Age at menarche and age at natural menopause in East Asian women: a genome-wide association study

Abstract

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 AGE (2016) ) 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.

Epidemiology of ovarian cancer: a review

“…A report from the Nurses’ Health Study (NHS) and NHS II found that age at natural menopause was associated with an increased risk of endometrioid tumors (RR=1.13, 95% CI: 1.04–1.22), but not serous invasive or mucinous tumors 29 . Studies conducted among populations with different distributions of age at menarche 99,111,118 and age at menopause 119 indicate differences in the genetic heritability of these factors across ancestral groups 120-122 . Regardless, the available evidence suggests that any magnitude of effect is likely small.…”

Age at menarche and epithelial ovarian cancer risk: A meta‐analysis and Mendelian randomization study

“…Figure B,C show the overview of the MR study. We searched for AAM GWAS performed in Chinese population and found four articles . One of them was excluded because of incomplete data .…”

“…Finally, a total of 25 SNPs were selected as instrumental variables in MR analyses for the Chinese population. We extracted the estimation of their associations with AAM from the published articles (Table ) …”

“…We searched for AAM GWAS performed in Chinese population and found four articles. [16][17][18][19] One of them was excluded because of incomplete data. 18 In the remaining three articles, we found 30 nominally…”

“…13 Robust genetic variants (eg, single nucleotide polymorphisms [SNPs]) have been identified by AAM genome-wide association studies (GWAS) in both European and Asian populations. [14][15][16][17][18][19][20][21][22][23][24] The genes identified by AAM GWAS were reported to be related to the Hypothalamus-Pituitary-Gonadal (HPG) axis, which acts on the secretion and regulation of hormones. 25 Thus, it is possible to use the AAM-associated genetic variants as instrumental variables to examine the effect of AAM in ovarian cancer etiology.…”