Centre for Fertility and Health, Norwegian Institute of Public Health, P.O. Box 222, 0213, Skøyen, Oslo, Norway.
MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
Eur J Epidemiol. 2022 Sep;37(9):971-982. doi: 10.1007/s10654-022-00903-3. Epub 2022 Sep 3.
Age at natural menopause (ANM) is associated with a range of health-related traits, including bone health, female reproductive cancers, and cardiometabolic health. Our objective was to conduct a Mendelian randomization phenome-wide association study (MR-pheWAS) of ANM. We conducted a hypothesis-free analysis of the genetic risk score (GRS) for ANM with 18,961 health-related traits among 181,279 women in UK Biobank. We also stratified the GRS according to the involvement of SNPs in DNA damage response. We sought to replicate our findings in independent cohorts. We conducted a negative control MR-pheWAS among men. Among women, we identified potential effects of ANM on 221 traits (1.17% of all traits) at a false discovery rate (P value ≤ 5.83 × 10), and 91 (0.48%) potential effects when using Bonferroni threshold (P value ≤ 2.64 × 10). Our findings included 55 traits directly related to ANM (e.g. hormone replacement therapy, gynaecological conditions and menstrual conditions), and liver function, kidney function, lung function, blood-cell composition, breast cancer and bone and cardiometabolic health. Replication analyses confirmed that younger ANM was associated with HbA1c (adjusted mean difference 0.003 mmol/mol; 95% CI 0.001, 0.006 per year decrease in ANM), breast cancer (adjusted OR 0.96; 95% CI 0.95, 0.98), and bone-mineral density (adjusted mean difference - 0.05; 95% CI - 0.07, - 0.03 for lumbar spine). In men, 30 traits were associated with the GRS at a false discovery rate (P value ≤ 5.49 × 10), and 11 potential effects when using Bonferroni threshold (P value ≤ 2.75 × 10). In conclusion, our results suggest that younger ANM has potential causal effects on a range of health-related traits.
绝经年龄（ANM）与一系列与健康相关的特征有关，包括骨骼健康、女性生殖系统癌症和心脏代谢健康。我们的目的是对 ANM 进行孟德尔随机化表型全基因组关联研究（MR-pheWAS）。我们对英国生物库 181279 名女性中与 18961 种健康相关特征相关的 ANM 遗传风险评分（GRS）进行了假设自由分析。我们还根据 SNP 是否参与 DNA 损伤反应对 GRS 进行了分层。我们试图在独立队列中复制我们的发现。我们在男性中进行了阴性对照 MR-pheWAS。在女性中，我们在错误发现率（P 值≤5.83×10）下确定了 ANM 对 221 种特征（所有特征的 1.17%）的潜在影响，而使用 Bonferroni 阈值（P 值≤2.64×10）时，有 91 种（0.48%）潜在影响。我们的发现包括 55 种直接与 ANM 相关的特征（例如激素替代疗法、妇科疾病和月经状况）以及肝功能、肾功能、肺功能、血细胞组成、乳腺癌和骨骼及心脏代谢健康。复制分析证实，较年轻的 ANM 与 HbA1c（每 1 年 ANM 降低 0.003mmol/mol；95%CI 0.001，0.006）、乳腺癌（调整后的比值比 0.96；95%CI 0.95，0.98）和骨矿物质密度（调整后的平均差异-0.05；95%CI-0.07，-0.03 为腰椎）相关。在男性中，有 30 种特征在错误发现率（P 值≤5.49×10）下与 GRS 相关，而使用 Bonferroni 阈值（P 值≤2.75×10）时有 11 种潜在影响。总之，我们的结果表明，较年轻的 ANM 可能对一系列与健康相关的特征产生因果影响。
