Age at menarche has been associated with various health outcomes. We aimed to identify potential causal effects of age at menarche on health-related traits in a hypothesis-free manner. We conducted a Mendelian randomization phenome-wide association study (MR-pheWAS) of age at menarche with 17,893 health-related traits in UK Biobank (n = 181,318) using PHESANT. The exposure of interest was the genetic risk score for age at menarche. We conducted a second MR-pheWAS after excluding SNPs associated with BMI from the genetic risk score, to examine whether results might be due to the genetic overlap between age at menarche and BMI. We followed up a subset of health-related traits to investigate MR assumptions and seek replication in independent study populations. Of the 17,893 tests performed in our MR-pheWAS, we identified 619 associations with the genetic risk score for age at menarche at a 5% false discovery rate threshold, of which 295 were below a Bonferroni-corrected P value threshold. These included potential effects of younger age at menarche on lower lung function, higher heel bone-mineral density, greater burden of psychosocial/mental health problems, younger age at first birth, higher risk of childhood sexual abuse, poorer cardiometabolic health, and lower physical activity. After exclusion of variants associated with BMI, the genetic risk score for age at menarche was related to 37 traits at a 5% false discovery rate, of which 29 were below a Bonferroni-corrected P value threshold. We attempted to replicate findings for bone-mineral density, lung function, neuroticism, and childhood sexual abuse using 5 independent cohorts/consortia. While estimates for lung function, higher bone-mineral density, neuroticism, and childhood sexual abuse in replication cohorts were consistent with UK Biobank estimates, confidence intervals were wide and often included the null. The genetic risk score for age at menarche was related to a broad range of health-related traits. Follow-up analyses indicated imprecise evidence of an effect of younger age at menarche on greater bone-mineral density, lower lung function, higher neuroticism score, and greater risk of childhood sexual abuse in the smaller replication samples available; hence, these findings need further exploration when larger independent samples become available.

中文翻译：

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确定初潮年龄的潜在因果影响：孟德尔随机化表组范围关联研究。

初潮年龄与各种健康结果相关。我们的目的是以无假设的方式确定初潮年龄对健康相关特征的潜在因果影响。我们使用 PHESANT 对英国生物库 (n = 181,318) 中的 17,893 个健康相关特征进行了孟德尔随机化全表型关联研究 (MR-pheWAS)。感兴趣的暴露是初潮年龄的遗传风险评分。在从遗传风险评分中排除与 BMI 相关的 SNP 后，我们进行了第二次 MR-pheWAS，以检查结果是否可能是由于初潮年龄和 BMI 之间的遗传重叠所致。我们跟踪了一部分与健康相关的特征，以调查 MR 假设并寻求在独立研究人群中的复制。在我们的 MR-pheWAS 中进行的 17,893 项测试中，我们以 5% 的错误发现率阈值确定了 619 项与初潮年龄遗传风险评分的关联，其中 295 项低于 Bonferroni 校正的 P 值阈值。这些包括初潮年龄较小对肺功能较低、脚跟骨矿物质密度较高、心理社会/心理健康问题负担较大、第一胎出生年龄较小、儿童性虐待风险较高、心脏代谢健康较差以及身体素质较低等潜在影响。活动。排除与 BMI 相关的变异后，初潮年龄的遗传风险评分与 37 个性状相关，错误发现率为 5%，其中 29 个性状低于 Bonferroni 校正的 P 值阈值。我们尝试使用 5 个独立队列/联盟来复制骨矿物质密度、肺功能、神经质和儿童性虐待的研究结果。虽然复制队列中对肺功能、较高骨矿物质密度、神经质和儿童性虐待的估计与英国生物银行的估计一致，但置信区间很宽，并且通常包括零值。初潮年龄的遗传风险评分与广泛的健康相关特征有关。后续分析表明，在较小的复制样本中，初潮年龄较小对骨矿物质密度较高、肺功能较低、神经质评分较高以及儿童期性虐待风险较高的影响并不精确；因此，当有更大的独立样本可用时，这些发现需要进一步探索。