Dataset Information

Integrating genome-wide association and eQTLs studies identifies the genes associated with age at menarche and age at natural menopause.

ABSTRACT:

Objective

An 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.

Method

We 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.

Results

We 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.

Conclusion

The 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.

SUBMITTER: Wang G

PROVIDER: S-EPMC6576755 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Integrating genome-wide association and eQTLs studies identifies the genes associated with age at menarche and age at natural menopause.

Wang Gang G Lv Jian J Qiu Xiaoxin X An Yujun Y

PloS one 20190617 6

<h4>Objective</h4>An 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 ...[more]

PMID: 31206546

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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.

Dataset Information

Integrating genome-wide association and eQTLs studies identifies the genes associated with age at menarche and age at natural menopause.

Objective

Method

Results

Conclusion

Publications

Integrating genome-wide association and eQTLs studies identifies the genes associated with age at menarche and age at natural menopause.

Similar Datasets

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