Correction to: Age at menarche and age at natural menopause in East Asian women: a genome-wide association study.
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ABSTRACT:
SUBMITTER: Shi J
PROVIDER: S-EPMC5832656 | biostudies-literature | 2018 Feb
REPOSITORIES: biostudies-literature
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Correction to: Age at menarche and age at natural menopause in East Asian women: a genome-wide association study.
Shi Jiajun J Zhang Ben B Choi Ji-Yeob JY Gao Yu-Tang YT Li Huaixing H Lu Wei W Long Jirong J Kang Daehee D Xiang Yong-Bing YB Wen Wanqing W Park Sue K SK Ye Xingwang X Noh Dong-Young DY Zheng Ying Y Wang Yiqin Y Chung Seokang S Lin Xu X Cai Qiuyin Q Shu Xiao-Ou XO
GeroScience 20180201 1
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Project description: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.
| S-EPMC5266214 | biostudies-literature
Project description:Age at menarche and age at natural menopause are associated with causes of substantial morbidity and mortality such as breast cancer and cardiovascular disease. We conducted a joint analysis of two genome-wide association studies of these two traits in a total of 17,438 women from the Nurses' Health Study (NHS, N = 2,287) and the Women's Genome Health Study (WGHS, N = 15,151). For age at menarche, we identified ten associated SNPs (P = 1 × 10(-7)-3 × 10(-13)) clustered at 6q21 (in or near the gene LIN28B) and 9q31.2 (in an intergenic region). For age at natural menopause, we identified 13 associated SNPs (P = 1 × 10(-7)-1 × 10(-21)) clustered at 20p12.3 (in the gene MCM8), 19q13.42 (in or near the gene BRSK1), 5q35.2 (in or near genes UIMC1 and HK3) and 6p24.2 (in the gene SYCP2L). These newly identified loci might expand understanding of the biological pathways regulating these two traits.
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Project description:ObjectiveAn early onset of menarche and, later, menopause are well-established risk factors for the development of breast cancer and endometrial cancer. Although the largest GWASs have identified 389 independent signals for age at menarche (AAM) and 44 regions for age at menopause (ANM), GWAS can only identify the associations between variants and traits. The aim of this study was to identify genes whose expression levels were associated with AAM or ANM due to pleiotropy or causality by integrating GWAS data with genome-wide expression quantitative trait loci (eQTLs) data. We also aimed to identify the pleiotropic genes that influenced both phenotypes.MethodWe employed GWAS data of AAM and ANM and genome-wide eQTL data from whole blood. The summary data-based Mendelian randomization method was used to prioritize the associated genes for further study. The colocalization analysis was used to identify the pleiotropic genes associated with both phenotypes.ResultsWe identified 31 genes whose expression was associated with AAM and 24 genes whose expression was associated with ANM due to pleiotropy or causality. Two pleiotropic genes were identified to be associated with both phenotypes.ConclusionThe results point out the most possible genes which were responsible for the association. Our study prioritizes the associated genes for further functional mechanistic study of AAM and ANM and illustrates the benefit of integrating different omics data into the study of complex traits.
| S-EPMC6576755 | biostudies-literature
Project description:Recent genome-wide association (GWA) studies have identified several novel genetic loci associated with age at menarche and age at natural menopause. However, the stringent significance threshold used in GWA studies potentially led to false negatives and true associations may have been overlooked. Incorporating biologically relevant information, we examined whether common genetic polymorphisms in candidate genes of nine groups of biologically plausible pathways and related phenotypes are associated with age at menarche and age at natural menopause. A total of 18,862 genotyped and imputed single nucleotide polymorphisms (SNPs) in 278 genes were assessed for their associations with these two traits among a total of 24,341 women from the Nurses' Health Study (NHS, N = 2,287) and the Women's Genome Health Study (WGHS, N = 22,054). Linear regression was used to assess the marginal association of each SNP with each phenotype. We adjusted for multiple testing within each gene to identify statistically significant SNP associations at the gene level. To evaluate the overall evidence for an excess of statistically significant gene associations over the proportion expected by chance, we applied a one-sample test of proportion to each group of candidate genes. The steroid-hormone metabolism and biosynthesis pathway was found significantly associated with both age at menarche and age at natural menopause (P = 0.040 and 0.011, respectively). In addition, the group of genes associated with precocious or delayed puberty was found significantly associated with age at menarche (P = 0.013), and the group of genes involved in premature ovarian failure with age at menopause (P = 0.025).
| S-EPMC2967297 | biostudies-literature
Project description:OBJECTIVE:Menarche and menopause mark the lower and upper limits of the female reproductive period. The timing of these events influences women's health in later life. The onsets of menarche and menopause have a strong genetic basis. We tested two genes, TNFRSF11A (RANK) and TNFSF11 (RANKL), for their association with age at menarche (AM) and age at natural menopause (ANM). METHODS:Nineteen single nucleotide polymorphisms (SNPs) of TNFRSF11A and 12 SNPs of TNFSF11 were genotyped in a random sample of 306 unrelated white women. This sample was analyzed for the association of the SNPs and common haplotypes with AM. Then, a subsample of 211 women with natural menopause was analyzed for the association of both genes with ANM. Smoking, alcohol intake, and duration of lactation were applied as covariates in the association analyses. RESULTS:Three polymorphisms of TNFSF11 were associated with AM: rs2200287 (P = 0.005), rs9525641 (P = 0.039), and rs1054016 (P = 0.047). Two SNPs of this gene, rs346578 and rs9525641, showed an association with ANM (P = 0.007 and P = 0.011, respectively). Two SNPs of TNFRSF11A were associated with AM (rs3826620; P = 0.022) and ANM (rs8086340; P = 0.015). Multiple SNP-SNP and SNP-environment interaction effects on AM and ANM were detected for both genes. One polymorphism of TNFRSF11A, rs4436867, was not directly associated with either trait but indicated significant interactions with four TNFSF11 polymorphisms on ANM. Two other TNFRSF11A polymorphisms, rs4941125 and rs7235803, showed interaction effects with several TNFSF11 polymorphisms on AM. Both genes manifested significant interaction with the duration of breast-feeding in their effect on ANM. CONCLUSIONS:The TNFRSF11A and TNFSF11 genes are associated with the onset of AM and ANM in white women.
| S-EPMC2939156 | biostudies-literature
Project description:Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with breast cancer risk. Some of these loci have unknown functional significance and may mediate the effects of hormonal exposures on breast cancer risk. We examined relationships between breast cancer susceptibility variants and menstrual/reproductive factors using data from two population-based studies.The first analysis was based on a sample of 1328 women age 20-74 who participated as controls in a case-control study of breast cancer conducted in three U.S. states. We evaluated the associations between age at menarche, age at natural menopause and the reproductive lifespan with 13 previously identified breast cancer variants. Associations were also examined with a genetic score created as the sum of at-risk alleles across the 13 variants. For validation, significant results were evaluated in a second dataset comprised 1353 women age 43-86 recruited as part of a cohort study in Wisconsin.Neither the genetic score nor any of the 13 variants considered individually were associated with age at menarche or reproductive lifespan. Two SNPs were associated with age at natural menopause; every increase in the minor allele (A) of rs17468277 (CASP8) was associated with a 1.12 year decrease in menopause age (p=0.02). The minor allele (G) of rs10941679 (5p12) was associated with a 1.01 year increase in age at natural menopause (p=0.01). The results were not replicated in the validation cohort (B=-0.61, p=0.14 and B=-0.01, p=.0.98, respectively).The evaluated variants and reproductive experiences may work through separate pathways to influence breast cancer risk.
| S-EPMC4023814 | biostudies-literature
Project description:STUDY QUESTION:Is age at menarche associated with age at menopause or with duration of the reproductive period (interval between menarche and menopause)? SUMMARY ANSWER:The association of age at menarche with age at menopause was weak and non-linear, and the duration of the reproductive period decreased by increasing age at menarche. WHAT IS KNOWN ALREADY:It remains uncertain whether age at menarche is associated with age at menopause. Some studies report that women with early menarche also have early menopause. Other studies report that women with early menarche have late menopause, or they report no association. The duration of the reproductive period may be an indicator of the cumulative endogenous exposure to estrogens and progestogens during life course and is associated with risk of breast cancer and endometrial cancer. STUDY DESIGN, SIZE, DURATION:A retrospective cohort study of 336 788 women, aged 48-71 years, in the BreastScreen Norway during the years 2006-2014 was performed. PARTICIPANTS/MATERIALS, SETTING, METHODS:Information about age at menarche and menopausal status was obtained by self-administered questionnaires. We used time to event approaches to estimate the associations. MAIN RESULTS AND THE ROLE OF CHANCE:Median age at menopause was 51 years in most menarche groups. Women with menarche at age 16 years or age ? 17 years had menopause 1 year later [median: 52 years, interquartile range (IQR): 49-54 years] than women with menarche at age 13 years (median: 51 years, IQR: 49-54 years, reference) (crude hazard ratio (HR) = 0.95; 95% CI: 0.93-0.97 and 0.95; 95% CI: 0.92-0.99, Pnon-linearity < 0.001). The reproductive period decreased with increasing age at menarche (Pnon-linearity < 0.001), and women with menarche at age ? 9 years had 9 years longer median reproductive period than women with menarche at age ? 17 years (median: 43 versus 34 years). Adjustment for year of birth did not change the HR estimates notably. LARGE SCALE DATA:Not applicable. LIMITATIONS, REASONS FOR CAUTION:Information about age at menarche and age at menopause was based on self-reports. Particularly for age at menarche, the long time interval between the event and data collection may have caused imprecise reporting. WIDER IMPLICATIONS OF THE FINDINGS:Our study suggests that age at menarche is a strong indicator for the duration of women's reproductive period. Our findings should encourage studies of the independent role of duration of the reproductive period on the risk of breast cancer and endometrial cancer, since these cancers have been associated with exposure to estrogens and progestogens. STUDY FUNDING/COMPETING INTEREST(S):The present study was funded by the Norwegian Cancer Society [Grant number 6863294-2015]. The authors declare no conflicts of interest.
| S-EPMC5972645 | biostudies-literature
Project description:African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2850 women (Stage 2). First, while no SNP passed the pre-specified P < 5 × 10(-8) threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Secondly, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60%) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women.
| S-EPMC3723312 | biostudies-literature
Project description:BackgroundHormonal reproductive factors have been suggested to play an important role in the etiology of rheumatoid arthritis (RA), an autoimmune inflammatory disorder affecting primarily women. We conducted a two-sample Mendelian randomization (MR) study examining three relevant exposures, age at menarche (AAM), age at natural menopause (ANM), and age at first birth (AFB) with the risk of RA.MethodsWe collected summary statistics from the hitherto largest GWAS conducted in AAM (N = 329,345), ANM (N = 69,360), AFB (N = 251,151), and RA (Ncase = 14,361, Ncontrol = 43,923), all of European ancestry. We constructed strong instruments using hundreds of exposure-associated genetic variants and estimated causal relationship through different MR approaches including an inverse-variance weighted method, an MR-Egger regression and a weighted median method. We conducted a multivariable MR to control for pleiotropic effect acting in particular through obesity and socioeconomic status. We also performed important sensitivity analyses to verify model assumptions.ResultsWe did not find any evidence in support for a causal association between genetically predicted reproductive factors and risk of RA (ORper-SD increment in AAM = 1.06 [0.98-1.15]; ORper-SD increment in ANM = 1.05 [0.98-1.11], OR per-SD increment in AFB = 0.85 [0.65-1.10]). Results remained consistent after removing palindromic SNPs (ORper-SD increment in AAM = 1.06 [0.97-1.15], ORper-SD increment in ANM = 1.05 [0.98-1.13], ORper-SD increment in AFB = 0.81 [0.61-1.07]) or excluding SNPs associated with potential confounding traits (ORper-SD increment in AAM = 1.03 [0.94-1.12], ORper-SD increment in ANM = 1.04 [0.95-1.14]). No outlying instrument was identified through the leave-one-out analysis.ConclusionsOur MR study does not convincingly support a casual effect of reproductive factors, as reflected by age at menarche, age at menopause, and age at first birth, on the development of RA. Despite the largely augmented set of instruments we used, these instruments only explained a modest proportion of phenotypic variance of exposures. Our knowledge regarding this topic is still insufficient and future studies with larger sample size should be designed to replicate or dispute our findings.
| S-EPMC8034136 | biostudies-literature
Project description:OBJECTIVE:To identify novel susceptibility genes for age at natural menopause (ANM). METHODS:Using transcription data generated in tissues from normal hypothalami (n = 73) and ovaries (n = 68) and high-density genotyping data provided by the Genotype-Tissue Expression (GTEx) database, we built 16 164 genetic models to predict gene expression across the transcriptome in these tissues. We used these models and summary statistics data from genome-wide association studies (GWAS) of ANM generated in 69 360 women of European ancestry to identify genes with their predicted expression related to ANM. RESULTS:We found the predicted expression of 34 genes to be significantly associated with ANM at a Bonferroni-corrected threshold of P < 3.09 ×10-6. These include 4 genes located more than 1 Mb away from any previously GWAS-identified ANM-associated variants, 24 genes that reside in known GWAS-identified loci but have not been previously implicated, and 6 genes previously implicated as ANM-associated genes. CONCLUSION:Results from this transcriptome-wide association study, which integrated Expression quantitative trait loci (eQTL) data with summary statistics of GWAS of ANM, improves our understanding of the genetics and biology of female reproductive aging.
| S-EPMC6421625 | biostudies-literature