Attending Physician in Pediatrics Boston Children's Hospital Canton, MA, United States
Background: In women, epidemiological studies have shown a U-shaped relationship between age at menarche (AAM) and risk of coronary artery disease (CAD): both earlier and later AAM are associated with an increased risk of CAD. For later AAM, our recent work demonstrated that different causes of later AAM have different associations with CAD risk. Specifically, later menarche attributable to common genetic variants (which we termed genetically predicted AAM, calculated using a polygenic score for AAM, Sonawalla et al, 2025) is associated with decreased CAD risk, whereas later menarche attributable to other factors, e.g., environmental or acquired factors (which we termed genetics-adjusted AAM), is associated with increased CAD risk. These differential associations show that later AAM itself does not increase CAD; rather, they indicate the presence of premenarchal factors that both delay menarche and increase risk of CAD. This study aimed to identify other adult health conditions with evidence for childhood antecedents through the lens of AAM.
Methods: We conducted phenome-wide association studies (PheWAS) in the UK Biobank (N = 201,037 women) using genetically predicted AAM and genetics-adjusted AAM as predictors, all available diagnoses based on ICD9/10 codes as outcomes, and a Bonferroni-adjusted significance threshold (α = 2.8x10-5). Because PheWAS assumes linearity, we also explored the possibility of nonlinear associations, by “mirroring” values of the predictors along the mean: │value – mean│. After this “mirroring,” a linear association would convert to a null association on linear regression analysis, whereas a U-shaped association would be uncovered/amplified.
Results: We identified many conditions associated with timing of menarche. For genetically predicted AAM, we observed negative associations (i.e., earlier AAM associated with greater risk) for 47 diagnoses related to obesity and the metabolic syndrome. Mirroring nullified all associations, indicating all relationships were close to linear. For genetics-adjusted AAM, we observed similar negative associations with 26 diagnoses largely related to obesity and the metabolic syndrome. To our surprise, mirroring uncovered U-shaped associations with a remarkably wide array of 142 diagnoses, including tobacco use disorder, type 1 diabetes, gastritis and duodenitis, functional digestive disorders, ischemic heart disease, urinary incontinence, and headaches.
Conclusion: Our results indicate the presence of premenarchal antecedents (which may be acquired or environmental) of a multitude of adult diagnoses. This work dramatically expands the range of conditions with evidence for childhood antecedents in women and provides genetics-adjusted AAM as a tool to identify the childhood origins of these adult health conditions.
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