Dataset Information

Age at menarche and lung function: a Mendelian randomization study.

ABSTRACT: A trend towards earlier menarche in women has been associated with childhood factors (e.g. obesity) and hypothesised environmental exposures (e.g. endocrine disruptors present in household products). Observational evidence has shown detrimental effects of early menarche on various health outcomes including adult lung function, but these might represent spurious associations due to confounding. To address this we used Mendelian randomization where genetic variants are used as proxies for age at menarche, since genetic associations are not affected by classical confounding. We estimated the effects of age at menarche on forced vital capacity (FVC), a proxy for restrictive lung impairment, and ratio of forced expiratory volume in one second to FVC (FEV1/FVC), a measure of airway obstruction, in both adulthood and adolescence. We derived SNP-age at menarche association estimates for 122 variants from a published genome-wide meta-analysis (N = 182,416), with SNP-lung function estimates obtained by meta-analysing three studies of adult women (N = 46,944) and two of adolescent girls (N = 3025). We investigated the impact of departures from the assumption of no pleiotropy through sensitivity analyses. In adult women, in line with previous evidence, we found an effect on restrictive lung impairment with a 24.8 mL increase in FVC per year increase in age at menarche (95% CI 1.8-47.9; p = 0.035); evidence was stronger after excluding potential pleiotropic variants (43.6 mL; 17.2-69.9; p = 0.001). In adolescent girls we found an opposite effect (-56.5 mL; -108.3 to -4.7; p = 0.033), suggesting that the detrimental effect in adulthood may be preceded by a short-term post-pubertal benefit. Our secondary analyses showing results in the same direction in men and boys, in whom age at menarche SNPs have also shown association with sexual development, suggest a role for pubertal timing in general rather than menarche specifically. We found no effect on airway obstruction (FEV1/FVC).

SUBMITTER: Gill D

PROVIDER: S-EPMC5591357 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Age at menarche and lung function: a Mendelian randomization study.

Gill Dipender D Sheehan Nuala A NA Wielscher Matthias M Shrine Nick N Amaral Andre F S AFS Thompson John R JR Granell Raquel R Leynaert Bénédicte B Real Francisco Gómez FG Hall Ian P IP Tobin Martin D MD Auvinen Juha J Ring Susan M SM Jarvelin Marjo-Riitta MR Wain Louise V LV Henderson John J Jarvis Deborah D Minelli Cosetta C

European journal of epidemiology 20170617 8

A trend towards earlier menarche in women has been associated with childhood factors (e.g. obesity) and hypothesised environmental exposures (e.g. endocrine disruptors present in household products). Observational evidence has shown detrimental effects of early menarche on various health outcomes including adult lung function, but these might represent spurious associations due to confounding. To address this we used Mendelian randomization where genetic variants are used as proxies for age at m ...[more]

PMID: 28624884

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Project description:Background: Although earlier menarche age has been associated with ischemic heart disease in previous observational studies, the relationship's causation has not been shown. Through two-sample Mendelian randomization (MR), we were able to define the causal connection. Methods: We performed Mendelian Randomization (MR) analysis to explore the associations between genetically predicted AAM and IHD. Summary-level databases for exposure and outcome were selected from the MR-Base database (https://gwas.mrcieu.ac.uk/). Single-nucleotide polymorphisms (SNPs) connected to AAM at genome-wide significance level (p < 5 × 10-8) were considered as instrumental variables (IVs). We used four methods to pool MR estimates, including fixed-effects inverse variance weighting (fe-IVW), multiplicative random-effects inverse variance weighting (mre-IVW), weighted median (WM), and MR-Egger regression methods. Sensitivity analyses were performed to evaluate the robustness of the results. PhenoScanner searches and Multivariable Mendelian randomization (MVMR) analysis was used for assessing confounders. Results: 117 SNPs significantly correlated with AAM were screened as instruments, the results of three main methods showed that genetically earlier AAM may have a causal effect on the higher risk of IHD (fe-IVW: OR = 0.80, 95% CI: 0.72-0.88, p < 0.001; mre-IVW: OR = 0.80, 95% CI: 0.70-0.90, p < 0.001; WE: OR = 0.79, 95% CI: 0.66-0.93, p = 0.006). These results were consistent across sensitivity analyses. MR analysis revealed that there was still a relationship between AAM and IHD even when pleiotropic SNPs of confounders were removed employing PhenoScanner searches. In MVMR, the significant association remained after adjusting for biological sex, but it was attenuated with adjustment of body mass index including childhood and adult. Conclusion: Our MR analysis revealed a substantial genetically determined confounder-mediated relationship between an increase in genetically predicted AAM and a lower risk of IHD. By addressing the intervention of body mass index, the risk of IHD may be lowered.

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.

Project description:BackgroundAge at menarche has been associated with various health outcomes. We aimed to identify potential causal effects of age at menarche on health-related traits in a hypothesis-free manner.MethodsWe conducted a Mendelian randomization phenome-wide association study (MR-pheWAS) of age at menarche with 17,893 health-related traits in UK Biobank (n = 181,318) using PHESANT. The exposure of interest was the genetic risk score for age at menarche. We conducted a second MR-pheWAS after excluding SNPs associated with BMI from the genetic risk score, to examine whether results might be due to the genetic overlap between age at menarche and BMI. We followed up a subset of health-related traits to investigate MR assumptions and seek replication in independent study populations.ResultsOf the 17,893 tests performed in our MR-pheWAS, we identified 619 associations with the genetic risk score for age at menarche at a 5% false discovery rate threshold, of which 295 were below a Bonferroni-corrected P value threshold. These included potential effects of younger age at menarche on lower lung function, higher heel bone-mineral density, greater burden of psychosocial/mental health problems, younger age at first birth, higher risk of childhood sexual abuse, poorer cardiometabolic health, and lower physical activity. After exclusion of variants associated with BMI, the genetic risk score for age at menarche was related to 37 traits at a 5% false discovery rate, of which 29 were below a Bonferroni-corrected P value threshold. We attempted to replicate findings for bone-mineral density, lung function, neuroticism, and childhood sexual abuse using 5 independent cohorts/consortia. While estimates for lung function, higher bone-mineral density, neuroticism, and childhood sexual abuse in replication cohorts were consistent with UK Biobank estimates, confidence intervals were wide and often included the null.ConclusionsThe genetic risk score for age at menarche was related to a broad range of health-related traits. Follow-up analyses indicated imprecise evidence of an effect of younger age at menarche on greater bone-mineral density, lower lung function, higher neuroticism score, and greater risk of childhood sexual abuse in the smaller replication samples available; hence, these findings need further exploration when larger independent samples become available.

Project description:ObjectiveThe occurrence and development of oesophageal neoplasia (ON) is closely related to hormone changes. The aim of this study was to investigate the causal relationships between age at menarche (AAMA) or age at menopause (AAMO) and benign oesophageal neoplasia (BON) or malignant oesophageal neoplasia (MON) from a genetic perspective.MethodsGenome-wide association study (GWAS) summary data of exposures (AAMA and AAMO) and outcomes (BON and MON) were obtained from the IEU OpenGWAS database. We performed a two-sample Mendelian randomization (MR) study between them. The inverse variance weighted (IVW) was used as the main analysis method, while the MR Egger, weighted median, simple mode, and weighted mode were supplementary methods. The maximum likelihood, penalized weighted median, and IVW (fixed effects) were validation methods. We used Cochran's Q statistic and Rucker's Q statistic to detect heterogeneity. The intercept test of the MR Egger and global test of MR pleiotropy residual sum and outlier (MR-PRESSO) were used to detect horizontal pleiotropy, and the distortion test of the MR-PRESSO analysis was used to detect outliers. The leave-one-out analysis was used to detect whether the MR analysis was affected by single nucleotide polymorphisms (SNPs). In addition, the MR robust adjusted profile score (MR-RAPS) method was used to assess the robustness of MR analysis.ResultsThe random-effects IVW results showed that AAMA had a negative genetic causal relationship with BON (odds ratio [OR] = 0.285 [95% confidence interval [CI]: 0.130-0.623], P = 0.002). The weighted median, maximum likelihood, penalized weighted median, and IVW (fixed effects) were consistent with random-effects IVW (P < 0.05). The MR Egger, simple mode and weighted mode results showed that AAMA had no genetic causal relationship with BON (P > 0.05). However, there were no causal genetic relationships between AAMA and MON (OR = 1.132 [95%CI: 0.621-2.063], P = 0.685), AAMO and BON (OR = 0.989 [95%CI: 0.755-1.296], P = 0.935), or AAMO and MON (OR = 1.129 [95%CI: 0.938-1.359], P = 0.200). The MR Egger, weighted median, simple mode, weighted mode, maximum likelihood, penalized weighted median, and IVW (fixed effects) were consistent with a random-effects IVW (P > 0.05). MR analysis results showed no heterogeneity, the horizontal pleiotropy and outliers (P > 0.05). They were not driven by a single SNP, and were normally distributed (P > 0.05).ConclusionOnly AAMA has a negative genetic causal relationship with BON, and no genetic causal relationships exist between AAMA and MON, AAMO and BON, or AAMO and MON. However, it cannot be ruled out that they are related at other levels besides genetics.

Dataset Information

Age at menarche and lung function: a Mendelian randomization study.

Publications

Age at menarche and lung function: a Mendelian randomization study.

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