Menarche—a journey into womanhood: age at menarche and health-related outcomes in East Asians
Authors: Chiou Jian-Shiun , Lin Ying-Ju , Chang Cherry Yin-Yi , Liang Wen-Miin , Liu Ting-Yuan , Yang Jai-Sing , Chou Chen-Hsing , Lu Hsing-Fang , Chiu Mu-Lin , Lin Ting-Hsu , Liao Chiu-Chu , Huang Shao-Mei , Chou I-Ching , Li Te-Mao , Huang Peng-Yan , Chien Tzu-Shun , Chen Hou-Ren , Tsai Fuu-Jen 
Published: March 2024

Abstract

STUDY QUESTION
Are there associations of age at menarche (AAM) with health-related outcomes in East Asians?

SUMMARY ANSWER
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.

WHAT IS KNOWN ALREADY
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.

MAIN RESULTS AND THE ROLE OF CHANCE
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.

WIDER IMPLICATIONS OF THE FINDINGS
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.

TRIAL REGISTRATION NUMBER
N/A.