Department of Epidemiology and Health Statistics, School of Public Health, Medical College, the first affiliated hospital of Soochow University, Suzhou, China.
Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College, Soochow University, Suzhou, China.
J Clin Endocrinol Metab. 2021 Aug 18;106(9):2574-2591. doi: 10.1210/clinem/dgab377.
Age at natural menopause (ANM) is an important index for women's health. Either early or late ANM is associated with a series of adverse outcomes later in life. Despite being an inheritable trait, its genetic determinant has not yet been fully understood.
Aiming to better characterize the genetic architecture of ANM, we conducted genome-wide association study (GWAS) meta-analyses in European-specific as well as trans-ancestry samples by using GWAS summary statistics from the following 3 large studies: the Reproductive Genetics Consortium (ReproGen; N = 69 626), the UK Biobank cohort (UKBB; N = 111 593) and the BioBank Japan Project (BBJ; N = 43 861), followed by a series of bioinformatical assessments and functional annotations.
By integrating the summary statistics from the 3 GWAS of up to 225 200 participants, this largest meta-analysis identified 49 novel loci and 3 secondary signals that were associated with ANM at the genome-wide significance level (P < 5 × 10-8). No population specificity or heterogeneity was observed at most of the associated loci. Functional annotations prioritized 90 candidate genes at the newly identified loci. Among the 26 traits that were genetically correlated with ANM, hormone replacement therapy (HRT) exerted a causal relationship, implying a causal pattern by which HRT was determined by ANM.
Our findings improved our understanding of the etiology of female menopause, as well as shed light on potential new therapies for abnormal menopause.
自然绝经年龄（ANM）是女性健康的一个重要指标。过早或过晚的 ANM 都与生命后期的一系列不良后果有关。尽管它是一种可遗传的特征，但它的遗传决定因素尚未完全理解。
为了更好地描述 ANM 的遗传结构，我们通过使用以下 3 个大型研究的 GWAS 汇总统计数据，在欧洲特有的和跨血统样本中进行了全基因组关联研究（GWAS）荟萃分析：生殖遗传学联盟（ReproGen；N=69626）、英国生物库队列（UKBB；N=111593）和日本生物银行项目（BBJ；N=43861），随后进行了一系列生物信息学评估和功能注释。
通过整合来自 3 项 GWAS 的汇总统计数据，这些 GWAS 的样本量高达 225200 人，这项最大规模的荟萃分析确定了 49 个新的位点和 3 个与 ANM 相关的二级信号，达到全基因组显著水平（P<5×10-8）。在大多数相关的位点上，没有观察到种群特异性或异质性。功能注释优先考虑了新发现的位点上的 90 个候选基因。在与 ANM 遗传相关的 26 个特征中，激素替代疗法（HRT）发挥了因果关系，暗示了 HRT 由 ANM 决定的因果模式。
我们的研究结果提高了我们对女性绝经病因的理解，也为异常绝经的潜在新疗法提供了线索。
