Genetic insights into biological mechanisms governing human ovarian ageing.

Genetic insights into biological mechanisms governing human ovarian ageing.
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DOI:
10.1038/s41586-021-03779-7
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发表时间:
2021-08
期刊:
影响因子:
64.8
通讯作者:
Perry JRB
Perry JRB
中科院分区:
综合性期刊1区
文献类型:
--
作者:
Ruth KS;Day FR;Hussain J;Martínez-Marchal A;Aiken CE;Azad A;Thompson DJ;Knoblochova L;Abe H;Tarry-Adkins JL;Gonzalez JM;Fontanillas P;Claringbould A;Bakker OB;Sulem P;Walters RG;Terao C;Turon S;Horikoshi M;Lin K;Onland-Moret NC;Sankar A;Hertz EPT;Timshel PN;Shukla V;Borup R;Olsen KW;Aguilera P;Ferrer-Roda M;Huang Y;Stankovic S;Timmers PRHJ;Ahearn TU;Alizadeh BZ;Naderi E;Andrulis IL;Arnold AM;Aronson KJ;Augustinsson A;Bandinelli S;Barbieri CM;Beaumont RN;Becher H;Beckmann MW;Benonisdottir S;Bergmann S;Bochud M;Boerwinkle E;Bojesen SE;Bolla MK;Boomsma DI;Bowker N;Brody JA;Broer L;Buring JE;Campbell A;Campbell H;Castelao JE;Catamo E;Chanock SJ;Chenevix-Trench G;Ciullo M;Corre T;Couch FJ;Cox A;Crisponi L;Cross SS;Cucca F;Czene K;Smith GD;de Geus EJCN;de Mutsert R;De Vivo I;Demerath EW;Dennis J;Dunning AM;Dwek M;Eriksson M;Esko T;Fasching PA;Faul JD;Ferrucci L;Franceschini N;Frayling TM;Gago-Dominguez M;Mezzavilla M;García-Closas M;Gieger C;Giles GG;Grallert H;Gudbjartsson DF;Gudnason V;Guénel P;Haiman CA;Håkansson N;Hall P;Hayward C;He C;He W;Heiss G;Høffding MK;Hopper JL;Hottenga JJ;Hu F;Hunter D;Ikram MA;Jackson RD;Joaquim MDR;John EM;Joshi PK;Karasik D;Kardia SLR;Kartsonaki C;Karlsson R;Kitahara CM;Kolcic I;Kooperberg C;Kraft P;Kurian AW;Kutalik Z;La Bianca M;LaChance G;Langenberg C;Launer LJ;Laven JSE;Lawlor DA;Le Marchand L;Li J;Lindblom A;Lindstrom S;Lindstrom T;Linet M;Liu Y;Liu S;Luan J;Mägi R;Magnusson PKE;Mangino M;Mannermaa A;Marco B;Marten J;Martin NG;Mbarek H;McKnight B;Medland SE;Meisinger C;Meitinger T;Menni C;Metspalu A;Milani L;Milne RL;Montgomery GW;Mook-Kanamori DO;Mulas A;Mulligan AM;Murray A;Nalls MA;Newman A;Noordam R;Nutile T;Nyholt DR;Olshan AF;Olsson H;Painter JN;Patel AV;Pedersen NL;Perjakova N;Peters A;Peters U;Pharoah PDP;Polasek O;Porcu E;Psaty BM;Rahman I;Rennert G;Rennert HS;Ridker PM;Ring SM;Robino A;Rose LM;Rosendaal FR;Rossouw J;Rudan I;Rueedi R;Ruggiero D;Sala CF;Saloustros E;Sandler DP;Sanna S;Sawyer EJ;Sarnowski C;Schlessinger D;Schmidt MK;Schoemaker MJ;Schraut KE;Scott C;Shekari S;Shrikhande A;Smith AV;Smith BH;Smith JA;Sorice R;Southey MC;Spector TD;Spinelli JJ;Stampfer M;Stöckl D;van Meurs JBJ;Strauch K;Styrkarsdottir U;Swerdlow AJ;Tanaka T;Teras LR;Teumer A;Þorsteinsdottir U;Timpson NJ;Toniolo D;Traglia M;Troester MA;Truong T;Tyrrell J;Uitterlinden AG;Ulivi S;Vachon CM;Vitart V;Völker U;Vollenweider P;Völzke H;Wang Q;Wareham NJ;Weinberg CR;Weir DR;Wilcox AN;van Dijk KW;Willemsen G;Wilson JF;Wolffenbuttel BHR;Wolk A;Wood AR;Zhao W;Zygmunt M;Biobank-based Integrative Omics Study (BIOS) Consortium;eQTLGen Consortium;Biobank Japan Project;China Kadoorie Biobank Collaborative Group;kConFab Investigators;LifeLines Cohort Study;InterAct consortium;23andMe Research Team;Chen Z;Li L;Franke L;Burgess S;Deelen P;Pers TH;Grøndahl ML;Andersen CY;Pujol A;Lopez-Contreras AJ;Daniel JA;Stefansson K;Chang-Claude J;van der Schouw YT;Lunetta KL;Chasman DI;Easton DF;Visser JA;Ozanne SE;Namekawa SH;Solc P;Murabito JM;Ong KK;Hoffmann ER;Murray A;Roig I;Perry JRB

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生殖寿命对于生育能力至关重要,并影响女性的健康老龄化,但对潜在生物学机制和保持生殖寿命的治疗方法的了解有限。在这里,我们确定了290个卵巢衰老的遗传决定因素,使用自然绝经年龄(ANM)的正常变化对约20万欧洲血统的妇女进行了评估。这些常见的等位基因与ANM的临床极端相关;遗传易感性最高的1%的女性与携带单基因FMR 1前突变的女性具有相同的卵巢功能不全风险。已鉴定的基因座涉及广泛的DNA损伤反应(DDR)过程,并包括关键DDR基因中的功能丧失变体。与实验模型的整合表明,这些DDR过程在整个生命过程中起作用,以塑造卵巢储备及其消耗率。此外,我们证明了人类遗传学所强调的DDR途径的实验操作可以提高小鼠的生育能力并延长其生殖寿命。使用已确定的遗传变异进行的因果推断分析表明,延长女性的生殖寿命可改善骨骼健康并降低2型糖尿病的风险,但会增加对癌症敏感的风险。这些发现提供了对卵巢衰老机制的深入了解,当它们在整个生命过程中发挥作用时,以及它们如何通过治疗方法来延长生育能力和预防疾病。
Reproductive longevity is critical for fertility and impacts healthy ageing in women, yet insights into the 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 ~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 premutations. Identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR 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 increase fertility and extend reproductive life in mice. Causal inference analyses using the identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. These findings provide insight into the mechanisms governing ovarian ageing, when they act across the life-course, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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