Serotonin transporter, tryptophan hydroxylase, and monoamine oxidase A gene polymorphisms in premenstrual dysphoric disorder

doi:10.1016/j.ajog.2006.06.087

American Journal of Obstetrics and Gynecology

Volume 195, Issue 5, November 2006, Pages 1254-1259

https://doi.org/10.1016/j.ajog.2006.06.087 Get rights and content

Objective

The purpose of this study was to investigate whether common polymorphisms of key genes that control the serotonin (5-hydroxytryptamine) pathway are associated with premenstrual dysphoric disorder.

Study design

The study sample comprised 53 women with clinically diagnosed premenstrual dysphoric disorder (age range, 27-46 years; mean age, 37.7 years) and 52 healthy control subjects (age range, 22-48 years; mean age, 36.2 years). Eight polymorphisms that encode the 5-hydroxytryptamine transporter (LPR, VNTR-2, and 3′ UTR G/T), tryptophan hydroxylase 1 (TPH1 G-6526A, G-5806T, and A218C), and monoamine oxidase A (monoamine oxidase A promoter VNTR-1 and exon 8 Fnu 4H1) were genotyped. Genotype and allelic frequencies were analyzed by chi-square test and stepwise logistic regression analysis.

Results

There was no significant association between any genotype and clinical category and no significant allelic distribution profiles in either the premenstrual dysphoric disorder group or the control group.

Conclusion

These findings do not support a major role for common 5-hydroxytryptamine transporter, TPH1, and monoamine oxidase A polymorphisms in contributing to susceptibility to premenstrual dysphoric disorder.

Section snippets

Material and methods

The study was approved by the University Hospital of North Staffordshire Ethics Committee, and informed written consent was obtained from each participant. Women were recruited from a variety of sources: from advertisement on the hospital Intranet system, from general gynecology clinics, and from a specialized PMS clinic. One hundred five European white women between the ages of 18 and 48 years were enlisted and categorized into 2 groups: women with PMDD and control subjects. All of the women

Results

One hundred five European white women were categorized into 2 groups: women with PMDD (n = 53; age range, 27-46 years; mean, 37.7 years) and control subjects (n = 52; age range, 22-48 years; mean, 36.2 years). For each marker, the genotype distribution and allelic frequencies in the PMDD and control groups are shown in Table II, Table III. All genotype distributions conformed to the Hardy-Weinberg equilibrium, except for MAOA Fnu 4H1 in the PMDD cohort (chi-square test, 5.5981; degree of

Comment

To our knowledge, this study represents the first genotypic analysis of any TPH1 and MAOA polymorphisms in premenstrual dysphoria. However, a PMDD case-control comparison of the 3 5-HTT markers that were studied here was reported by Melke et al,²⁹ who also found no significant association between 5-HTT genotype and PMDD.

There may be several explanations for our negative findings. First, clinical categorization of patients with PMDD can present a formidable challenge because of the subjective

Acknowledgment

We thank Dr Paul Hoban for his expert advice and for proofreading of the manuscript.

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As a recurrent, cyclical phenomenon, premenstrual syndrome (PMS) affects a significant proportion of women of the reproductive age, and leads to regular monthly days of functional impairment. Symptoms of PMS include somatic and psychological symptoms, such as headaches, sleep disturbances, social withdrawal and mood changes, during the late luteal phase of the menstrual cycle, which alleviate during the follicular phase. This study investigated neurocognitive functioning in women with moderate to severe PMS symptoms (n=13) compared to women with mild/no PMS (n=27) through administration of a battery of neuropsychological tests during the asymptomatic follicular phase of the menstrual cycle.
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For the most part, studies have reported a lack of association of the 218A/C polymorphism and other Tph1 polymorphisms with various anxiety disorders, including panic disorder (Fehr et al., 2001; Maron et al., 2005; Kim et al., 2006}, generalized anxiety disorder (Fehr et al., 2001; You et al., 2005) and obsessive-compulsive disorder (Han et al., 1999). Similarly, a lack of association of various Tph1 gene polymorphisms has been reported for many other disorders, including anorexia nervosa (Han et al., 1999), seasonal affective disorder (Johansson et al., 2001), premenstrual dysphoric disorder (Magnay et al., 2006), bulimia (Monteleone et al., 2007), autism (Ramoz et al., 2006) and narcolepsy (Fehr et al., 2001). Given the recent discovery of the Tph2 gene, only a limited number of genetic association studies of this gene have been reported.
5-hydroxytryptamine (5-HT, serotonin) is a major neurotransmitter involved in the modulation of behavior, the manifestation of various psychiatric disorders, and is a pharmacological target in the treatment of depression and anxiety disorders. The physiological effects of serotonin are modulated by a variety of proteins that regulate its synthesis, storage, release, uptake and degradation. In addition, serotonin signaling is mediated by at least 14 distinct receptors. Alterations in the expression of genes that regulate the biological effects of serotonin in the brain could alter serotonergic signaling, and thus could ultimately alter behaviors where serotonin has been implicated. The purpose of this chapter is to describe the behavioral consequences of manipulation of genes that regulate serotonergic signaling in rodents and to review analogous genetic association studies in humans that relate to psychiatric disorders, with a particular focus on depression and anxiety disorders. Many of these studies provide supportive evidence of a role for the serotonergic system in various behavioral responses related to depression and anxiety, as well as other psychiatric disorders. In particular, dysfunction of tryptophan hydroxylase, the serotonin transporter (SERT) or 5-HT_1A receptors can induce behaviors in rodents that are associated with anxiety and depression, and can also alter behavioral responses to antidepressant treatments. Moreover, many of these findings are supported by human genetic association studies. Studies in rodents also suggest that interference with SERT or 5-HT_1A receptor function specifically during brain development can program anxiety levels and depression in adulthood. Finally, while some evidence suggests that other components of the serotonergic system might also play important roles in these disorders, such findings remain to be refined using genetically modified mice, selective pharmacological tools or human genetic association studies.
Analysis of the serotonin transporter promoter rs25531 polymorphism in premenstrual dysphoric disorder
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DNA was extracted from leukocytes in ethylenediaminetetraacetic acid-anticoagulated blood with the use of standard techniques. A genomic region of SLC6A4 that encompassed both 5-HTTLPR and rs25531 was amplified in duplicate by polymerase chain reaction (PCR) with the use of the Qiagen HotStar PCR kit (Qiagen, Crawley, West Sussex, UK), as previously described,12 except that the initial denaturation step was reduced to 5 minutes, and 25 pmol of each primer was used per 25 μL reaction. To genotype 5-HTTLPR into L and S alleles, aliquots of the PCR products were electrophoresed on 2% agarose gels that contained 0.5 μg/mL ethidium bromide, and the bands were viewed under ultraviolet light.
The objective of this study was to investigate whether the functional rs25531 promoter polymorphism in the serotonin transporter gene is associated with premenstrual dysphoric disorder.
The study sample comprised 53 women with clinically diagnosed premenstrual dysphoric disorder (age range, 27–46 years; mean, 37.7 years) and 52 healthy control subjects (age range, 22–48 years; mean, 36.2 years). The rs25531 polymorphism was genotyped in both groups. Because of its close proximity to rs25531, the 5-HTTLPR promoter polymorphism was also genotyped. Genotype and allele frequencies for rs25531 and for the composite 5-HTTLPR/rs25531 marker were analyzed by χ² test.
There was no significant association between any genotype and clinical category and no significant allele distribution profiles for rs25531 or 5-HTTLPR/rs25531 in either the premenstrual dysphoric disorder or the control groups.
These findings do not support a major role for rs25531, either in isolation or combined with 5-HTTLPR, in contributing to susceptibility to premenstrual dysphoria.
Understanding and Treating Premenstrual Dysphoric Disorder: An Update for the Women's Health Practitioner
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Several studies have attempted to delineate the genetic basis for differences in serotonin function and metabolism in women with PMDD. Research into AP-2, 5HT transporter, tryptophan hydroxylase, and monoamine oxidase genotypes has mostly been inconclusive.52,59,60 However, Praschak-Rieder and colleagues61 found an association between PMDD and 5HTLLPR heterozygosity in women with seasonal affective disorder, and Steiner and colleagues46 identified a relationship between polymorphism in the serotonin transporter gene and severity of PMDD symptoms.
Premenstrual dysphoric disorder
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Premenstrual dysphoric disorder (PMDD) is defined as a depressive disorder, not otherwise specified, in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders. It is characterized by mood, appetite, energy, and cognitive changes that occur during the late luteal (premenstrual) phase of the menstrual cycle and remit shortly after the onset of menses. Symptoms are severe enough to interfere with functioning at home, school, or work. It occurs in an estimated 5% of women, and if left untreated, may become more severe and extend in duration over time. Based on current evidence, serotonergic dysfunction appears to be linked with its hormonal etiology, as selective serotonin reuptake inhibitors (SSRIs) demonstrate efficacy and safety. Both fluoxetine and sertraline have been approved by the Food and Drug Administration for use in PMDD. More recent studies suggest that at least among the SSRIs with longer half-lives, such as fluoxetine, the medication can be given in the second-half (luteal phase) only to achieve beneficial effects. Once the medication is stopped, however, symptoms recur in a majority of women within a few months. Other nonpharmacological approaches to treatment, such as sleep and light therapies, are being developed based on chronobiological hypotheses.

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: Supported by a research grant awarded by the North Staffordshire Medical Institute.

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Genetic Association Studies in Obstetrics and GynecologySerotonin transporter, tryptophan hydroxylase, and monoamine oxidase A gene polymorphisms in premenstrual dysphoric disorder

Objective

Study design

Results

Conclusion

Section snippets

Material and methods

Results

Comment

Acknowledgment

Biol Psychiatry

Neuropsychopharmacology

Am J Gynecol

Lancet

J Affect Disord

J Adolesc Health

Psychoneuroendocrinol

The epidemiology of perimenstrual psychological symptoms

Acta Psychiatr Scand

Diagnostic and statistical manual of mental disorders

Altered serotonergic activity in women with dysphoric premenstrual syndrome

Int J Psychiatry Med

The role of central serotonergic dysfunction in the aetiology of premenstrual dysphoric disorder: therapeutic implications

CNS Drugs

Cerebrospinal fluid levels of monoamine metabolites: a preliminary study of their relationship to menstrual cycle phase, sex steroids and pituitary hormones in healthy women and in women with PMS

Neuropsychopharmacology

Blunted serotonin response to fenfluramine challenge in premenstrual dysphoric disorder

Am J Psychiatry

The relationship of dysphoric premenstrual changes to depressive disorders

Acta Psychiatr Scand

Mood disorder and personality assessment in premenstrual dysphoric disorder

J Clin Psychiatry

Premenstrual tension predicts future major depressive disorder

Am J Psychiatry

Genetic Association Studies in Obstetrics and Gynecology
Serotonin transporter, tryptophan hydroxylase, and monoamine oxidase A gene polymorphisms in premenstrual dysphoric disorder