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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    • "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.
    PLoS ONE 12/2013; 8(12):e82806. DOI:10.1371/journal.pone.0082806 · 3.23 Impact Factor
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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.
    Neurobiology of aging 10/2013; 35(3). DOI:10.1016/j.neurobiolaging.2013.09.026 · 5.01 Impact Factor
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    • "A genetic haplotype is identified as a combination of sets of alleles on the same chromosomal segment that tend to be transmitted as a block [24]. When we combined PvuII and XbaI genotypes into haplotypes, a statistically significant difference between control and SA groups for ppxx genotype combination with the higher frequency of ppxx in the healthy controls was observed (P = 0.01), verifying the protective role of ppxx genotype against spontaneous abortion. "
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    ABSTRACT: Estrogen plays a crucial role in fetal and placental development through estrogen receptors. Association of estrogen receptor alpha gene (ESR1) polymorphisms with spontaneous abortion has been shown in some studies. Our main goal was to study the potential association of spontaneous abortion with the ESR1 gene variations (PvuII and XbaI) in fetal tissue. Totally, 161 samples were recruited including 80 samples of formalin-fixed paraffin-embedded fetal tissue from spontaneous abortion and 81 samples of normal term placental tissue. The restriction fragment length polymorphism (RFLP) method was performed for genotyping the rs2234693 (A/G XbaI) and rs9340799 (T/C PvuII) single nucleotide polymorphisms located in intron 1 of ESR1. The results have been confirmed by DNA sequencing analysis. The different genotypes distribution was detected in two study groups. Haplotype analysis indicated that ppxx is protective genotype against spontaneous abortion (P = 0.01). In conclusion, the potential role of ESR1 genetic variation in spontaneous abortion might be valuable in high-risk subjects, and that needs to be confirmed with future studies.
    10/2013; 2013(2):256470. DOI:10.1155/2013/256470
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