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

By Katherine S Ruth, Robin N Beaumont, Jonathan M Locke, Jessica Tyrrell, Carolyn J Crandall, Gareth Hawkes, Timothy M. Frayling, Julia K Prague, Kashyap A Patel, Andrew R Wood, Michael N Weedon, Anna Murray

Posted 26 May 2022
medRxiv DOI: 10.1101/2022.05.25.22275501

Background Menopausal 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. Methods In 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. Findings Our 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=1.1x10-26), 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=9x10-11). Younger menopause age was causally-associated with greater HRT use before 2002 but not after. Interpretation Using 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.

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