Shared genetic influences on depression and menopause symptoms

Abstract

Background: Women experience major depression and post-traumatic stress disorder (PTSD) approximately twice as often as men. Estrogen is thought to contribute to sex differences in these disorders, and reduced estrogen is also known to be a key driver of menopause symptoms such as hot flashes. Moreover, estrogen is used to treat menopause symptoms. In order to test for potential shared genetic influences between menopause symptoms and psychiatric disorders, we conducted a genome-wide association study (GWAS) of estrogen medication use (as a proxy for menopause symptoms) in the UK Biobank.

Methods: The analysis included 232 993 women aged 39-71 in the UK Biobank. The outcome variable for genetic analyses was estrogen medication use, excluding women using hormonal contraceptives. Trans-ancestry GWAS meta-analyses were conducted along with genetic correlation analyses on the European ancestry GWAS results. Hormone usage was also tested for association with depression and PTSD.

Results: GWAS of estrogen medication use (compared to non-use) identified a locus in the TACR3 gene, which was previously linked to hot flashes in menopause [top rs77322567, odds ratio (OR) = 0.78, p = 7.7 × 10^-15]. Genetic correlation analyses revealed shared genetic influences on menopause symptoms and depression (rg = 0.231, s.e.= 0.055, p = 2.8 × 10^-5). Non-genetic analyses revealed higher psychiatric symptoms scores among women using estrogen medications.

Conclusions: These results suggest that menopause symptoms have a complex genetic etiology which is partially shared with genetic influences on depression. Moreover, the TACR3 gene identified here has direct clinical relevance; antagonists for the neurokinin 3 receptor (coded for by TACR3) are effective treatments for hot flashes.

Keywords: Depression; GWAS; PTSD; estrogen; genetic correlation; hormone replacement therapy; hormone therapy; menopause; progestogen; vasomotor symptoms.

Figure 1.. Timeline of assessments in the UK Biobank.

*Genetic samples are in green, **medication usage variables are in red, and ***psychiatric phenotypes are in blue. Medication usage was assessed concurrently with the depression phenotypes and 6–10 years prior to the assessment of PTSD.

Figure 2.. Density plots of age for women taking (and not taking) each of three classes of medications.

G03C=estrogens only, G03F=estrogens and progestogens in combination, and G03D=progestogens only. The red grid pattern depicts ages for women using each medication group and the grey shading depicts controls, meaning women who took none of these medications. Women using contraceptive medications were excluded. Percentages of women who had a hysterectomy are also given for each group. Consistent with indications for prescription, estrogens and estrogens and progestogens in combination were taken by women around the time of menopause, whereas progestogens only tended to be taken by younger women.

Figure 3.. Forest plot of medication associations with depression and PTSD.

The vertical blue bar denotes OR=1, which is the null hypothesis. Error bars denote 95% confidence intervals. Note wide confidence intervals for progestogen only medication analyses (G03D); wider confidence intervals are consistent with the smaller sample sizes of these analyses.

Figure 4.. SNP-based Manhattan plots for genome-wide association studies (GWAS) of estrogen medication use

A) estrogen medications only (G03C) and B) estrogens + estrogens and progestogens in combination (G03C+F). The dotted line represents genome-wide statistical significance (p=5×10⁻⁸). The chromosome 4 locus, in the TACR3 gene, is a known locus for hot flashes and night sweats (i.e. vasomotor symptoms). The chromosome 4 locus observed in the estrogen medication only GWAS (A) is more statistically significant in the larger sample (B). Results for European ancestry participants are depicted here but are almost identical to trans-ancestry results.