Risk for Premenstrual Dysphoric Disorder Is Associated with Genetic Variation in ESR1, the Estrogen Receptor Alpha Gene

doi:10.1016/j.biopsych.2006.12.019

Biological Psychiatry

Volume 62, Issue 8, 15 October 2007, Pages 925-933

https://doi.org/10.1016/j.biopsych.2006.12.019 Get rights and content

Background

Premenstrual dysphoric disorder (PMDD) is a heritable mood disorder that is triggered by gonadal steroids during the luteal phase in susceptible women.

Methods

We performed haplotype analyses of estrogen receptors alpha and beta (ESR1 and ESR2) in 91 women with prospectively confirmed PMDD and 56 control subjects to investigate possible sources of the genetic susceptibility to affective dysregulation induced by normal levels of gonadal steroids. We also examined associations with the valine (Val)158methionine (Met) single nucleotide polymorphism (SNP) of the gene for catechol-O-methyltransferase (COMT), an enzyme involved in estrogen metabolism and prefrontal cortical activation.

Results

Four SNPs in intron 4 of ESR1 showed significantly different genotype and allele distributions between patients and control subjects. Significant case-control differences were seen in sliding-window analyses of two-, three-, and four-marker haplotypes but only in those haplotypes containing SNPs in intron 4 that were positive in the single-locus analysis. No significant associations were observed with ESR2 or with the COMT Val158Met polymorphism, although the significant associations with ESR1 were observed only in those with the Val/Val genotype.

Conclusions

These are the first positive (albeit preliminary) genetic findings in this reproductive endocrine-related mood disorder and involve the receptor for a hormone that is pathogenically relevant.

Section snippets

Subjects and Recruitment Procedures

We studied 91 women with PMDD and 56 women who served as an asymptomatic comparison group. Medication-free Caucasian women with regular menstrual cycles were selected from respondents to newspaper advertisements for volunteers with a history of PMDD or without any history of menstrual cycle related mood changes. Subjects from both groups had similar demographic and socioeconomic characteristics. Before entry into the study, prospective participants were screened with a daily visual analogue

Genotype Distribution

The marker-to-marker linkage disequilibrium map constructed by the program Haploview is shown in Figure 1. All 16 SNPs tested in ESR1 (Table 1 and Figure 2) were in Hardy-Weinberg equilibrium in both PMDD and control groups. Four SNPs, all located in intron 4, showed significantly different allele and genotype frequencies between patients and control subjects (Table 3A and Figure 2), and for each SNP, the 1 was the risk allele. Reanalysis of the data after excluding the 29 PMDD subjects with a

Discussion

Our demonstration of an association between allelic variants in the estrogen receptor alpha gene and PMDD is the first positive genetic finding in this disorder, a condition estimated to affect 5% to 8% of reproductive age women and to be responsible for 14.5 million disability adjusted life years in the United States (Halbreich et al. 2003). The gene for ER alpha (ESR1), a 595 amino acid protein, contains 8 exons that code for two activation domains, a DNA binding domain and a ligand binding

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Premenstrual dysphoric disorder (PMDD) is a severe mood disorder, with affective symptoms that rise and fall in concert with the hormonal fluctuations of the menstrual cycle. PMDD’s pathophysiology is poorly understood. This review describes recent research on potential biological contributors to PMDD, with a focus on neuroactive steroids, genetics, neuroimaging and cellular studies. Studies suggest that a key contributor is abnormal central nervous system (CNS) response to fluctuations in neuroactive steroid hormones. Imaging studies are limited but support alterations in serotonergic and GABA transmission. Genetic studies suggest heritability, yet specific genetic contributors have not been characterized. Finally, recent cutting-edge cellular studies indicate an underlying vulnerability to the effect of sex hormones at a cellular level. Overall the findings across studies do not yet fit together into a complete description of the underlying biology of PMDD. It is possible that PMDD consists of biological subtypes, and future research may benefit from a subtyping approach.
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Cortical gamma-aminobutyric acid levels also declined during the menstrual cycle in healthy women but increased in women with PMDD between the follicular phase and the mid- to late-luteal stages (Epperson et al., 2002). Furthermore, PMDD has been associated with the estrogen receptor alpha gene ESR1 (Huo et al., 2007) and the ESC/E(Z) genes affecting the interactions of sex hormones with other genes (Dubey et al., 2017). A Delphi survey led to the proposal of three symptom-based types of PMDD, viz. a predominantly physical type, a predominantly emotional type, and a mixed type (Ismail et al., 2013); and Diagnostic and Statistical Manual of Mental Disorders (DSM)-V proposed that PMDD is defined by one or more marked symptoms of affective lability, irritability or anger, depressed mood and hopelessness, and anxiety and tension, plus at least one of seven other symptoms (American Psychiatric Association, 2013).
Premenstrual dysphoric disorder (PMDD) affects nearly 5% of women of reproductive age. Symptomatic heterogeneity, together with largely unknown genetics, has greatly hindered its effective treatment. In the present study, analysis of genomic sequencing-based copy number variations (CNVs) called from 100 kb white blood cell DNA sequence windows by means of semisupervized clustering led to the segregation of patient genomes into the D and V groups, which correlated with the depression and invasion clinical types, respectively, with 89.0% consistency. Application of diagnostic CNV features selected using the correlation-based machine learning method enabled the classification of the CNVs obtained into the D group, V group, total patient group, and control group with an average accuracy of 83.0%. The power of the diagnostic CNV features was 0.98 on average, suggesting that these CNV features could be used for the molecular diagnosis of the major clinical types of PMDD. This demonstrated concordance between the CNV profiles and clinical types of PMDD supported the validity of symptom-based diagnosis of PMDD for differentiating between its two major clinical types, as well as the predominantly genetic nature of PMDD with a host of overlaps between multiple susceptibility genes/pathways and the diagnostic CNV features as indicators of involvement in PMDD etiology.
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Estrogen receptor (ER) signaling is key regulator for maintaining successful pregnancy. Several research suggested that genetic variation in ER genes (ESR)1 and ESR2 is associated with the susceptibility to unexplained recurrent pregnancy loss (RPL), often with inconclusive results. In this study, we investigate the relationship between ESR1 and ESR2 polymorphisms and idiopathic RPL. A total of 444 patients with RPL, defined as three or more consecutive pregnancy losses of unknown etiology, and 446 control women were recruited to the study and their genotypes for ESR1-rs2234693, ESR1-rs3020314, and ESR2-rs928554 variants were determined using allelic exclusion method on real-time polymerase chain reaction. Minor allele frequencies (MAF) of tagging SNPs ESR1 rs2234693 and rs3020314, and ESR2 rs928554 were not significantly different between RPL cases and control women. Considerable higher frequencies of homozygous (2/2) ESR1 rs2234693 genotype carriers were seen between patients vs. control women, which maintained after controlling for age, body mass index (BMI), and menarche. ESR1 haplotype analysis demonstrated two common haplotype (rs2234693-rs3020314) with no linkage disequilibrium between both polymorphisms, and no 2-locus haplotype linked with RPL risk was revealed.
The present study confirmed a significant association of specific ESR1 variant (rs2234693) with an increased risk of RPL, further supporting a role for ESR1 as an important candidate locus inducing RPL.
Neuroimaging premenstrual dysphoric disorder: A systematic and critical review
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Endocrine organizational and activational influences on cognitive and affective circuits are likely critical to the development of premenstrual dysphoric disorder (PMDD), a sex-specific hormone-dependent mood disorder. An overview of the anatomical and functional neural characterization of this disorder is presented here by means of neuroimaging correlates, identified from eighteen publications (n = 361 subjects). While white matter integrity remains uninvestigated, greater cerebellar grey matter volume and metabolism were observed in patients with PMDD, along with altered serotonergic and GABAergic neurotransmission. Differential corticolimbic activation in response to emotional stimuli distinguishes the PMDD brain, namely enhanced amygdalar and diminished fronto-cortical function. Thus far, the emotional distress and dysregulation linked to PMDD seem to be defined by structural, chemical and functional brain signatures; however, their characterization remains sparsely studied and somewhat inconsistent. Clear and well-replicated neurobiological features of PMDD are needed to promote timely diagnoses and inform development of prevention and treatment strategies.

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Original ArticleRisk for Premenstrual Dysphoric Disorder Is Associated with Genetic Variation in ESR1, the Estrogen Receptor Alpha Gene

Background

Methods

Results

Conclusions

Section snippets

Subjects and Recruitment Procedures

Genotype Distribution

Discussion

Biol Psychiatry

Am J Hum Genet

Neurosci Lett

Psychoneuroendocrinology

Neuropharmacology

Psychoneuroendocrinology

Neurobiol Learn Mem

Psychoneuroendocrinology

Psychoneuroendocrinology

Biochem Biophys Res Commun

Lancet

Front Neuroendocrinol

Biol Psychiatry

Toxicology

J Psychiatr Res

Biol Psychiatry

Pharmacol Biochem Behav

J Adolesc Health

Strain differences in tamoxifen sensitivity of Sprague-Dawley and Fischer 344 rats

Anticancer Drugs

Haploview: Analysis and visualization of LD and haplotype maps

Bioinformatics

Presence of multiple functional polyadenylation signals and a single nucleotide polymorphism in the 3′ untranslated region of the human serotonin transporter gene

J Neurochem

Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: Specificity in prostate and non-prostate cell lines

J Mol Endocrinol

Modulation of cognition-specific cortical activity by gonadal steroids: A positron-emission tomography study in women

Proc Natl Acad Sci U S A

Genetic polymorphisms in the estrogen receptor α gene and risk of breast cancer: Results from the Shanghai Breast Cancer Study

Cancer Epidemiol Biomarkers Prev

The premenstrual syndrome: A twin study

Br J Psychiatry

Genetic contributions to generalized arousal of brain and behavior

Proc Natl Acad Sci U S A

The CAG repeat within the androgen receptor gene and its relationship to prostate cancer

Proc Natl Acad Sci U S A

Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene

J Neural Transm Gen Sect

Haplotypes and the systematic analysis of genetic variation in genes and genomes

Pharmacogenomics

Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder

Proc Natl Acad Sci U S A

Longitudinal population-based twin study of retrospectively reported premenstrual symptoms and lifetime major depression

Am J Psychiatry

Original Article
Risk for Premenstrual Dysphoric Disorder Is Associated with Genetic Variation in ESR1, the Estrogen Receptor Alpha Gene