Wei Zhong ¹ Wang Qihang ¹ Dingchuan Peng ² Yangyun Zou ³ Yulin Chen ³ Yingying Xia ³ Xin Zhang ³ Shu Mingming ² Chunlan Song ² Yiran Wang ² Yiyao Fu ⁴ Sishuo Wang ⁴ Yanmin Ma ⁵ Xiaomeng Bu ⁵ Yuexiu Liang ⁶ Yuzhen Chen ⁶ Wenpei Bai ⁷ Yanrong Chen ⁷ Chengyan Deng ⁸ Wanyu Zhang ⁸ ZHOU MING ² Lijuan Lv ⁹ Linyan Zhang ¹⁰ Sijia Lu ^3* Wei Shang ^1*

• ¹ Seventh Medical Center of PLA General Hospital, Beijing, China
• ² Sixth Medical Center of PLA General Hospital, Beijing, Beijing Municipality, China
• ³ Yikon Genomics Company, Ltd., Suzhou, Jiangsu Province, China
• ⁴ Chinese PLA Medical School, Beijing, China
• ⁵ Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, Beijing Municipality, China
• ⁶ Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangx, China
• ⁷ Beijing Shijitan Hospital, Capital Medical University, Beijing, Beijing Municipality, China
• ⁸ Peking Union Medical College Hospital (CAMS), Beijing, Beijing Municipality, China
• ⁹ Huanghua Development Zone Boai Hospital, Cangzhou, China
• ¹⁰ Maternal and Child Health Hospital of Zhuji, Zhuji, China

Objective: This study aims to evaluate the utility of polygenic risk scores (PRS) in women with early menopause (EM) and to investigate the clinical characteristics and risk factors associated with EM based on genetic risk.Genotyping data and clinical data from women with EM and women with normal age of menopause retrieved from UK Biobank were used for early menopause risk prediction model establishment. Subsequently, 99 women diagnosed with EM and 1027 control women underwent PGT-M were recruited for model validation from across eight hospitals in China. According to PRS percentiles, these participants were further classified into high risk and intermediate risk groups.Characteristics among women at different risk levels were compared, and risk factors with early menopause were also statistical analyzed.The proportion of women at high risk in EM and control groups;Characteristics with significant difference among women at different risk levels; risk factors associated with EM.The proportion of high-risk women in the EM group was significantly higher than that in control women underwent PGT-M (Group PGT-M) (OR = 3.78), and that in women with normal age menopause from UK Biobank (Group UKB) (OR = 5.11). Notably, the women with high risk of EM exhibited distinct characteristics compared to women with the intermediate-risk of EM, and identified several risk factors associated with EM.We established a PRS model to serves as a valuable instrument for EM risk prediction.The exploratory analysis revealed that women with high risk of EM exhibited a higher height, suggesting EM related genetic loci may also influence growth and development level. Several risk factors were found to be potentially associated with EM, such as excessive familial contentment, COVID-19 vaccination, staying up late, and the husband's engagement in smoking and alcohol abuse.