Shared genetic influences on depression and menopause symptoms

Meijsen, Joeri; Shen, Hanyang; Vemuri, Mytilee; Rasgon, Natalie; Duncan, Laramie

doi:10.1017/s0033291721004037

Cited by 10 publications

(5 citation statements)

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“…The proxy phenotype of taking HRT did not distinguish between types of medication and is based on retrospectively collected questionnaire data, which may be subject to recall bias. However, another published study that analysed self-reported medication data in UK Biobank identified the same genetic signal for HRT use [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…Neurokinin signalling also plays an important role in controlling the onset of puberty [ 10 ], with genetic variants that knock out the TACR3 gene (which encodes NK3R) resulting in pubertal failure in homozygous carriers [ 11 , 12 ] and delayed puberty in heterozygous carriers [ 13 ]. A genome-wide association study (GWAS) in 17,695 women (12,276 with VMS) identified a genetic signal for VMS in the TACR3 gene region [ 14 ], further replicated in a GWAS of oestrogen-replacement use [ 15 ]. Additionally, population-based genome-wide association studies (GWAS) have identified several more common genetic variants in or near the TACR3 gene associated with normal variation in age at menarche [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

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Insights into the genetics of menopausal vasomotor symptoms: genome-wide analyses of routinely-collected primary care health records

Ruth,

Beaumont,

Locke

et al. 2023

BMC Med Genomics

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Background Vasomotor symptoms (VMS) can often significantly impact women’s quality of life at menopause. In vivo studies have shown that increased neurokinin B (NKB) / neurokinin 3 receptor (NK3R) signalling contributes to VMS, with previous genetic studies implicating the TACR3 gene locus that encodes NK3R. Large-scale genomic analyses offer the possibility of biological insights but few such studies have collected data on VMS, while proxy phenotypes such as hormone replacement therapy (HRT) use are likely to be affected by changes in clinical practice. We investigated the genetic basis of VMS by analysing routinely-collected health records. Methods We performed a GWAS of VMS derived from linked primary-care records and cross-sectional self-reported HRT use in up to 153,152 women from UK Biobank, a population-based cohort. In a subset of this cohort (n = 39,356), we analysed exome-sequencing data to test the association with VMS of rare deleterious genetic variants. Finally, we used Mendelian randomisation analysis to investigate the reasons for HRT use over time. Results Our GWAS of health-records derived VMS identified a genetic signal near TACR3 associated with a lower risk of VMS (OR=0.76 (95% CI 0.72,0.80) per A allele, P=3.7x10-27), which was consistent with previous studies, validating this approach. Conditional analyses demonstrated independence of genetic signals for puberty timing and VMS at the TACR3 locus, including a rare variant predicted to reduce functional NK3R levels that was associated with later menarche (P = 5 × 10–9) but showed no association with VMS (P = 0.6). Younger menopause age was causally-associated with greater HRT use before 2002 but not after. Conclusions We provide support for TACR3 in the genetic basis of VMS but unexpectedly find that rare genomic variants predicted to lower NK3R levels did not modify VMS, despite the proven efficacy of NK3R antagonists. Using genomics we demonstrate changes in genetic associations with HRT use over time, arising from a change in clinical practice since the early 2000s, which is likely to reflect a switch from preventing post-menopausal complications in women with earlier menopause to primarily treating VMS. Our study demonstrates that integrating routinely-collected primary care health records and genomic data offers great potential for exploring the genetic basis of symptoms.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Insights into the genetics of menopausal vasomotor symptoms: genome-wide analyses of routinely-collected primary care health records

Ruth,

Beaumont,

Locke

et al. 2023

BMC Med Genomics

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“…However, another published study that analysed self-reported medication data in UK Biobank identified the same genetic signal for HRT use. 49…”

Section: Discussionmentioning

confidence: 99%

Genomic insights into the mechanism of NK3R antagonists for treatment of menopausal vasomotor symptoms

Ruth

Beaumont

Locke

et al. 2022

Preprint

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BackgroundMenopausal vasomotor symptoms (VMS) significantly impact women’s quality of life, and whilst hormone replacement therapy (HRT) is effective, it is not appropriate for all. We aimed to identify new drug targets for VMS and understand reasons for HRT use through genomic analyses.MethodsIn up to 153,152 women from UK Biobank, a population-based cohort, we performed a genome-wide association study (GWAS) of VMS derived from linked primary-care records and cross-sectional self-reported data. In a subset of this cohort (n=39,356), we analysed exome-sequencing data to test the association of rare deleterious genetic variants with VMS. Finally, we used Mendelian randomisation analysis to investigate the reasons for HRT use and whether these changed over time.FindingsOur GWAS identified a genetic signal near the gene encoding NK3R (TACR3) associated with a lower risk of VMS (OR=0·85 (95% CI 0·82,0·87) per AT allele, P=1·1×10-26), which was consistent with previous studies. However, rare genetic variants predicted to reduce functional NK3R levels were not associated with VMS (P=0·9), though did delay puberty (P=9×10-11). Younger menopause age was causally-associated with greater HRT use before 2002 but not after.InterpretationUsing genomics we demonstrate that changed HRT use since the early 2000s reflects a switch from preventing post-menopausal complications to primarily treating VMS. We provide support for TACR3 in the genetic basis of VMS but unexpectedly find that rare genomic variants predicted to lower NK3R levels did not modify VMS, despite the proven efficacy of NK3R antagonists, suggesting that further biological understanding could benefit therapeutic efficacy.FundingCancer Research UK and UKRI.Research in contextEvidence before the studyIn vivo studies of animal models and clinical studies in humans have determined that menopausal vasomotor symptoms (VMS) result from increased neurokinin B (NKB) signalling via the neurokinin 3 receptor (NK3R) in response to decreased circulating oestradiol levels.Recent Phase II clinical trials have demonstrated the efficacy of NK3R antagonists in reducing VMS.A previous GWAS in 17,695 women identified a genetic signal at the TACR3 locus (which codes for NK3R) as associated with VMS. The locus was also genome-wide significant in a GWAS of oestrogen-replacement use (15,305 cases) derived from self-reported medications in UK Biobank.Added value of this studyThis study represents a novel approach to analysing the rarely captured phenotype of VMS, since few population-based cohorts have asked about menopausal symptoms.To the best of our knowledge, this is the first analyses of VMS identified from linked primary care health records. Literature searches of published papers and codelists have not identified any previous studies of VMS in primary care data. The replication of the known GWAS signal for VMS provides a validation of the coding of this phenotype from primary care data.This is the largest genomic study of VMS currently carried out (92,028 women). Our current analyses are limited by the availability of primary care linked data in ∼45% of the UK Biobank cohort and are based on exome sequencing in 200,000 women. Recently released exome data for the full cohort and further releases of primary care linked data in UK Biobank will allow us to re-visit these analyses further.Implications of all the available evidenceOur analyses of rare coding variation in TACR3 identified an intriguing difference that requires further study; while NK3R antagonist drug treatment reduces VMS, women carrying rare genetic variants resulting in reduced NK3R levels were no less likely to experience VMS.Our genome-wide analyses replicate the genetic signals for VMS at the TACR3 gene locus, however we were unable to unequivocally identify TACR3 as the causal gene at this locus.We suggest that the effect of the common genetic variant on reducing VMS may be through as yet uncharacterised regulatory pathways, and that complete inhibition of NK3R signalling is required to eliminate (rather than reduce) VMS.

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“…Epidemiological surveys have reported that the twelve-month and lifetime prevalence of major depression exceeds 10% and 20%, respectively, with over 39% of patients exhibiting suicidal tendencies [ 3 ]. Notably, there are significant gender differences in the incidence of depression [ 4 ], Linnéa Nöbbelin et al described a significantly higher incidence of depression and Major depressive disorder (MDD) in women [ 5 ]. For a cross-sectional trial aimed at the general population in China, Wang et al found that the incidence rate of depression in women is three times that in men [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Role of estrogen in treatment of female depression

Sun,

Li,

Zhao

et al. 2024

Aging

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Depression is a neurological disorder that profoundly affects human physical and mental health, resulting in various changes in the central nervous system. Despite several prominent hypotheses, such as the monoaminergic theory, hypothalamic-pituitary-adrenal (HPA) axis theory, neuroinflammation, and neuroplasticity, the current understanding of depression’s pathogenesis remains incomplete. Importantly, depression is a gender-dimorphic disorder, with women exhibiting higher incidence rates than men. Given estrogen's pivotal role in the menstrual cycle, it is reasonable to postulate that its fluctuating levels could contribute to the pathogenesis of depression. Estrogen acts by binding to a diversity of receptors, which are widely distributed in the central nervous system. An abundance of research has established that estrogen and its receptors play a crucial role in depression, spanning pathogenesis and treatment. In this comprehensive review, we provide an in-depth analysis of the fundamental role of estrogen and its receptors in depression, with a focus on neuroinflammation, neuroendocrinology, and neuroplasticity. Furthermore, we discuss potential mechanisms underlying the therapeutic effects of estrogen in the treatment of depression, which may pave the way for new antidepressant drug development and alternative treatment options.

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Shared genetic influences on depression and menopause symptoms

Cited by 10 publications

References 65 publications

Insights into the genetics of menopausal vasomotor symptoms: genome-wide analyses of routinely-collected primary care health records

Insights into the genetics of menopausal vasomotor symptoms: genome-wide analyses of routinely-collected primary care health records

Genomic insights into the mechanism of NK3R antagonists for treatment of menopausal vasomotor symptoms

Role of estrogen in treatment of female depression

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