Potential role of the estrogen receptor gene (ESR1) in anxiety

Abstract

In addition to neurotransmitters, hormones, acting through the blood stream, also play a role in behavior. To test the potential contribution of genetic variations in hormone receptors we have examined the association between the alleles of the dinucleotide repeat of the estrogen receptor 1 gene (ESR1) and the nine subscores and total score of the SCL-90 in a group of 179 adult males treated for substance abuse. Based on our prior hypothesis that the length of repeat polymorphisms may play a direct role in gene regulation, the alleles were divided into two groups, short (S) and long (L). ANOVA of the SS, LS, and LL genotypes showed a significant association at ␣ Յ0.05 for three of the SCL-90 scores: anxiety, phobic anxiety, and total symptoms. Of these the anxiety score remained significant at a Bonferroni corrected ␣ of Յ0.005. By regression analysis, the ESR1 gene accounted for 7% of the variance of the anxiety score (P Յ 0.0004). These results are consistent with a role of the ESR1 gene in human behavior. Since estrogen levels are much higher in women than men, this could account for the increased frequency of anxiety in women.Pert 1 (p 139) pointed out that the majority of neurons that release specific neurotransmitters or neuropeptides are not immediately adjacent to the neurons that carry the corresponding receptors. This suggests that many of the most important events in the brain may occur at a distance-as hormones. Estrogen exerts a profound effect on mood and memory through its action on monoamine and neuropeptide transmitter mechanisms in the brain. 2 We previously observed that the alleles of two trinucleotide repeat polymorphisms of the first exon of the androgen receptor gene (AR) are significantly associated with a range of disruptive behavioral disorders. 3 This led us to also examine the estrogen receptor gene (ESR1). Evidence that this gene plays a role in behavior in animals comes from studies showing that ESR1 knockout mice show aggressive behaviors. 4 While variants of the ESR1 gene have been implicated in osteoporosis and osteoarthritis, 5-7 there have been no prior studies of the role variants of the ESR1 in human behavior. To examine this we have genotyped 179 subjects with substance abuse at a highly polymorphic dinucleotide repeat of the ESR1 gene. 8 The SCL-90 9 was utilized as a screening test for depression, anxiety, and related disorders.The distribution of the 787 alleles of the ESR1 gene that we have genotyped in our laboratory, for this and other studies, is shown in Figure 1 There was no significant difference in the frequency of the S vs the L alleles in the three racial groups. Table 1 shows the results of ANOVA for the ATU subjects of all racial groups, for the nine sub-scores of the SCL-90 and the total SCL-90 score (number of nonzero scores). There was a progressive decrease in the mean anxiety score from the LL, to SL to SS groups (P Ͻ 0.002) (Figure 2). By linear ANOVA P = 0.0005. Two other scores were significant at P Յ 0.05, phobic anxiety and total symptoms, but did no...

Variation in the ESR1 and ESR2 genes and genetic susceptibility to anorexia nervosa

“…Previous studies using this microsatellite have suggested a rationale for dividing the alleles into two groups, or modes, representing short alleles (S) (alleles 1-12) and long alleles (L) (alleles [13][14][15][16][17][18][19]. 11 Analysis of our data in this way still failed to show any association with AN ( 2 = 2.60, P Ͼ 0.2, df = 2).…”

“…The dinucleotide repeat regions of ESR1 and ESR2 were amplified using fluorescently labelled primers the sequence of which has been previously described. 11 …”

“…9 ESR1 has been shown to play a role in behaviour in mice 10 and more recently variants of the ESR1 gene have been implicated in anxiety. 11 As it has previously been suggested that anxiety may accentuate the anorexic effects of estrogen, 12 we postulate that the interaction of stress and estrogen may modulate the HPA axis in the pathogenesis of anorexia nervosa. Both ESR1 and 2 are localised to the amygdaloid complex, 13 an area known to be critical in the control of emotions.…”

Estrogen receptor α gene polymorphisms and anxiety disorder in an elderly population

“…3 Other studies concentrated on personality traits rather than specific mood states. 4,5 Furthermore, opposite findings were reported in men and women. A gender difference like in our study may be explained by the cessation of gonadal function in postmenopausal women, who have lower estrogen levels than men.…”

“…3 Among more than 30 interacting proteins, we selected Citron for further analyses because the gene encoding Citron is located on chromosome 12q24, a frequently reported locus linked with BP. [4][5][6] Citron is a synaptic and cytoskeletal protein that can potentially modulate glutamatergic neurotransmission, 7 a hypothesized mechanism for BP. In dividing cells, Citron is required for cytokinesis and is also implicated for neurogenesis.…”