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Observational studies are prone to bias and have limited statistical power. Mendelian randomization (MR) minimises bias and may be used to examine causal effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Two-sample and age-specific MR analyses for BC were performed. For AAM, two-sample multivariable MR and mediation analyses to account for the confounding effect of body mass index (BMI), were undertaken.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Genetic scores for ANM and AAM predicted the respective traits in PV carriers. Inverse-variance weighted hazard ratios (HR) for genetically predicted ANM per-year were HR\u2009=\u20090.99 (95%CI:0.97\u20131.01,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.45) and HR\u2009=\u20091.04 (95% CI:1.01\u20131.06,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.003) for\n                      <jats:italic>BRCA1<\/jats:italic>\n                      and\n                      <jats:italic>BRCA2<\/jats:italic>\n                      PV carriers, respectively. After adjusting for genetic associations with BMI, AAM per-year on BC risk were HR\u2009=\u20090.90 (95%CI:0.83\u20130.98,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.01) and HR\u2009=\u20090.95 (95%CI:0.86\u20131.04,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.26) for\n                      <jats:italic>BRCA1<\/jats:italic>\n                      and\n                      <jats:italic>BRCA2<\/jats:italic>\n                      carriers, respectively, consistent with a protective effect of later AAM.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      MR analyses support causal associations between ANM and BC risk in\n                      <jats:italic>BRCA2<\/jats:italic>\n                      , but not\n                      <jats:italic>BRCA1<\/jats:italic>\n                      , and between AAM and BC risk in\n                      <jats:italic>BRCA1<\/jats:italic>\n                      and\n                      <jats:italic>BRCA2<\/jats:italic>\n                      PV carriers. These results may aid risk prediction models and genetic counselling of carriers.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1038\/s41416-026-03365-6","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T09:13:05Z","timestamp":1774861985000},"page":"1479-1487","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Natural menopause, menarche and breast cancer risk in BRCA1 and BRCA2 pathogenic variant carriers: a Mendelian randomization analysis"],"prefix":"10.1038","volume":"134","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0307-055X","authenticated-orcid":false,"given":"Nasim","family":"Mavaddat","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3781-7570","authenticated-orcid":false,"given":"Daniel 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JRBP is an employee\/shareholder of Insmed Innovation UK \/ Insmed, receives research funding from GSK and consultancy fees from WW International and Ovartix. All other authors report no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The EMBRACE study was approved by the East of England\u2014Cambridge South Ethics Committee (ref 98\/5\/026, IRAS 20971). All patients gave written informed consent. Each participating study in CIMBA and BCAC obtained informed consent from the participants and was approved by the appropriate institutional ethics review board or committee. 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