A review of estrogen receptor gene (ESR1) polymorphisms, mood, and cognition

Department of Psychology, University of Illinois, Chicago, IL, USA.
Menopause (New York, N.Y.) (Impact Factor: 3.36). 07/2010; 17(4):874-86. DOI: 10.1097/gme.0b013e3181df4a19
Source: PubMed


There are significant individual differences in the extent to which mood and cognition change as a function of reproductive stage, menstrual phase, postpartum, and hormone therapy use. This review explores the extent to which variations or polymorphisms in the estrogen receptor alpha gene (ESR1) predict cognitive and mood outcomes.
A literature search was conducted from 1995 to November 2009 through PubMed, Embase, and PsychINFO. Twenty-five manuscripts that summarize investigations of ESR1 in mental health were reviewed.
Among studies investigating ESR1 in relation to cognition, 11 of 14 case-control studies reported an association between ESR1 polymorphisms and risk for developing dementia. Three of four prospective cohort studies reported an association between ESR1 polymorphisms and significant cognitive decline. There are inconsistencies between case-control and cohort studies regarding whether specific ESR1 alleles increase or decrease the risk for cognitive dysfunction. The relationships between ESR1 and cognitive impairment tend to be specific to or driven by women and restricted to risk for Alzheimer disease rather than other dementia causes. Three of five studies examining ESR1 polymorphisms in relation to anxiety or depressive symptoms found significant associations. Significant associations have also been reported between ESR1 polymorphisms and childhood-onset mood disorder and premenstrual dysphoric disorder.
A strong relationship between ESR1 variants and cognitive outcomes is evident, and preliminary evidence suggests a role of the ESR1 gene in certain mood outcomes. Insights into the discordant results will come from future studies that include haplotype analyses, analyses within specific ethnic/racial populations, and sex-stratified analyses.

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Available from: Erin Sundermann
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    • "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 neu- Table 1 Studies across previously investigated MAOA, COMT, MTHFR and ESR1 gene variants associated with depression. "
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    ABSTRACT: Objective: The aim of the study was assessment of a possible relationship between the polymorphisms of the candidate genes participating in the etiology of some neurological and psychiatric disorders and the risk of depression in perimenopausal and postmenopausal women. Methods: A total of 167 (54 perimenopausal and 113 postmenopausal) Caucasian women from western Poland, aged 42-67, were recruited as the patient group in the study because of depressive symptoms, and another 321 healthy women (102 perimenopausal and 219 postmenopausal) served as the controls. All study participants were evaluated for climacteric and depressive disorders according to the Kupperman index and Hamilton rating scale for depression (HRSD), respectively. The following candidate genes were selected for the study: 5HTR2A, 5HTR1B, 5HTR2C, TPH1, TPH2, MAOA, COMT, NET, GABRB1, ESR1, MTHFR, MTR and MTHFD1. In each group the frequencies of the polymorphisms were determined using PCR-RFLP analysis. Results: After correcting for Bonferroni multiple tests, we found associations between the MAOA c.1460C>T (SNP 1137070), COMT c.472G>A (SNP 4680), MTHFR c.677C>T (SNP 1801133) and ESR1 454(-351) A>G (SNP 9340799) polymorphisms to mild and moderate depressive symptoms in menopausal women. In the perimenopausal and postmenopausal women, genotype association of the MAOA c.1460 CT and c.1460 CT+TT (OR=1.83; pcorr=0.009 and OR=1.85; pcorr=0.003, resp.), and of the MTHFR c.677 TT and c.677 CT+TT (OR=3.52; pcorr=0.00009 and OR=2.06; pcorr=0.0006, resp.), as well as of the COMT c.472 GA and COMT c.472 GA+AA genotypes (OR=2.23; pcorr=0.03 and OR=2.17; pcorr=0.027, resp.) in the postmenopausal women revealed significantly higher frequencies of these variants in depressed female patients than in controls, whereas the ESR1 454(-351) AG and 454(-351) AG+GG genotypes were associated with lower risk of depression in postmenopausal women (OR=0.48; pcorr=0.012, and OR=0.52; pcorr=0.015, resp.). Conclusions: Our study substantiates the involvement of the MAOA and MTHFR polymorphisms in climacteric depression and offers evidence that the COMT and ESR1 genes may also play a role in the susceptibility to depressive mood in postmenopausal women.
    Full-text · Article · Oct 2015 · Maturitas
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    • "Estrogen receptor α, a member of the nuclear receptor super-family of ligand-activated transcription factors, is one of the key mediators of hormonal response in estrogen-sensitive tissues [16], [17]. The estrogen-ESR1 complex is primarily responsible for regulating cellular signal pathways in vivo, as well as bone mass in skeletal systems [18], [19]. "
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    ABSTRACT: Genetic factors are important in the pathogenesis of fractures. Notably, estrogen receptor α (ESR1) has been suggested as a possible candidate gene for hip fractures; however, published studies of ESR1 gene polymorphisms have been hampered by small sample sizes and inconclusive or ambiguous results. The aim of this meta-analysis is to investigate the associations between two novel common ESR1 polymorphisms (intron 1 polymorphisms PvuII-rs2234693: C>T and XbaI-rs9340799: A>G) and hip fracture. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of the association. Five case-control and three cohort studies were assessed, including a total of 1,838 hip fracture cases and 14,972 healthy controls. This meta-analysis revealed that the PvuII T allele is a highly significant risk factor for hip fracture susceptibility, with an effect magnitude similar in male and pre-menopausal and post-menopausal female patients. In stratified analysis based on ethnicity, the PvuII T allele remained significantly correlated with increased risk of hip fracture in Caucasian populations; this correlation, however, was not found in Asian populations. Unlike the PvuII polymorphism, we did not find significant differences in the XbaI (A>G) polymorphism allele or genotype distributions of hip fracture patients and controls. We also found no obvious association between the XbaI polymorphism and hip fracture in any of the racial or gender subgroups. Our findings show that the ESR1 PvuII T allele may increase the risk of hip fracture and that the XbaI polymorphism is not associated with hip fracture.
    Full-text · Article · Dec 2013 · PLoS ONE
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    • "WML are thought to reflect small-vessel cerebrovascular disease (LADIS Study Group, 2011; Raz et al., 2007), which increases in occurrence with age (Ylikoski et al., 1995) and which has been associated with poorer cognitive performance (Inzitari et al., 2009), mild cognitive impairment (Ritchie et al., 2010), and an increased risk of dementia (Debette and Markus, 2010; Mortamais et al., 2013), particularly in women (Sawada et al., 2000). In line with this, previous studies have also reported significant associations between rs2234693 and cognitive function (Yaffe et al., 2002), the risk of Alzheimer's disease (Sundermann et al., 2010), and cardiovascular disease in older women (Herrington et al., 2002b; Schuit et al., 2004); however, the direction of the association has not been consistently found. We have recently found that, in older women specifically, the CC genotype of rs2234693 tended to be associated with lower decline in executive function (Ryan et al., 2013a), which is considered as among the earliest signs of vascular MCI (Howieson et al., 2008; Iachini et al., 2009). "
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    ABSTRACT: Structural imaging studies suggest gender differences in brain volumes; however, whether hormone treatment (HT) can protect against age-related structural changes remains unknown, and no prior neuroimaging study has investigated potential interactions between HT and estrogen receptor (ESR) polymorphisms. Magnetic resonance imaging was used to measure gray and white matter, hippocampal volume, corpus callosum, cerebrospinal fluid (CSF), total intracranial volume (ICV) and white matter lesions (WML) in 582 non-demented older adults. In multivariable analysis, when compared to women who had never used HT, men and women currently on treatment, but not past users, had significantly smaller ratios of gray matter to ICV and increased atrophy (CSF/ICV ratio). Hippocampal and white matter volume as well as the corpus callosum area were not significantly different across groups. ESR2 variants were not significantly associated with brain measures, but women with the ESR1 rs2234693 C allele had significantly smaller WML. Furthermore this association was modified by HT use. Our results do not support a beneficial effect of HT on brain volumes in older women, but suggest the potential involvement of ESR1 in WML.
    Full-text · Article · Oct 2013 · Neurobiology of aging
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