Joint Genome-Wide Association Analyses Identified 49 Novel Loci For Age at Natural Menopause

• Published in: The journal of clinical endocrinology and metabolism 2021-09, Vol.106 (9), p.2574-2591
• Main Authors: Zhang, Lei, Wei, Xin-Tong, Niu, Jun-Jie, Lin, Zi-Xuan, Xu, Qian, Ni, Jing-Jing, Zhang, Wan-Lin, Han, Bai-Xue, Yan, Shan-Shan, Feng, Gui-Juan, Zhang, Hong, Yang, Xiao-Lin, Zhang, Zi-Jia, Hai, Rong, Ren, Hai-Gang, Zhang, Feng, Pei, Yu-Fang
• Format: Article
• Language: English
• Subjects: Age Factors; Biobanks; Development and progression; Estrogen Replacement Therapy; Female; Genetic Loci; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Health aspects; Hormone replacement therapy; Hormone therapy; Humans; Linkage Disequilibrium; Menopause; Menopause - ethnology; Menopause - genetics; Polymorphism, Single Nucleotide; Signal Transduction; Statistical analysis; Women
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/clinem/dgab377

Abstract Background 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. Methods 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. Results 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. Conclusion Our findings improved our understanding of the etiology of female menopause, as well as shed light on potential new therapies for abnormal menopause.