Department of Psychiatry and Behavioral Sciences, Stanford University, 401 Quarry Road, Stanford, CA 94305, USA.
Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Boserupvej 2, 4000 Roskilde, Denmark.
Psychol Med. 2023 Apr;53(6):2241-2251. doi: 10.1017/S0033291721004037. Epub 2021 Dec 6.
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.
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.
GWAS of estrogen medication use (compared to non-use) identified a locus in the gene, which was previously linked to hot flashes in menopause [top rs77322567, odds ratio (OR) = 0.78, = 7.7 × 10]. Genetic correlation analyses revealed shared genetic influences on menopause symptoms and depression ( = 0.231, s.e. 0.055, = 2.8 × 10). Non-genetic analyses revealed higher psychiatric symptoms scores among women using estrogen medications.
These results suggest that menopause symptoms have a complex genetic etiology which is partially shared with genetic influences on depression. Moreover, the gene identified here has direct clinical relevance; antagonists for the neurokinin 3 receptor (coded for by ) are effective treatments for hot flashes.
女性患重度抑郁症和创伤后应激障碍（PTSD）的概率大约是男性的两倍。雌激素被认为是导致这些疾病存在性别差异的原因之一，而雌激素的减少也是绝经期症状（如热潮红）的一个关键驱动因素。此外，雌激素被用于治疗绝经期症状。为了检验绝经期症状和精神疾病之间是否存在潜在的共同遗传影响，我们对英国生物库中使用雌激素药物（作为绝经期症状的替代指标）进行了全基因组关联研究（GWAS）。
该分析包括英国生物库中 232993 名年龄在 39-71 岁的女性。遗传分析的因变量是雌激素药物的使用情况（不包括使用激素避孕药的女性）。进行了跨种族的 GWAS 荟萃分析，以及对欧洲血统 GWAS 结果的遗传相关性分析。还测试了激素使用与抑郁和 PTSD 的关联。
与不使用雌激素药物相比，对雌激素药物使用情况的 GWAS 确定了一个位于 基因中的位点，该基因先前与绝经期的热潮红有关[最显著的 rs77322567，比值比（OR）=0.78，P=7.7×10]。遗传相关性分析显示，绝经期症状和抑郁之间存在共同的遗传影响（P=0.231，s.e.0.055，P=2.8×10）。非遗传分析显示，使用雌激素药物的女性的精神症状评分更高。
这些结果表明，绝经期症状具有复杂的遗传病因，部分与抑郁的遗传影响有关。此外，这里鉴定的 基因具有直接的临床相关性；神经激肽 3 受体拮抗剂（由 编码）是治疗热潮红的有效药物。
