Early menarche and childbirth accelerate aging-related outcomes and age-related diseases: Evidence for antagonistic pleiotropy in humans
- The Buck Institute for Research on Aging, United States
- Department of Biology and Chemistry, Embry-Riddle Aeronautical University, United States
- Department of Urology, University of California, San Francisco, United States
Figures
Figure 1
Research pipeline.
(A, B) All the traits for exposures and outcomes included in the analysis. Exposures include age at menarche and age at first birth. Outcomes include general aging, organ aging and diseases, and organ cancers. (C) The primary analyses for Mendelian randomization (MR) research, including instrumental variables selection, two-sample MR analysis, and sensitivity tests. (D) The advanced analyses include mediator analysis of body mass index (BMI) with two-step MR, colocalization analysis on single-nucleotide polymorphism (SNP)–SNP level, genetic correlation analysis based on LDSC, and gene target analysis based on RNA and protein expression analysis and Ingenuity Pathway Analysis. (E) The results are validated based on the UK Biobank with regression analysis. LOAD, late-onset Alzheimer’s disease; CHF, chronic heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; GAD, gastrointestinal or abdominal disease.
Figure 2
Schematic representation of early reproduction exposures and age-related outcomes.
†Significant age-related outcomes in Mendelian randomization (MR) analysis. ‡Significant age-related outcomes in UK Biobank (UKB) cohorts. LOAD, late-onset Alzheimer’s disease; COPD, chronic obstructive pulmonary diseases; T2D, type 2 diabetes; CHF, chronic heart failure; BMI, body mass index; Parental DA, parental death age; GAD, gastrointestinal and abdominal diseases; AD, Alzheimer’s disease. The figure is created with BioRender.com.
Figure 3
Genetic associations between exposures and outcomes.
(A) Genetic associations between exposures and aging outcomes. Later age at menarche was associated with a lower frailty index and facial aging, higher parental ages at death, and later menopause. Later age at first birth was associated with lower frailty index and GrimAge, higher parental ages at death, and later menopause. (B) Genetic associations between age at menarche and outcomes of organ diseases. Later age at menarche was associated with lower risks of LOAD, CHF, essential hypertension, early onset COPD, breast cancer, and endometrial cancer. (C) Genetic associations between age at first birth and outcomes of organ diseases. Later age at first birth was associated with lower risks of type 2 diabetes, CHF, essential hypertension, gastrointestinal or abdominal disease, and cervical cancer. The significant associations were not detected after BMI-related SNPs were excluded for outcomes of CHF and cervical cancer. BMI included, BMI-related SNPs included; LOAD, late-onset Alzheimer’s disease; CHF, chronic heart failure; COPD, chronic obstructive pulmonary; GAD, gastrointestinal or abdominal disease; BMI, body mass index.
Figure 4
List and heatmap of single-nucleotide polymorphisms (SNPs)/genes from post-Mendelian randomization (MR) analysis showing an association between age at menarche and first birth with three or more aging outcomes.
Genomic region location for each variant is depicted by different characters: intron variant#; 2 KB upstream variant$; Missense variant*; Intergenic variant&; Regulatory region variant@; 3′ UTR variant†; Synonymous Variant~. A heatmap is representative of an association of each gene/SNP with different aging outcomes. Red bar represents a harmful association (−beta for Father’s DA, Mother’s DA, and menopause;+beta for other outcomes); The blue bar represents a beneficial association (+beta for Father’s DA, Mother’s DA, and menopause; −beta for other outcomes); the white bar represents no association. AFB, age at first birth; FI, frailty index; Father’s DA, father’s age at death; Mother’s DA, mother’s age at death; Menopause, age at menopause; LOAD, late-onset Alzheimer’s disease; OS, osteoporosis; T2D, type 2 diabetes; CHF, chronic heart failure; EH, essential hypertension; FA, facial aging; COPD, chronic obstructive pulmonary disease; GAD, gastrointestinal or abdominal disease; BC, breast cancer; EC, endometrial cancer; CC, cervical cancer; BMI, body mass index.
Figure 5
Ingenuity Pathway Analysis (IPA).
Single-nucleotide polymorphisms (SNPs)/gene outcomes from Mendelian randomization (MR) analysis were subjected to IPA. (A) Canonical signaling pathways in age at menarche and first birth. The adjusted p-values of the top 25 signaling pathways are listed. (B) Disease and functions in age at first birth and menarche. The adjusted p-value of the top 20 significantly involved diseases and functions is listed. (C) IPA network 1 and (D) IPA network 2. The genes from our post-MR analysis are in bold. Solid lines indicate direct connections, while dotted lines indicate indirect connections (circular arrows mean influence itself). Color coding: pink—receptors, green—enzymes, blue—transcriptional regulators, red—growth factor, orange—other proteins.
Figure 6 with 1 supplement
The distributions of outcome age and risk according to age group of menarche and first live birth as well as number of births before and after correcting confounders.
Condition Baseline, no confounder was corrected. Conditions Highest education and Lowest education, confounders of education, smoking, and drinking were corrected, and bars were painted based on most smoking and drinking situations with the highest and lowest education levels. Conditions Median education with BMI 18.5–24.9, Median education with BMI 25–29.9, and Median education with BMI 30-, confounders of education, smoking, drinking, and BMI were corrected, and bars were painted based on median education and most smoking and drinking situation with three BMI categories. A-I, Age at menarche and aging outcomes at different conditions (264,335 participants included). J-S, Age at first live birth and aging outcomes at different conditions (184,481 participants included). T-AC, Number of births and aging outcomes at different conditions (259,758 participants included). BMI, body mass index; HBP, high blood pressure; COPD, chronic obstructive pulmonary disease; AD, Alzheimer’s disease.
Figure 6—figure supplement 1
The combined effect of age at menarche and first live birth for different outcomes.
Participants were divided into 25 groups according to the menarche and first live birth ages to evaluate the combined effect of age at menarche and first live birth on diabetes (A), HBP (B), heart failure (C), and obesity (D). Females with menarche of ‘13–14 years’ and first birth of ‘26–30 years’ were set as the baseline group in the analysis. Red block means higher risk. Blue block means lower risk. White block means baseline. Gray block means no significant difference. HBP, high blood pressure; BMI, body mass index.
Additional files
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MDAR checklist
- https://cdn.elifesciences.org/articles/102447/elife-102447-mdarchecklist1-v1.pdf
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Supplementary file 1
Overview of GWAS data used for MR analysis.
- https://cdn.elifesciences.org/articles/102447/elife-102447-supp1-v1.xlsx
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Supplementary file 2
SNPs included in MR analysis for each outcome.
- https://cdn.elifesciences.org/articles/102447/elife-102447-supp2-v1.xlsx
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Supplementary file 3
Overview results of two-sample MR analysis.
- https://cdn.elifesciences.org/articles/102447/elife-102447-supp3-v1.xlsx
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Supplementary file 4
Overview results of two-step MR analysis with BMI as the mediator.
- https://cdn.elifesciences.org/articles/102447/elife-102447-supp4-v1.xlsx
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Supplementary file 5
Results of two-sample MR analysis after colocalization.
- https://cdn.elifesciences.org/articles/102447/elife-102447-supp5-v1.xlsx
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Supplementary file 6
The genetic correlation based on LDSC.
- https://cdn.elifesciences.org/articles/102447/elife-102447-supp6-v1.xlsx
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Supplementary file 7
List of SNPs/genes from post-MR analysis showing an association between age at menarche onset and first birth with one or two aging outcomes.
- https://cdn.elifesciences.org/articles/102447/elife-102447-supp7-v1.xlsx
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Supplementary file 8
Ingenuity pathway analysis networks in age at menarche onset and first birth.
- https://cdn.elifesciences.org/articles/102447/elife-102447-supp8-v1.xlsx
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Supplementary file 9
FDA-approved drugs against targets identified post-MR analysis.
- https://cdn.elifesciences.org/articles/102447/elife-102447-supp9-v1.xlsx
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Supplementary file 10
Participants included for population validation from UK Biobank.
- https://cdn.elifesciences.org/articles/102447/elife-102447-supp10-v1.xlsx
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Supplementary file 11
Estimate effect compared to youngest/smallest group for outcomes in regression.
- https://cdn.elifesciences.org/articles/102447/elife-102447-supp11-v1.xlsx
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Supplementary file 12
Estimate effect of combined age at menarche and first live birth and sample distribution.
- https://cdn.elifesciences.org/articles/102447/elife-102447-supp12-v1.xlsx
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Early menarche and childbirth accelerate aging-related outcomes and age-related diseases: Evidence for antagonistic pleiotropy in humans
eLife 13:RP102447.
https://doi.org/10.7554/eLife.102447.4
