小柯机器人

近日，英国剑桥大学John R. B. Perry等研究人员合作揭示人类卵巢衰老生物机制的遗传关联。相关论文于2021年8月4日在线发表于国际学术期刊《自然》。

利用自然绝经年龄（ANM）的正常变异对大约20万名欧洲血统的妇女进行评估，研究人员确定了290个卵巢衰老的遗传决定因素。这些常见的等位基因与ANM的临床极值有关；处于遗传易感性前1%的妇女，其卵巢早衰的风险与携带单基因FMR1前突的妇女相当。确定的基因座涉及广泛的DNA损伤反应（DDR）过程，包括关键DDR相关基因的功能缺失变异。与实验模型的结合表明，这些DDR过程在整个生命过程中发挥作用，并影响了卵巢储备及其耗竭率。

此外，研究人员证明了对人类遗传学所强调的DDR途径可以在实验上增加小鼠的生育能力并延长生殖期。使用发现的遗传变体进行的因果推理分析表明，延长妇女的生殖期可以改善骨骼健康，降低2型糖尿病的风险，但会增加激素敏感型癌症的风险。这些发现使人们深入了解支配卵巢衰老的机制，它们何时起作用，以及如何通过治疗方法针对它们来延长生育能力和预防疾病。

据悉，生殖寿命对生育能力至关重要，并影响到妇女的健康衰老，但对其潜在的生物机制和保护它的治疗方法的见解是有限的。

附：英文原文

Title: Genetic insights into biological mechanisms governing human ovarian ageing

Author: Ruth, Katherine S., Day, Felix R., Hussain, Jazib, Martnez-Marchal, Ana, Aiken, Catherine E., Azad, Ajuna, Thompson, Deborah J., Knoblochova, Lucie, Abe, Hironori, Tarry-Adkins, Jane L., Gonzalez, Javier Martin, Fontanillas, Pierre, Claringbould, Annique, Bakker, Olivier B., Sulem, Patrick, Walters, Robin G., Terao, Chikashi, Turon, Sandra, Horikoshi, Momoko, Lin, Kuang, Onland-Moret, N. Charlotte, Sankar, Aditya, Hertz, Emil Peter Thrane, Timshel, Pascal N., Shukla, Vallari, Borup, Rehannah, Olsen, Kristina W., Aguilera, Paula, Ferrer-Roda, Mnica, Huang, Yan, Stankovic, Stasa, Timmers, Paul R. H. J., Ahearn, Thomas U., Alizadeh, Behrooz Z., Naderi, Elnaz, Andrulis, Irene L., Arnold, Alice M., Aronson, Kristan J., Augustinsson, Annelie, Bandinelli, Stefania, Barbieri, Caterina M., Beaumont, Robin N., Becher, Heiko, Beckmann, Matthias W., Benonisdottir, Stefania, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E., Bolla, Manjeet K., Boomsma, Dorret I., Bowker, Nicholas, Brody, Jennifer A., Broer, Linda, Buring, Julie E., Campbell, Archie, Campbell, Harry, Castelao, Jose E., Catamo, Eulalia, Chanock, Stephen J., Chenevix-Trench, Georgia, Ciullo, Marina, Corre, Tanguy

Issue&Volume: 2021-08-04

Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

DOI: 10.1038/s41586-021-03779-7

Source: https://www.nature.com/articles/s41586-021-03779-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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