Age at menarche and adult body mass index: a Mendelian randomization study

Gill, Dipender; Brewer, Christopher F; M, Fabiola Del Greco; Sivakumaran, Prasanthi; Bowden, Jack; Sheehan, Nuala A.; Minelli, Cosetta

doi:10.1038/s41366-018-0048-7

Cited by 83 publications

(89 citation statements)

References 64 publications

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“…As the age at first sexual intercourse GWAS (22) was conducted solely in a sub-sample of UK Biobank participants, we conducted a fixed-effects meta-analysis of the SNP-outcome estimates in the full UK Biobank sample in addition to MR analysis in the non-overlapping sub-sample of UK Biobank. This fixed-effects meta-analysis is equivalent to performing an unweighted allele score analysis (31) and suffers from less bias than a weighted analysis.…”

Section: Resultsmentioning

confidence: 99%

“…Age at menarche analysis using the 116 SNP instrument was repeated after removing SNPs associated with body mass index at p < 5 × 10 -8 (31,38,39). This resulted in 9 SNPs being removed (rs10938397, rs12446632, rs2947411, rs3101336, rs543874, rs7103411, rs7138803, rs7514705, rs8050136).…”

Section: Resultsmentioning

confidence: 99%

“…Secondly, we used SNPs for age at first sexual intercourse, and their associations, identified in pooled sex GWAS, due to reductions in power of using SNPs identified in females only and our exposure and outcome data therefore consists of different populations (20). Thirdly, the SNPexposure associations were used from discovery analysis, which may cause upward bias of estimates (31,49), however using discovery data is common in MR studies and our unweighted analysis for age at first sexual intercourse did not use GWAS estimates (31,50). Fourthly, UK Biobank data is unrepresentative of the population, with a 5% response rate, and therefore and suffers from selection bias which may generate spurious associations (25,51).…”

Section: Discussionmentioning

confidence: 99%

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

Lawn

Sallis

Wootton

et al. 2018

Preprint

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There 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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Lawn

Sallis

Wootton

et al. 2018

Preprint

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“…On the outcome side, we accessed data for coronary artery disease (CAD) 28 for its analysis in relationship to known major risk factors BMI, blood lipids and blood pressure [29][30][31][32][33][34][35] ; breast cancer in relationship to several known epidemiologic risk-factors, including height, age-at-menarche, BMI, cholesterol level [36][37][38][39] ; and major depressive disorder (MDD) 40 in relationship to BMI and years of education [41][42][43] . In addition, we explored potential causal interrelationship among some of the exposures themselves, such as between BMI and blood pressure, and between BMI and age-at-menarche 44,45 .…”

Section: Summary Level Datamentioning

confidence: 99%

Mendelian Randomization Analysis Using Mixture Models (MRMix) for Genetic Effect-Size-Distribution Leads to Robust Estimation of Causal Effects

Chatterjee

2018

Preprint

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We propose a novel method for robust estimation of causal effects in two-sample Mendelian randomization analysis using potentially large number of genetic instruments.We consider a "working model" for bi-variate effect-size distribution across pairs of traits in the form of normal-mixtures which assumes existence of a fraction of the genetic markers that are valid instruments, i.e. they have only direct effect on one trait, while other markers can have potentially correlated, direct and indirect effects, or have no effects at all. We show that model motivates a simple method for estimating causal effect ( ) through a procedure for maximizing the probability concentration of the residuals, ( − ), at the "null" component of a two-component normal-mixture model.Simulation studies showed that MRMix provides nearly unbiased or/and substantially more robust estimates of causal effects compared to alternative methods under various scenarios. Further, the studies showed that MRMix is sensitive to direction and can achieve much higher efficiency (up to 3-4 fold) relative to other comparably robust estimators. We applied the proposed methods for conducting MR analysis using largest publicly available datasets across a number of risk-factors and health outcomes. Notable findings included identification of causal effects of genetically determined BMI and ageat-menarche, which have relationship among themselves, on the risk of breast cancer; detrimental effect of HDL on the risk of breast cancer; no causal effect of HDL and triglycerides on the risk of coronary artery disease; a strong detrimental effect of BMI, but no causal effect of years of education, on the risk of major depressive disorder.All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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“…In a recent systematic review and meta-analysis of 11 cohort studies, pre-pubertal obesity among females was associated with earlier menarche but there was insufficient and inconsistent evidence in males 18 . A recent Mendelian randomisation (MR) analysis suggested that earlier age at menarche causes higher adult BMI but lacked data on pre-pubertal BMI for adjustment 19 . In contrast, another recent MR which did have pre-pubertal BMI data suggested that associations of earlier puberty with higher adult BMI are largely confounded by childhood BMI 20 .…”

Section: Introductionmentioning

confidence: 99%

Puberty timing and adiposity change across childhood and adolescence: disentangling cause and consequence

O’Keeffe

Frysz

Bell

et al. 2019

Preprint

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ObjectiveTo better understand if earlier puberty is more likely a result of adiposity gain in childhood than a cause of adiposity gain in adulthood.DesignProspective birth cohort study.SettingPopulation based study of children born in 1991/1992 in Bristol UK (Avon Longitudinal Study of Parents and Children (ALSPAC)).Participants4,186 participants (2,176 female and 1,990 male) of predominantly White ethnicity with 18,232 repeated measures throughout follow-up.Exposures & outcomesRepeated measures of height from 5y to 20y to identify puberty timing (age at peak height velocity) and repeated measures of dual-energy X-ray absorptiometry-derived fat mass from age 9y to 18y, modelled separately in females and males using models based on chronological age and time before and after puberty onset.ResultsMean age at peak height velocity was 11.7y (standard deviation (SD)=0.8y) for females and 13.6y (SD=0.9y) for males. In adjusted models of fat mass by chronological age, a one-year later age at peak height velocity was associated with 20.4% (95% Confidence Interval (CI): 18.5% to 22.3%) and 22.8% (95% (CI): 20.7% to 24.8%) lower fat mass in females and males respectively at 9y. These differences were smaller at age 18y: 7.8% (95% (CI):5.9% to 9.6%) and 11.9% (95% (CI): 9.1%, to 14.7%) lower fat mass in females and males respectively per year later age at peak height velocity. Trajectories of fat mass by time before and after puberty onset provided strong evidence for an association of pre-pubertal fat mass with puberty timing, and little evidence of an association of puberty timing with post-pubertal changes in fat mass in females. In males, findings were less clear before puberty though there was some evidence for an association of earlier puberty timing with great post-pubertal gain in fat mass.ConclusionsEarlier puberty is more likely a result of adiposity gain in childhood than a cause of adiposity gain in adulthood in females. In males early to puberty, differences in fat mass after puberty are driven partially by tracking of adiposity from early childhood but also greater gains in post-pubertal adiposity. Reducing levels of childhood adiposity may help prevent both earlier puberty, later life adiposity and their associated adverse social, mental and physical health sequelae.

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Age at menarche and adult body mass index: a Mendelian randomization study

Abstract: MR provides evidence to support the hypothesis that earlier age at menarche causes higher adult BMI. Complex hormonal and psychological factors may be responsible.

Cited by 83 publications

References 64 publications

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

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

Mendelian Randomization Analysis Using Mixture Models (MRMix) for Genetic Effect-Size-Distribution Leads to Robust Estimation of Causal Effects

Puberty timing and adiposity change across childhood and adolescence: disentangling cause and consequence

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