Genetic associations between exposures and outcomes.

(A), genetic associations between exposures and general aging. Later age at menarche was associated with a lower frailty index and higher parental ages at death. Later age at first birth was associated with lower frailty index and GrimAge and higher parental ages at death. (B), genetic associations between age at menarche and outcomes of organ aging and diseases as well as organ cancer. Later age at menarche was associated with later age at menopause onset and lower risks of LOAD, CHF, essential hypertension, facial aging, early onset COPD, breast cancer, and endometrial cancer. (C), genetic associations between age at first birth and outcomes of organ aging and diseases as well as organ cancer. Later age at first birth was associated with later age at menopause onset and 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 excluded for outcomes of CHF and cervical cancer. BMI included, BMI-related SNPs included; CHF, chronic heart failure; GAD, gastrointestinal or abdominal disease.

List and heatmap of SNPs/genes from post-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#; 2KB upstream variant; Missense variant*; Intergenic variant&; Regulatory region variant@. 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); Blue bar represents a beneficial association (+beta for Father’s DA, Mother’s DA, and menopause; −beta for other outcomes); 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 II 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; BMI, body mass index.

Ingenuity Pathway Analysis (IPA). SNPs/gene outcomes from 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 are 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, purple-channels, orange-other proteins.

The distributions of outcome age and risk according to age group of menarche and fist 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 3 BMI categories. BMI, body mass index; HBP, high blood pressure; COPD, chronic obstructive pulmonary disease; AD, Alzheimer’s disease.