genes of enzymes of the noradrenergic and dopaminergic systems (COMT, NET), one gene of the GABAergic system (GABRB1), the gene of estrogen receptor α (ESR1), and genes of the key enzymes of the methyl cycle (MTHFR, MTR and MTHFD1).
Section snippets
Patients
The study group consisted of 488 women, aged 42–67 years, recruited from Polish Caucasian residents of Greater Poland (Wielkopolska region). All women were admitted to the Outpatient Clinic at the Obstetrics and Gynecology Clinic at the University Hospital of Medical Sciences in Poznan because of climacteric complaints, and recruited to the study according to medical documentation and hormonal levels examined in the Department of Gynecological Endocrinology. The study participants did not abuse
Results
The study involved 488 (156 perimenopausal and 332 postmenopausal) Caucasian women recruited from western Poland. All women were chosen in a consecutive manner because of menopausal symptoms and examined. According to the HRSD, 65.8% (n = 321) of the women did not show any depressive symptoms; however, these symptoms were present in 34.2% (n = 167) of the women. Two groups of women without depression, 102 perimenopausal and 219 postmenopausal (all with HRSD score ≤7), were considered controls for
Discussion
Our study investigated selected polymorphic variants for the genes of monoaminergic (5HTR2A, 5HTR1B, 5HTR2C, TPH1, TPH2, MAOA, COMT, NET) and GABAergic (GABRB1) systems, the key genes of the methyl cycle (MTHRF, MTR and MTHFD1) and ESR1 in the context of depressive symptoms in menopausal women. We found that depressive mood in climacteric women may be dependent on the MAOA, COMT, MTHFR and ESR1 polymorphisms; however, this could also vary relative to individual menopausal status.
Research
Study limitations
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This study offers preliminary evidence for a relationship between the MAOA, COMT, MTHFR and ESR1 polymorphisms and the risk for menopausal depression. Considering the small sample size of our study, further investigation of these variants’ distribution in other populations is needed.
- 2.
Studies of depression in midlife women have generally relied on the assessment of depressive symptoms rather than a formal diagnosis of depression, and therefore, it is possible that misclassification could have
Competing interests
The authors do not have any competing interests to declare.
Funding
This work was supported by grant No. 50305-01109136-12261-08039 from the Polish Ministry of Scientific Research and Information Technology.
All participants gave their written informed consent for the study, approved by the Ethics Committee, Poznań University of Medical Sciences.
List of contributors
Różycka Agata and Słopień Radosław:
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Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; and
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Drafting the work or revising it critically for important intellectual content; and
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Final approval of the version to be published; and
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Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
The other author’s role
Słopień Agnieszka: Clinical Investigator: provided and cared for study patients, and collected data, contributed to the conception of the work.
Dorszewska Jolanta: served as scientific advisor, revised the work, interpreted of data for the work.
Seremak-Mrozikiewicz Agnieszka, Grzelak Teresa, Kurzawińska Grażyna, Drews Krzysztof and Klejewski Andrzej participated in revision of the manuscript, collected data and made statistical analysis.
Lianeri Margarita: participated in writing and technical
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These authors contributed equally to this work.