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
中科院分区:
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
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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影响因子:
7.7
作者:
Bowden J;Spiller W;Del Greco M F;Sheehan N;Thompson J;Minelli C;Davey Smith G
通讯作者:
Davey Smith G
影响因子:
64.8
作者:
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者:
Marchini J
影响因子:
168.9
作者:
Christensen, Kaare;Doblhammer, Gabriele;Rau, Roland;Vaupel, James W.
通讯作者:
Vaupel, James W.
影响因子:
2.1
作者:
Bowden J;Davey Smith G;Haycock PC;Burgess S
通讯作者:
Burgess S
DOI:
10.1056/nejmoa1309635
发表时间:
2014-03-06
期刊:
The New England journal of medicine
影响因子:
--
作者:
Caburet S;Arboleda VA;Llano E;Overbeek PA;Barbero JL;Oka K;Harrison W;Vaiman D;Ben-Neriah Z;García-Tuñón I;Fellous M;Pendás AM;Veitia RA;Vilain E
通讯作者:
Vilain E