Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK.
Division of General Internal Medicine and Health Services Research, David Geffen School of Medicine at University of California, Los Angeles, CA, 90024, USA.
BMC Med Genomics. 2023 Oct 2;16(1):231. doi: 10.1186/s12920-023-01658-w.
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.
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.
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), 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) but showed no association with VMS (P = 0.6). Younger menopause age was causally-associated with greater HRT use before 2002 but not after.
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.
血管舒缩症状（VMS）在女性绝经期常严重影响其生活质量。体内研究表明，神经激肽 B（NKB）/神经激肽 3 受体（NK3R）信号的增加导致 VMS，先前的遗传研究表明 TACR3 基因座编码 NK3R。全基因组分析提供了生物学见解的可能性，但很少有此类研究收集 VMS 的数据，而激素替代疗法（HRT）使用等替代表型可能受到临床实践变化的影响。我们通过分析英国生物库中常规收集的健康记录，研究了 VMS 的遗传基础。
我们对来自英国生物库的多达 153152 名女性的原发性护理记录中得出的 VMS 进行了全基因组关联研究，并对横断面上的自我报告 HRT 使用情况进行了全基因组关联研究，这些女性均来自一个基于人群的队列。在该队列的一个亚组（n=39356）中，我们分析了外显子组测序数据，以检测罕见有害遗传变异与 VMS 的关联。最后，我们使用孟德尔随机化分析来研究随时间推移 HRT 使用的原因。
我们对源自健康记录的 VMS 的全基因组关联研究，在 TACR3 附近鉴定出与 VMS 风险降低相关的遗传信号（每一个 A 等位基因的 OR=0.76（95% CI 0.72，0.80），P=3.7x10），这与先前的研究一致，验证了这种方法。条件分析表明，TACR3 基因座的青春期和 VMS 的遗传信号是独立的，包括一个预测降低 NK3R 水平的罕见变异，该变异与月经初潮较晚有关（P=5×10），但与 VMS 无关（P=0.6）。绝经年龄越小，与 2002 年前使用 HRT 的关系越大，但之后就没有关系了。
我们为 TACR3 在 VMS 的遗传基础提供了支持，但出乎意料的是，尽管 NK3R 拮抗剂已被证明有效，但预测 NK3R 水平降低的罕见基因组变异并未改变 VMS。我们使用基因组学证明，随着时间的推移，HRT 使用的遗传关联发生了变化，这是自 21 世纪初以来临床实践变化的结果，这可能反映了从预防绝经后并发症转变为主要治疗 VMS。我们的研究表明，整合常规收集的初级保健健康记录和基因组数据为探索症状的遗传基础提供了巨大的潜力。
