Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

Stolk, Lisette; Perry, John; Chasman, Daniel I.; He, Chunyan; Mangino, Massimo; Sulem, Patrick; Barbalić, Maja; Broer, Linda; Byrne, Enda M.; Ernst, Florian; Esko, Tõnu; Franceschini, Nora; Guðbjartsson, Daníel F.; Hottenga, Jouke Jan; Kraft, Peter; McArdle, Patrick F.; Porcu, Eleonora; Shin, So Youn; Smith, Albert V.; Wingerden, S. van; Zhai, Guangju; Zhuang, Wei Vivian; Albrecht, Eva; Alizadeh, Behrooz Z.; Aspelund, Thor; Bandinelli, Stefania; Lauc, Lovorka Barać; Beckmann, Jacques S.; Boban, Mladen; Boerwinkle, Eric; Broekmans, Frank J.; Burri, Andrea; Campbell, Harry; Chanock, Stephen J.; Chen, Constance; Cornelis, Marilyn C.; Corre, Tanguy; Coviello, Andrea D.; D’Adamo, Pio; Davies, Gail; Fairé, Ulf dé; Geus, Eco J. C. de; Deary, Ian J.; Dedoussis, George; Deloukas, Panos; Ebrahim, Shah; Eiríksdóttir, Guðný; Emilsson, Valur; Eriksson, Johan G.; Fauser, Bart C.J.M.; Ferreli, Liana; Ferrucci, Luigi; Fischer, Krista; Folsom, Aaron R.; García, Melissa; Gasparini, Paolo; Gieger, Christian; Glazer, Nicole L.; Grobbee, Diederick E.; Hall, Per; Haller, Toomas; Hankinson, Susan E.; Hass, Merli; Hayward, Caroline; Heath, Andrew C.; Hofman, Albert; Ingelsson, Erik; Janssens, A. Cecile J.W.; Johnson, Andrew D.; Karasik, David; Kardia, Sharon L.R.; Keyzer, Jules J.; Kiel, Douglas P.; Kolčić, Ivana; Kutalik, Zoltn; Lahti, Jari; Lai, Sandra; Laisk, Triin; Laven, Joop; Lawlor, Debbie A.; Li, Jianjun; Lopez, Lorna M.; Louwers, Yvonne V.; Magnusson, Patrik K. E.; Marongiu, Mara; Martin, Nicholas G.; Klarić, Irena Martinović; Masciullo, Corrado; McKnight, Barbara; Medland, Sarah E.; Melzer, David; Mooser, Vincent; Navarro, Pau; Newman, Anne B.; Nyholt, Dale R.; Onland‐Moret, N. Charlotte; Palotie, Aarno; Paré, Guillaume; Parker, Alex; Pedersen, Nancy L.; Peeters, Petra H.; Pistis, Giorgio; Plump, Andrew S.; Polašek, Ozren; Pop, Victor J M; Psaty, Bruce M.; Signikkönen, Katri R Currency; Rehnberg, Emil; Rotter, Jerome I.; Rudan, Igor; Sala, Cinzia; Salumets, Andres; Scuteri, Angelo; Singleton, Andrew B.; Smith, Jennifer A.; Snieder, Harold; Soranzo, Nicole; Stacey, Simon; Starr, John M.; Stathopoulou, Maria G.; Stirrups, Kathleen; Stolk, Ronald; Styrkársdóttir, Unnur; Sun, Yan V.; Tenesa, Albert; Thorand, Barbara; Toniolo, Daniela; Tryggvadóttír, Laufey; Tsui, Kim; Ulivi, Sheila; Dam, Rob M. van; Schouw, Yvonne T. van der; Gils, Carla H. van; Nierop, Peter Van; Vink, Jacqueline M.; Visscher, Peter M.; Voorhuis, Marlies; Waeber, Gérard; Wallaschofski, Henri; Wichmann, Heinz‐Erich; Widén, Elisabeth; Gent, Colette J M Wijnands-van; Willemsen, Gonneke; Wilson, James F.; Wolffenbuttel, Bruce H. R.; Wright, Alan F.; Yerges‐Armstrong, Laura M.; Zemunik, Tatijana; Zgaga, Lina; Zillikens, M. Carola; Zygmunt, Marek; Arnold, Alice M.; Boomsma, Dorret I.; Buring, Julie E.; Crisponi, Laura; Demerath, Ellen W.; Gudnason, Vilmundur; Harris, Tamara B.; Hu, Frank B.; Hunter, David J.; Launer, Lenore J.; Metspalu, Andres; Montgomery, Grant W.; Oostra, Ben A.; Ridker, Paul M.; Sanna, Serena; Schlessinger, David; Spector, Tim D.; Stefánsson, Kāri; Streeten, Elizabeth A.; Þorsteinsdóttir, Unnur; Uda, Manuela; Uitterlinden, André G.; Duijn, Cornelia M. van; Völzke, Henry; Murray, Anna; Murabito, Joanne M.; Visser, Jenny A.; Lunetta, Kathryn L.

doi:10.1038/ng.1051

Cited by 330 publications

(352 citation statements)

References 80 publications

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“…The coding-synonymous SNP rs365132, in the ubiquitin interaction motif-containing 1 gene (UIMC1), is an expression-quantitative trait locus for nearby genes FGFR4 and ZNF346 in the cortex. UIMC1 functions in DNA repair via interaction with BRCA1 and estrogen receptor α (Stolk et al 2012). BRSK1 is an AMPactivated protein kinase (AMPK)-related serine/ threonine kinase, which regulates neurotransmitter release at the axonal terminals (Inoue et al 2006).…”

Section: −8mentioning

confidence: 99%

“…It has been well recognized that genetic makeup influences both AM (Sharma 2002;Anderson et al 2008) and ANM (de Bruin et al 2001;Murabito et al 2005;Morris et al 2011). Recent genome-wide association studies (GWASs) among women of European ancestry have identified at least 106 genetic loci for AM (He et al 2009;Ong et al 2009;Perry et al 2009;Sulem et al 2009;Elks et al 2010;Perry et al 2014) and 21 loci for ANM (He et al 2009;Stolk et al 2009;Stolk et al 2012). However, only 24 AM loci and 9 ANM loci have been replicated in women of either Asian or African ancestry and no novel loci have been identified in these non-European populations (Liu et al 2009;Chen et al 2012;Shen et al 2013;Spencer et al 2013;Tanikawa et al 2013;Delahanty et al 2013;Carty et al 2013;Demerath et al 2013;Pyun et al 2014;Chen et al 2014).…”

Section: Introductionmentioning

confidence: 99%

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Age at menarche and age at natural menopause in East Asian women: a genome-wide association study

Shi

Zhang

Choi

et al. 2016

AGE

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Age at menarche (AM) and age at natural menopause (ANM) are complex traits with a high heritability. Abnormal timing of menarche or menopause is associated with a reduced span of fertility and risk for several age-related diseases including breast, endometrial and ovarian cancer, cardiovascular disease, and osteoporosis. To identify novel genetic loci for AM or ANM in East Asian women and to replicate previously identified loci primarily in women of European ancestry by genome-wide association studies (GWASs), we conducted a two-stage GWAS. Stage I aimed to discover promising novel AM and ANM loci using GWAS data of 8073 women from Shanghai, China. The Stage II replication study used the data from another Chinese GWAS (n = 1230 for AM and n = 1458 for ANM), a Korean GWAS (n = 4215 for AM and n = 1739 for ANM), and de novo genotyping of 2877 additional Chinese women. Previous GWAS-identified loci for AM and ANM were also AGE (2016) ) and rs1023935 at 4p15.1 (beta = −0.145 years, P = 4.9 × 10 −6) and one menopausal age locus tagged by rs3818134 at 22q12.2 (beta = −0.276 years, P = 8.8 × 10 −6). These suggestive loci warrant a further validation in independent populations. Although limited by low statistical power, we replicated 19 of the 98 menarche loci and 5 of the 20 menopause loci previously identified in women of European ancestry in East Asian women, suggesting a shared genetic architecture for these two traits across populations.

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Section: −8mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Age at menarche and age at natural menopause in East Asian women: a genome-wide association study

Shi

Zhang

Choi

et al. 2016

AGE

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“…In this case, early menopause could be considered as only a marker of risk. In support of a shared genetic basis, a large-scale genome-wide association study of age at menopause identified a number of loci, including the ones relevant to CVD, that were involved in inflammatory response, oxidative stress and genome stability 22 . Speculative environmental factors could include obstetric history, such as parity or having a stillbirth.…”

Section: Interpretation Of Findingsmentioning

confidence: 99%

Association of Age at Onset of Menopause and Time Since Onset of Menopause With Cardiovascular Outcomes, Intermediate Vascular Traits, and All-Cause Mortality

et al. 2016

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms Role of the Funder/Sponsor: Metagenics Inc. had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review or approval of the manuscript.The funder/sponsor did not have the ability to veto publication of study results. Data Extraction: Data were extracted by two independent reviewers using a pre-designed data collection form. Word count text: 3494 wordsMain outcomes and Measures: CVD outcomes (composite CVD, fatal and non-fatal coronary heart disease (CHD) and overall stroke and stroke mortality), CVD-mortality, all-cause mortality and intermediate CVD endpoints.Results: Out of initially identified references, 32 studies were selected, including 310,329 non-overlapping women. Women with a menopausal age of younger than 45 years compared to women with a menopausal age of 45 years or older, the relative risk (RR) [95% confidence intervals (CI)] was 1.50(1.28-1.76) for overall CHD, 1.11(1.03-1.20) for fatal CHD, 1.23 (0.98-1.53) for overall stroke, 0.99 (0.92-1.07) for stroke mortality, 1.19(1.08-1.31) for CVD mortality and 1.12(1.03-1.21) for all-cause mortality. For women with a menopausal age between 50-54 years compared to women with a menopausal age of younger than 50 years, there was a decreased risk of fatal CHD (RR:0.87(95%CI:0.80-0.96)), and no effect on stroke. Duration since menopause in relation to risk of developing intermediate cardiovascular traits or CVD outcomes was reported in 4 observational studies, reporting no consistent results. Conclusions and Relevance:The findings of this review indicate an excess CHD, CVD-mortality and overall mortality risk in women who have an early or premature menopause.

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“…Age at menopause is determined by a combination of initial oocyte numbers and the rate of loss of ovarian follicles across the course of the female lifespan (Broekmans et al 2009;Bukovsky 2010;Hansen et al 2008;te Velde et al 1998) both of which can be influenced by genetic (Stolk et al 2012), environmental (Sakata et al 2011), and lifestyle factors (Gold et al 2001;Morris et al 2012). As a result, a wide range of variation in age at menopause has been documented across diverse populations (Henderson et al 2008;Johnston 2001;Reynolds and Obermeyer 2005;Sievert 2006; Thomas et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Life course effects on age at menopause among Bangladeshi sedentees and migrants to the UK

Murphy

Sievert

Begum

et al. 2012

American J Hum Biol

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Objectives:To assess how different variables experienced across the life course, but particularly during early life, might affect age at menopause among 174 Bangladeshi migrants to London by comparing them to 157 nonmigrant sedentees and 154 women of European descent in London.Methods:Participants were aged 35–59 years, with no exogenous hormone use in the past three months, not pregnant or lactating, with no history of hysterectomy or oophorectomy. Face‐to‐face interviews and anthropometric measures were carried out. In addition to mean recalled age at natural menopause, median age was computed by probit analysis. Ages at menopause were examined by bivariate and Cox regression analyses in relation to demographic, reproductive, and lifestyle variables, and in relation to potential exposure to cyclones in early childhood.Results:Ages at menopause were significantly earlier among Bangladeshi sedentees and immigrants compared to Londoners of European origin. Ages at menopause were earlier among sedentees compared to immigrants. Urban birthplace, more infectious diseases during childhood, and lower levels of education increased the risk of an earlier menopause.Conclusions:Changes in environmental conditions during adulthood appeared to modify age at menopause among Bangladeshi immigrants in London compared to women living in Bangladesh; however, Bangladeshi immigrants still experienced an earlier age at menopause compared with their London neighbors of European descent. Am. J. Hum. Biol., 2013. © 2012 Wiley Periodicals, Inc.

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Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

Cited by 330 publications

References 80 publications

Age at menarche and age at natural menopause in East Asian women: a genome-wide association study

Age at menarche and age at natural menopause in East Asian women: a genome-wide association study

Association of Age at Onset of Menopause and Time Since Onset of Menopause With Cardiovascular Outcomes, Intermediate Vascular Traits, and All-Cause Mortality

Life course effects on age at menopause among Bangladeshi sedentees and migrants to the UK

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