考虑到初潮年龄持续下降的趋势,初潮时间与青年成人身体质量指数之间的因果关系。

Causal relationship between the timing of menarche and young adult body mass index with consideration to a trend of consistently decreasing age at menarche.

机构信息

Genome and Health Big Data Laboratory, Department of Public Health, Graduate School of Public Health, Seoul National University, Seoul, Korea.

Department of Preventive Medicine, Korea University College of Medicine, Seoul, Korea.

出版信息

PLoS One. 2021 Feb 26;16(2):e0247757. doi: 10.1371/journal.pone.0247757. eCollection 2021.

Abstract

Younger age at menarche (AAM) is associated with higher body mass index (BMI) for young women. Considering that continuous trends in decreasing AAM and increasing BMI are found in many countries, we attempted to assess whether the observed negative association between AAM and young adult BMI is causal. We included 4,093 women from the Korean Genome and Epidemiology Study (KoGES) and Healthy twin Study (HTS) with relevant epidemiologic data and genome-wide marker information. To mitigate the remarkable differences in AAM across generations, we converted the AAM to a generation-standardized AAM (gsAAM). To test causality, we applied the Mendelian randomization (MR) approach, using a genetic risk score (GRS) based on 14 AAM-associated single nucleotide polymorphisms (SNPs). We constructed MR models adjusting for education level and validated the results using the inverse-variance weighted (IVW), weighted median (WM), MR-pleiotropy residual sum and outliers test (MR-PRESSO), and MR-Egger regression methods. We found a null association using observed AAM and BMI level (conventional regression; -0.05 [95% CIs -0.10-0.00] per 1-year higher AAM). This null association was replicated when gsAAM was applied instead of AAM. Using the two-stage least squares (2SLS) approach employing a univariate GRS, the association was also negated for both AAM and gsAAM, regardless of model specifications. All the MR diagnostics suggested statistically insignificant associations, but weakly negative trends, without evidence of confounding from pleiotropy. We did not observe a causal association between AAM and young adult BMI whether we considered the birth cohort effect or not. Our study alone does not exclude the possibility of existing a weak negative association, considering the modest power of our study design.

摘要

初潮年龄(AAM)较年轻与年轻女性的体重指数(BMI)较高有关。考虑到许多国家的 AAM 持续呈下降趋势,BMI 呈上升趋势,我们试图评估 AAM 与年轻成人 BMI 之间观察到的负相关是否具有因果关系。我们纳入了韩国基因组与流行病学研究(KoGES)和健康双胞胎研究(HTS)中的 4093 名女性,这些女性具有相关的流行病学数据和全基因组标记信息。为了减轻 AAM 在各世代之间的显著差异,我们将 AAM 转化为世代标准化的 AAM(gsAAM)。为了检验因果关系,我们应用了基于 14 个与 AAM 相关的单核苷酸多态性(SNP)的遗传风险评分(GRS)的孟德尔随机化(MR)方法。我们构建了调整教育水平的 MR 模型,并使用逆方差加权(IVW)、加权中位数(WM)、MR 多效性残差和异常值检验(MR-PRESSO)以及 MR-Egger 回归方法验证了结果。我们发现使用观察到的 AAM 和 BMI 水平进行的常规回归分析得到了零关联(-0.05[95%CI-0.10-0.00],每 1 年 AAM 升高 1 岁)。当应用 gsAAM 替代 AAM 时,这种零关联得到了复制。使用单变量 GRS 的两阶段最小二乘法(2SLS)方法,无论模型规格如何,AAM 和 gsAAM 的关联均被否定。所有的 MR 诊断均表明关联无统计学意义,但存在微弱的负向趋势,没有证据表明多效性造成混杂。无论我们是否考虑出生队列效应,都没有观察到 AAM 与年轻成人 BMI 之间存在因果关系。考虑到我们研究设计的适度效力,我们的研究单独并不能排除存在微弱负相关的可能性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ec/7909625/91f77c67699d/pone.0247757.g001.jpg

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