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

Lawn, Rebecca B; Sallis, Hannah M; Wootton, Robyn E; Taylor, Amy E; Demange, Perline; Fraser, Abigail; Penton-Voak, Ian S.; Munafò, Marcus R.

doi:10.1101/423251

Cited by 5 publications

(5 citation statements)

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“…Furthermore, our findings support one study that found little evidence for an association between age at menarche and parity [26]. Additionally, we corroborated the findings of previous MR studies that identified a positive causal relationship between age at menarche and AFB, ALB and age at menopause, and between AFS and ALB [67][68][69].…”

Section: Discussionsupporting

confidence: 90%

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

Prince

Sharp

Howe

et al. 2022

BMC Med

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Background Women’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. Methods We 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 first had sexual intercourse 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 randomisation (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. Results LDSC 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). Conclusion This 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.

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Section: Discussionsupporting

confidence: 90%

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

Prince

Sharp

Howe

et al. 2022

BMC Med

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“…One way of evaluating causality is to use single nucleotide polymorphisms (SNPs) as instrumental variables for the exposure of interest (here age at menarche), under the assumption that the allocation of SNPs at conception is random and unrelated to potential confounding factors [10]. Mendelian randomization has previously been used to explore effects of age at menarche on cardiometabolic traits [9,11,12], depression [13,14], breast cancer [15,16], educational level [17], lung function [18], osteoporosis [19], fracture risk [20], and reproductive/behavioral outcomes [21]. However, these have focused on hypothesized effects by exploring whether associations that have been widely examined in the literature have causal evidence from Mendelian randomization analyses.…”

Section: Introductionmentioning

confidence: 99%

Identifying potential causal effects of age at menarche: a Mendelian randomization phenome-wide association study

Magnus

Guyatt

Lawn

et al. 2020

BMC Med

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Background: Age 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. Methods: We 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. Results: Of 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 bonemineral 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. Conclusions: The 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.

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“…(26) Additionally, we corroborated the findings of previous MR studies that identified a positive causal relationship between AAM and AFB, ALB and age at menopause, and between AFS and ALB. (59)(60)(61) Many estimates identified in the primary analysis appear consistent across sensitivity analyses that aim to account for biases. However, some results did not persist in sensitivity analyses checking for robustness to sample overlap and winner's curse.…”

Section: Discussionmentioning

confidence: 74%

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

Prince

Sharp²,

Howe³

et al. 2021

Preprint

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Background: Women'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. Methods: We 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. Results: LDSC 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). Conclusion: This 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.

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

Cited by 5 publications

References 53 publications

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

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

Identifying potential causal effects of age at menarche: a Mendelian randomization phenome-wide association study

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

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