The relationships between women’s reproductive factors: a Mendelian randomization analysis

AbstractBackgroundWomen’s reproductive factors include their age at menarche and menopause, the age at which they start and stop having children, and the number of children they have. Studies that have linked these factors with disease risk have largely investigated individual reproductive factors and have not considered the genetic correlation and total interplay that may occur between them. This study aimed to investigate the nature of the relationships between eight female reproductive factors.MethodsWe used data from the UK Biobank and genetic consortia with data available for the following reproductive factors: age at menarche, age at menopause, age at first birth, age at last birth, number of births, being parous, age at first sex and lifetime number of sexual partners. Linkage disequilibrium score regression (LDSC) was performed to investigate the genetic correlation between reproductive factors. We then applied Mendelian randomization (MR) methods to estimate the causal relationships between these factors. Sensitivity analyses were used to investigate directionality of the effects, test for evidence of pleiotropy and account for sample overlap.ResultsLDSC indicated that most reproductive factors are genetically correlated (rg range: |0.06 – 0.94|), though there was little evidence for genetic correlations between lifetime number of sexual partners and age at last birth, number of births and ever being parous (rg < 0.01). MR revealed potential causal relationships between many reproductive factors, including later age at menarche (1 SD increase) leading to a later age at first sexual intercourse (Beta (B)=0.09 SD, 95% confidence intervals (CI)=0.06,0.11), age at first birth (B=0.07 SD, CI=0.04,0.10), age at last birth (B=0.06 SD, CI=0.04,0.09) and age at menopause (B=0.06 SD, CI=0.03,0.10). Later age at first birth was found to lead to a later age at menopause (B=0.21 SD, CI=0.13,0.29), age at last birth (B=0.72 SD, CI=0.67,0.77) and a lower number of births (B=-0.38 SD, CI=-0.44,-0.32).ConclusionThis study presents evidence that women’s reproductive factors are genetically correlated and causally related. Future studies examining the health sequelae of reproductive factors should consider a woman’s entire reproductive history, including the causal interplay between reproductive factors.

Download Full-text

Schizophrenia risk and reproductive success: a Mendelian randomization study

Royal Society Open Science ◽

10.1098/rsos.181049 ◽

2019 ◽

Vol 6 (3) ◽

pp. 181049 ◽

Cited By ~ 2

Author(s):

Rebecca B. Lawn ◽

Hannah M. Sallis ◽

Amy E. Taylor ◽

Robyn E. Wootton ◽

George Davey Smith ◽

...

Keyword(s):

Reproductive Success ◽

Mendelian Randomization ◽

Causal Effect ◽

Sexual Partners ◽

Age At First Birth ◽

First Birth ◽

Genetic Liability ◽

Number Of Children ◽

Fitness Advantage ◽

Number Of Sexual Partners

Schizophrenia is a debilitating and heritable mental disorder associated with lower reproductive success. However, the prevalence of schizophrenia is stable over populations and time, resulting in an evolutionary puzzle: how is schizophrenia maintained in the population, given its apparent fitness costs? One possibility is that increased genetic liability for schizophrenia, in the absence of the disorder itself, may confer some reproductive advantage. We assessed the correlation and causal effect of genetic liability for schizophrenia with number of children, age at first birth and number of sexual partners using data from the Psychiatric Genomics Consortium and UK Biobank. Linkage disequilibrium score regression showed little evidence of genetic correlation between genetic liability for schizophrenia and number of children ( r g = 0.002, p = 0.84), age at first birth ( r g = −0.007, p = 0.45) or number of sexual partners ( r g = 0.007, p = 0.42). Mendelian randomization indicated no robust evidence of a causal effect of genetic liability for schizophrenia on number of children (mean difference: 0.003 increase in number of children per doubling in the natural log odds ratio of schizophrenia risk, 95% confidence interval (CI): −0.003 to 0.009, p = 0.39) or age at first birth (−0.004 years lower age at first birth, 95% CI: −0.043 to 0.034, p = 0.82). We find some evidence of a positive effect of genetic liability for schizophrenia on number of sexual partners (0.165 increase in the number of sexual partners, 95% CI: 0.117–0.212, p = 5.30×10 −10 ). These results suggest that increased genetic liability for schizophrenia does not confer a fitness advantage but does increase mating success.

Download Full-text

Age at Menarche, Age at Natural Menopause and Risk of Rheumatoid Arthritis – A Mendelian Randomization Study

10.21203/rs.3.rs-95577/v1 ◽

2020 ◽

Author(s):

Jingjing Zhu ◽

Zheng Niu ◽

Lars Alfredsson ◽

Lars Klareskog ◽

Leonid Padyukov ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Mendelian Randomization ◽

Reproductive Factors ◽

European Ancestry ◽

Age At Menarche ◽

Age At First Birth ◽

First Birth ◽

Natural Menopause ◽

Menarche Age ◽

Mr Study

Abstract Background Hormonal 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.Methods We 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 and 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.Results We did not find any evidence in support for a causal association between genetically predicted reproductive factors and risk of RA (ORAAM=1.06 [0.98-1.15], ORANM=1.05 [0.98-1.11], ORAFB=0.85 [0.65-1.10]). Results remained consistent after removing palindromic SNPs (ORAAM=1.06 [0.97-1.15], ORANM=1.05 [0.98-1.13], ORAFB=0.81 [0.61-1.07]) or excluding SNPs associated with potential confounding traits (ORAAM=1.03 [0.94-1.12], ORANM=1.04 [0.95-1.14]). No outlying instrument was identified through the leave-one-out analysis.Conclusions Our 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.

Download Full-text

Age at menarche, age at natural menopause and risk of rheumatoid arthritis – a Mendelian randomization study

10.21203/rs.3.rs-95577/v2 ◽

2021 ◽

Author(s):

Jingjing Zhu ◽

Zheng Niu ◽

Lars Alfredsson ◽

Lars Klareskog ◽

Leonid Padyukov ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Mendelian Randomization ◽

Reproductive Factors ◽

European Ancestry ◽

Age At Menarche ◽

Age At First Birth ◽

First Birth ◽

Natural Menopause ◽

Menarche Age ◽

Mr Study

Abstract Background Hormonal 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.Methods We 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.Results We 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.Conclusions Our 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.

Download Full-text

Age at menarche, age at natural menopause, and risk of rheumatoid arthritis — a Mendelian randomization study

Arthritis Research & Therapy ◽

10.1186/s13075-021-02495-x ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Jingjing Zhu ◽

Zheng Niu ◽

Lars Alfredsson ◽

Lars Klareskog ◽

Leonid Padyukov ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Mendelian Randomization ◽

Reproductive Factors ◽

European Ancestry ◽

Age At Menarche ◽

Age At First Birth ◽

First Birth ◽

Natural Menopause ◽

Menarche Age ◽

Mr Study

Abstract Background Hormonal 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. Methods We 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. Results We 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. Conclusions Our 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.

Download Full-text

Reproductive characteristics are associated with gene-specific promoter methylation status in breast cancer

BMC Cancer ◽

10.1186/s12885-019-6120-4 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Lauren E. McCullough ◽

Lindsay J. Collin ◽

Kathleen Conway ◽

Alexandra J. White ◽

Yoon Hee Cho ◽

...

Keyword(s):

Breast Cancer ◽

Promoter Methylation ◽

Tumor Tissue ◽

Methylation Status ◽

Reproductive Factors ◽

Gene Promoter ◽

Age At Menarche ◽

Age At First Birth ◽

First Birth ◽

Reproductive Characteristics

Abstract Background Reproductive characteristics are well-established risk factors for breast cancer, but the underlying mechanisms are not fully resolved. We hypothesized that altered DNA methylation, measured in tumor tissue, could act in concert with reproductive factors to impact breast carcinogenesis. Methods Among a population-based sample of women newly diagnosed with first primary breast cancer, reproductive history was assessed using a life-course calendar approach in an interviewer-administered questionnaire. Methylation-specific polymerase chain reaction and Methyl Light assays were used to assess gene promotor methylation status (methylated vs. unmethylated) for 13 breast cancer-related genes in archived breast tumor tissue. We used case-case unconditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations with age at menarche and parity (among 855 women), and age at first birth and lactation (among a subset of 736 parous women) in association with methylation status. Results Age at first birth > 27 years, compared with < 23 years, was associated with lower odds of methylation of CDH1 (OR = 0.44, 95% CI = 0.20–0.99) and TWIST1 (OR = 0.48, 95% CI = 0.28–0.82), and higher odds of methylation of BRCA1 (OR = 1.63, 95% CI = 1.14–2.35). Any vs. no lactation was associated with higher odds of methylation of the PGR gene promoter (OR = 1.59, 95% CI = 1.01–2.49). No associations were noted for parity and methylation in any of the genes assayed. Conclusions Our findings indicate that age at first birth, lactation and, perhaps age at menarche, are associated with gene promoter methylation in breast cancer, and should be confirmed in larger studies with robust gene coverage.

Download Full-text

Influence of Selected Reproductive Factors and Smoking on Age at Menopause

The Journal of South Asian Federation of Menopause Societies ◽

10.5005/jsafoms-3-2-64 ◽

2015 ◽

Vol 3 (2) ◽

pp. 64-66 ◽

Cited By ~ 1

Author(s):

B Rumianowski ◽

I Rotter ◽

A Brodowska ◽

G Adler ◽

J Kowalski ◽

...

Keyword(s):

Hormone Replacement ◽

Reproductive Factors ◽

Age At Menarche ◽

First Birth ◽

Natural Menopause ◽

Age At Menopause ◽

The Difference ◽

Surrounding Areas ◽

Effect Of Age

ABSTRACT Introduction Early menopause may be associated with serious health risks resulting from, e.g. decreased estrogen levels. This may occur despite hormone replacement therapy. Aim The aim of this study was the determination of the effect of selected reproductive factors and smoking on age at the onset of menopause in women from Szczecin and surrounding areas. Materials and methods Three hundred and five women after natural menopause were asked to complete a questionnaire, and blood samples were collected from them to test for the levels of follicle stimulating hormone (FSH) andoestradiol (E2). Results Smoking women experienced menopause on average more than a year earlier than non-smokers, but this difference was not statistically significant. There was no statistically significant effect of age at menarche or first birth on age at the last menstrual period. Conclusion Age at menarche and first birth were not related to age at menopause. In smoking women, menopause occurred earlier but the difference was not statistically significant.

Download Full-text

Variations in reproductive events across life: a pooled analysis of data from 505 147 women across 10 countries

Human Reproduction ◽

10.1093/humrep/dez015 ◽

2019 ◽

Vol 34 (5) ◽

pp. 881-893 ◽

Cited By ~ 11

Author(s):

Keyword(s):

Age At Menarche ◽

Age At First Birth ◽

First Birth ◽

Natural Menopause ◽

Individual Level ◽

Level Data ◽

Education Levels ◽

Reproductive Events ◽

Racial Ethnic ◽

Reproductive Indices

Abstract STUDY QUESTION How has the timing of women’s reproductive events (including ages at menarche, first birth, and natural menopause, and the number of children) changed across birth years, racial/ethnic groups and educational levels? SUMMARY ANSWER Women who were born in recent generations (1970–84 vs before 1930) or those who with higher education levels had menarche a year earlier, experienced a higher prevalence of nulliparity and had their first child at a later age. WHAT IS KNOWN ALREADY The timing of key reproductive events, such as menarche and menopause, is not only indicative of current health status but is linked to the risk of adverse hormone-related health outcomes in later life. Variations of reproductive indices across different birth years, race/ethnicity and socioeconomic positions have not been described comprehensively. STUDY DESIGN, SIZE, DURATION Individual-level data from 23 observational studies that contributed to the International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events (InterLACE) consortium were included. PARTICIPANTS/MATERIALS, SETTING, METHODS Altogether 505 147 women were included. Overall estimates for reproductive indices were obtained using a two-stage process: individual-level data from each study were analysed separately using generalised linear models. These estimates were then combined using random-effects meta-analyses. MAIN RESULTS AND THE ROLE OF CHANCE Mean ages were 12.9 years at menarche, 25.7 years at first birth, and 50.5 years at natural menopause, with significant between-study heterogeneity (I2 > 99%). A linear trend was observed across birth year for mean age at menarche, with women born from 1970 to 1984 having menarche one year earlier (12.6 years) than women born before 1930 (13.5 years) (P for trend = 0.0014). The prevalence of nulliparity rose progressively from 14% of women born from 1940–49 to 22% of women born 1970–84 (P = 0.003); similarly, the mean age at first birth rose from 24.8 to 27.3 years (P = 0.0016). Women with higher education levels had fewer children, later first birth, and later menopause than women with lower education levels. After adjusting for birth year and education level, substantial variation was present for all reproductive events across racial/ethnic/regional groups (all P values < 0.005). LIMITATIONS, REASONS FOR CAUTION Variations of study design, data collection methods, and sample selection across studies, as well as retrospectively reported age at menarche, age at first birth may cause some bias. WIDER IMPLICATIONS OF THE FINDINGS This global consortium study found robust evidence on variations in reproductive indices for women born in the 20th century that appear to have both biological and social origins. STUDY FUNDING/COMPETING INTEREST(S) InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). GDM is supported by the Australian National Health and Medical Research Council Principal Research Fellowship (APP1121844).

Download Full-text

The relationship between chronic diseases and number of sexual partners: an exploratory analysis

BMJ Sexual & Reproductive Health ◽

10.1136/bmjsrh-2019-200352 ◽

2020 ◽

Vol 46 (2) ◽

pp. 100-107 ◽

Cited By ~ 1

Author(s):

Igor Grabovac ◽

Lee Smith ◽

Lin Yang ◽

Pinar Soysal ◽

Nicola Veronese ◽

...

Keyword(s):

Older Adults ◽

Health Outcomes ◽

Longitudinal Research ◽

Sexual Partners ◽

Cross Sectional ◽

Lifetime Number ◽

Number Of Sexual Partners ◽

Health Related ◽

Diagnosis Of Cancer ◽

The Relationship

BackgroundWe investigated sex-specific associations between lifetime number of sexual partners and several health outcomes in a large sample of older adults in England.MethodsWe used cross-sectional data from 2537 men and 3185 women aged ≥50 years participating in the English Longitudinal Study of Ageing. Participants reported the number of sexual partners they had had in their lifetime. Outcomes were self-rated health and self-reported limiting long-standing illness, cancer, coronary heart disease, and stroke. We used logistic regression to analyse associations between lifetime number of sexual partners and health outcomes, adjusted for relevant sociodemographic and health-related covariates.ResultsHaving had 10 or more lifetime sexual partners was associated with higher odds of reporting a diagnosis of cancer than having had 0–1 sexual partners in men (OR 1.69, 95% CI 1.01 to 2.83) and women (OR 1.91, 95% CI 1.04 to 3.51), respectively. Women who had 10 or more lifetime sexual partners also had higher odds of reporting a limiting long-standing illness (OR 1.64, 95% CI 1.15 to 2.35). No other statistically significant associations were observed.ConclusionsA higher lifetime number of sexual partners is associated with increased odds of reported cancer. Longitudinal research is required to establish causality. Understanding the predictive value of lifetime number of sexual partners as a behavioural risk factor may improve clinical assessment of cancer risk in older adults.

Download Full-text

Reduced Prevalence of the C825T Polymorphism of the G-Protein Beta Subunit Gene in Women with Breast Cancer

The International Journal of Biological Markers ◽

10.5301/jbm.2011.8751 ◽

2011 ◽

Vol 26 (4) ◽

pp. 234-240

Author(s):

Renata G. Paleari ◽

Raquel M.R. Peres ◽

Juliana O. Florentino ◽

Juliana K. Heinrich ◽

Welbe O. Bragança ◽

...

Keyword(s):

Breast Cancer ◽

Reproductive Factors ◽

Breast Disease ◽

Control Group ◽

Age At Menarche ◽

Case Group ◽

Significance Level ◽

Age At Menopause ◽

Beta Subunit Gene ◽

C825t Polymorphism

Objective To evaluate the prevalence of the C825T polymorphism in the GNB3 gene in women with and without breast cancer and its possible association with clinical or pathological features of breast disease. Subjects and methods We included 134 women with breast cancer and a control group of 129 healthy women. The case group responded to a questionnaire on lifestyle, reproductive factors and family history. Clinical data were also evaluated. The risk for cancer was calculated and PCR was carried out for the detection of the polymorphism. Statistical analysis was performed using the package R Environment, with confidence intervals of 95% and a significance level of 5% (P<0.05). Results The frequency of the TT genotype was significantly greater in women of the control group (30.2%) than women with breast cancer (14.9%) (p=0.02). The polymorphism was not associated with clinical features, age at diagnosis (p=0.07), age at menarche (p=0.17), and age at menopause (p=0.60). The TT genotype did not have a higher frequency in patients with high BMI (p=0.98). The risk for cancer showed no correlation with the presence of the polymorphism. Conclusions Our data indicate that the C825T polymorphism in the GNB3 gene has no relationship to the risk for breast cancer or the characteristics of the disease.

Download Full-text

The effects of age at menarche and first sexual intercourse on reproductive and behavioural outcomes: a Mendelian randomization study

10.1101/423251 ◽

2018 ◽

Cited By ~ 2

Author(s):

Rebecca B Lawn ◽

Hannah M Sallis ◽

Robyn E Wootton ◽

Amy E Taylor ◽

Perline Demange ◽

...

Keyword(s):

Life History ◽

Sexual Intercourse ◽

Life History Theory ◽

Mendelian Randomization ◽

Causal Effect ◽

Life History Strategies ◽

Age At Menarche ◽

Age At First Birth ◽

Risky Behaviour ◽

First Sexual Intercourse

SummaryThere is substantial variation in the timing of significant reproductive life events such as menarche and first sexual intercourse. Life history theory explains this variation as an adaptive response to the developmental environment. In environments characterized by harsh conditions, adopting a fast life history strategy may increase fitness. In line with this, there is evidence demonstrating that greater childhood adversity is associated with earlier age at menarche. Here we applied Mendelian randomization (MR) methods to investigate whether there is a causal effect of variation in age at menarche and age at first sexual intercourse on outcomes related to reproduction, education and risky behaviour in UK Biobank (N = 114883–181,255). Our results suggest that earlier age at menarche affects some traits that characterize life history strategies including earlier age at first and last birth, decreased educational attainment, and decreased age at leaving education (for example, we found evidence for a 0.26 year decrease in age at first birth per year decrease in age at menarche, 95% confidence interval: −0.34 to −0.17; p < 0.0001). We find no clear evidence of effects of age at menarche on other outcomes, such as risk taking behaviour. Age at first sexual intercourse was also related to many life history outcomes, although there was evidence of horizontal pleiotropy which violates an assumption of MR and results should be treated with caution. Taken together, these results highlight how MR can be applied to test predictions of life history theory and to better understand determinants of health and social behaviour.

Download Full-text