Age at menarche and age at natural menopause in East Asian women: a genome-wide association study
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Age at menarche (AM) and age at natural menopause (ANM) are complex traits with a high heritability. Abnormal timing of menarche or menopause is associated with a reduced span of fertility and risk for several age-related diseases including breast, endometrial and ovarian cancer, cardiovascular disease, and osteoporosis. To identify novel genetic loci for AM or ANM in East Asian women and to replicate previously identified loci primarily in women of European ancestry by genome-wide association studies (GWASs), we conducted a two-stage GWAS. Stage I aimed to discover promising novel AM and ANM loci using GWAS data of 8073 women from Shanghai, China. The Stage II replication study used the data from another Chinese GWAS (n = 1230 for AM and n = 1458 for ANM), a Korean GWAS (n = 4215 for AM and n = 1739 for ANM), and de novo genotyping of 2877 additional Chinese women. Previous GWAS-identified loci for AM and ANM were also evaluated. We identified two suggestive menarcheal age loci tagged by rs79195475 at 10q21.3 (beta = −0.118 years, P = 3.4 × 10−6) and rs1023935 at 4p15.1 (beta = −0.145 years, P = 4.9 × 10−6) and one menopausal age locus tagged by rs3818134 at 22q12.2 (beta = −0.276 years, P = 8.8 × 10−6). These suggestive loci warrant a further validation in independent populations. Although limited by low statistical power, we replicated 19 of the 98 menarche loci and 5 of the 20 menopause loci previously identified in women of European ancestry in East Asian women, suggesting a shared genetic architecture for these two traits across populations.
KeywordsMenarche Menopause Genome-wide association Single nucleotide polymorphism
This study was supported, in part, by grants from the US National Institutes of Health (grants R01CA124558, R01CA090899, R01CA070867; R01CA064277 and R01CA092585, R01CA118229, R01CA122756, R01CA137013, R01CA148667), Ingram professorship funds, and Allen Foundation funds at Vanderbilt Epidemiology Center and Division of Epidemiology; SeBCS was supported by the Basic Research Laboratory (BRL) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2011-0001564). NHAPC was supported by research grants including the National Basic Research Program of China (2012CB524905 and 2011CB504002), Knowledge Innovation Program (KSCX2-EW-R-10), the National Natural Science Foundation of China (81321062, 81170734, 81471013, 81200581, 81202272), and the Knowledge Innovation Program of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (2013KIP107 and 2014KIP107). The authors wish to thank Jing He, Hui Cai, Gong Yang, Jie Wu, and Regina Courtney for their contributions to this project, as well as Nan Kennedy for editing and preparing the manuscript. We also thank the research staff of the Shanghai Breast Cancer Genetics Study, Shanghai Endometrial Cancer Genetics Study, the Shanghai Diabetes Genetics Study, the Shanghai Colorectal Cancer Study, the Nutrition and Health of Aging Population in China study, and the Seoul Breast Cancer Study. In addition, sample preparation and GWAS genotyping assays at Vanderbilt were conducted at the Survey and Biospecimen Shared Resources and the Vanderbilt Microarray Shared Resource, which are supported in part by the Vanderbilt-Ingram Cancer Center (P30CA068485).
Compliance with ethical standards
Conflict of interest
The authors have no conflict of interest to declare. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or any other funding agency.
Details of ethics approval
Written informed consent was obtained from all participants, and the study protocols were approved by the institutional review boards of all institutions involved in the study.
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