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

Autor: Ruth KS; Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK. K.S.Ruth@exeter.ac.uk., Beaumont RN; Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK., Locke JM; Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK., Tyrrell J; Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK., Crandall CJ; Division of General Internal Medicine and Health Services Research, David Geffen School of Medicine at University of California, Los Angeles, CA, 90024, USA., Hawkes G; Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK., Frayling TM; Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK., Prague JK; Exeter Centre of Excellence for Diabetes Research, University of Exeter, Exeter, EX2 5DW, UK.; Macleod Diabetes and Endocrinology Centre, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, EX2 5DW, UK., Patel KA; Exeter Centre of Excellence for Diabetes Research, University of Exeter, Exeter, EX2 5DW, UK.; Macleod Diabetes and Endocrinology Centre, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, EX2 5DW, UK., Wood AR; Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK., Weedon MN; Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK., Murray A; Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK.
Jazyk: angličtina
Zdroj: BMC medical genomics [BMC Med Genomics] 2023 Oct 02; Vol. 16 (1), pp. 231. Date of Electronic Publication: 2023 Oct 02.
DOI: 10.1186/s12920-023-01658-w
Abstrakt: 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.
(© 2023. BioMed Central Ltd., part of Springer Nature.)
Databáze: MEDLINE
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