Joint Associations of Actual Age and Genetically Determined Age at Menarche With Risk of Mortality

Key Points Question What are the joint associations of actual age and genetically determined age at menarche with risk of all-cause mortality? Findings This cohort study found that that both actual age and genetically determined age at menarche showed similar U-shaped associations with risk of all-cause mortality in a large group of women. The study also found a significant interaction between actual and genetically determined age at menarche with all-cause mortality; women with mismatch of actual age and genetically determined age at menarche had the highest risk of all-cause mortality. Meaning This study suggests that women with a mismatch of actual age and genetically determined age at menarche may have a significantly higher risk of all-cause mortality than women whose actual age and genetically determined age at menarche are matched.
Importance Previous studies have shown an association between actual age at menarche and risk of all-cause mortality; however, the results are inconsistent, and no study has analyzed the joint associations between genetic susceptibility and actual age at menarche with the risk of mortality in prospective cohorts. Objectives To investigate joint associations of actual age and genetically determined age at menarche with risk of all-cause mortality. Design, Setting, and Participants This prospective cohort study was conducted using data from the UK Biobank population across the United Kingdom from March 13, 2006, to October 1, 2010. A total of 264 546 women aged between 39 and 71 years with actual menarcheal age were included in this study; 246 676 of these women had genetic data available. Actual age at menarche was obtained from the touchscreen questionnaire at recruitment from 2006 to 2010. Genetically determined age at menarche was assessed by a genetic risk score. Statistical analysis was performed from August 22 to December 12, 2019. Exposure Age at menarche. Main Outcomes and Measures A multivariable Cox proportional hazards regression model was used to assess associations of actual or genetically determined age at menarche with risk of all-cause mortality. Results The mean (SD) age of the study population at baseline was 56.4 (8.0) years, and the mean (SD) age at menarche included in the analyses was 13.0 (1.6) years. During a median of 9.0 years (range, 8.3-9.7 years) of follow-up, 7761 deaths were documented among the women with actual age at menarche, and 7054 deaths were documented among the women with genetically determined age at menarche. Both the actual age at menarche and the genetically determined age at menarche showed a U-shaped association with the risk of all-cause mortality (lowest actual age [
This cohort study uses data from the UK Biobank to investigate joint associations of actual age and genetically determined age at menarche with risk of all-cause mortality.