PhD Program for Health Science and Industry, College of Health Care, China Medical University, Taichung, Taiwan.
Department of Health Services Administration, China Medical University, Taichung, Taiwan.
Hum Reprod. 2024 Jun 3;39(6):1336-1350. doi: 10.1093/humrep/deae060.
Are there associations of age at menarche (AAM) with health-related outcomes in East Asians?
AAM is associated with osteoporosis, Type 2 diabetes (T2D), glaucoma, and uterine fibroids, as demonstrated through observational studies, polygenic risk scores, genetic correlations, and Mendelian randomization (MR), with additional findings indicating a causal effect of BMI and T2D on earlier AAM.
Puberty timing is linked to adult disease risk, but research predominantly focuses on European populations, with limited studies in other groups.
STUDY DESIGN, SIZE, DURATION: We performed an AAM genome-wide association study (GWAS) with 57 890 Han Taiwanese females and examined the association between AAM and 154 disease outcomes using the Taiwanese database. Additionally, we examined genetic correlations between AAM and 113 diseases and 67 phenotypes using Japanese GWAS summary statistics.
PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed AAM GWAS and gene-based GWAS studies to obtain summary statistics and identify potential AAM-related genes. We applied phenotype, polygenic risk scores, and genetic correlation analyses of AAM to explore health-related outcomes, using multivariate regression and linkage disequilibrium score regression analyses. We also explored potential bidirectional causal relationships between AAM and related outcomes through univariable and multivariable MR analyses.
Fifteen lead single-nucleotide polymorphisms and 24 distinct genes were associated with AAM in Taiwan. AAM was genetically associated with later menarche and menopause, greater height, increased osteoporosis risk, but lower BMI, and reduced risks of T2D, glaucoma, and uterine fibroids in East Asians. Bidirectional MR analyses indicated that higher BMI/T2D causally leads to earlier AAM.
LIMITATIONS, REASONS FOR CAUTION: Our findings were specific to Han Taiwanese individuals, with genetic correlation analyses conducted in East Asians. Further research in other ethnic groups is necessary.
Our study provides insights into the genetic architecture of AAM and its health-related outcomes in East Asians, highlighting causal links between BMI/T2D and earlier AAM, which may suggest potential prevention strategies for early puberty.
STUDY FUNDING/COMPETING INTEREST(S): The work was supported by China Medical University, Taiwan (CMU110-S-17, CMU110-S-24, CMU110-MF-49, CMU111-SR-158, CMU111-MF-105, CMU111-MF-21, CMU111-S-35, CMU112-SR-30, and CMU112-MF-101), the China Medical University Hospital, Taiwan (DMR-111-062, DMR-111-153, DMR-112-042, DMR-113-038, and DMR-113-103), and the Ministry of Science and Technology, Taiwan (MOST 111-2314-B-039-063-MY3, MOST 111-2314-B-039-064-MY3, MOST 111-2410-H-039-002-MY3, and NSTC 112-2813-C-039-036-B). The funders had no influence on the data collection, analyses, or conclusions of the study. No conflict of interests to declare.
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初潮年龄（AAM）与东亚人群健康相关结局之间是否存在关联？
通过观察性研究、多基因风险评分、遗传相关性和孟德尔随机化（MR）研究，初潮年龄与骨质疏松症、2 型糖尿病（T2D）、青光眼和子宫肌瘤相关，此外还有研究表明 BMI 和 T2D 对初潮年龄更早存在因果效应。
青春期时间与成年疾病风险相关，但研究主要集中在欧洲人群，其他人群的研究有限。
研究设计、规模和持续时间：我们对 57890 名台湾汉族女性进行了初潮年龄全基因组关联研究（GWAS），并使用台湾数据库检查了初潮年龄与 154 种疾病结局之间的关联。此外，我们使用日本 GWAS 汇总统计数据，检查了初潮年龄与 113 种疾病和 67 种表型之间的遗传相关性。
参与者/材料、设置、方法：我们进行了初潮年龄 GWAS 和基于基因的 GWAS 研究，以获得汇总统计数据并确定潜在的与初潮年龄相关的基因。我们使用多元回归和连锁不平衡评分回归分析，将初潮年龄的表型、多基因风险评分和遗传相关性分析应用于探索健康相关结局。我们还通过单变量和多变量 MR 分析探索了初潮年龄与相关结局之间潜在的双向因果关系。
在台湾，有 15 个单核苷酸多态性和 24 个不同的基因与初潮年龄相关。初潮年龄与东亚人群的晚初潮和晚绝经、更高的身高、更高的骨质疏松症风险相关，但与 BMI 较低和 T2D、青光眼和子宫肌瘤风险降低相关。双向 MR 分析表明，较高的 BMI/T2D 会导致初潮年龄更早。
局限性、谨慎的原因：我们的发现仅限于台湾汉族人群，遗传相关性分析在东亚人群中进行。需要在其他种族群体中进行进一步的研究。
本研究提供了东亚人群初潮年龄及其与健康相关结局的遗传结构的见解，强调了 BMI/T2D 与更早初潮之间的因果关系，这可能提示了预防早期青春期的潜在策略。
研究资金/利益冲突：这项工作得到了中国医药大学（CMU）、台湾（CMU110-S-17、CMU110-S-24、CMU110-MF-49、CMU111-SR-158、CMU111-MF-105、CMU111-MF-21、CMU111-S-35、CMU112-SR-30 和 CMU112-MF-101）、中国医药大学附属医院（DMR-111-062、DMR-111-153、DMR-112-042、DMR-113-038 和 DMR-113-103）和台湾科技部（MOST 111-2314-B-039-063-MY3、MOST 111-2314-B-039-064-MY3、MOST 111-2314-B-039-065-MY3、MOST 111-2410-H-039-002-MY3 和 NSTC 112-2813-C-039-036-B）的支持。资助者对研究的数据收集、分析或结论没有影响。没有利益冲突需要声明。
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