Mendelian randomization investigation into testosterone's trade-offs between longevity and reproductive fitness.

Exploring the Causal Relationship Between Sex Hormones and Depression by Means of Two-Sample Mendelian Randomization Analysis.

This study indicates a potential causal association between genetically predicted PROG levels and a decreased risk of depression.

Investigating the potential causal relationship between parity and long-term maternal cardiometabolic health outcomes using Mendelian randomization

Findings indicate a possible causal relationship between NEB and long-term cardiometabolic health, although causal effects are likely to be small.

Growth Hormone and Cancer Risk: A Two-Sample Bidirectional Mendelian Randomization Study with Mediation Testing.

These findings demonstrate tissue-specific effects of GH on carcinogenesis, partially mediated through metabolic pathways, and suggest metabolite monitoring could help mitigate cancer risk in susceptible individuals.

Genetic Perspective on the Relationship between Female Reproductive Traits, Exercise, and Bone Health Outcomes: Evidence from a National Database

Abstract Introduction Female reproductive traits influence bone mineral density (BMD) and fracture risks through estrogen exposure. However, these causal relationships remain unclear due to confounding. Understanding these relationships is crucial for osteoporosis prevention strategies. This study aimed to investigate the causal impact of age at natural menopause (ANM) and age at menarche (AAM) on BMD and osteoporosis risk, and to explore gene-exercise interactions influencing bone health in East Asian women. Methods We conducted two-sample Mendelian randomization (MR) using 15 genetic variants for AAM and 36 variants for ANM in 51,049 women from the Taiwan Biobank, split into discovery (n = 25,549) and validation (n = 25,500) cohorts. Outcomes were BMD Z scores, T scores, and clinical osteoporosis. We performed univariable and multivariable MR, followed by regression analyses, focusing on exercise effects on BMD and genetic predisposition scores for AAM and ANM. Results In multivariable MR, genetically determined later ANM was associated with higher BMD Z scores (β = 0.045, 95% confidence interval [0.021, 0.069]), higher T scores (β = 0.046, [0.020, 0.072]), and lower osteoporosis risk (β = −0.106, [−0.154, −0.058]). No consistent causal effect was observed for AAM due to genetic pleiotropy. ANM polygenic risk score and regular exercise were independently associated with improved BMD Z- and T scores and reduced risk of osteoporosis. Specific gene-exercise interactions were identified in which the AAM polygenic risk score interacted significantly with gymnastics, while the ANM polygenic risk score interacted with lower-limb exercise and swimming. Conclusion Late ANM provides causal protection against osteoporosis in East Asian women, while the effects of AAM remain insignificant. Exercise benefits bone health with activity-specific genetic interactions. These findings support personalized osteoporosis prevention strategies incorporating both genetic risk assessment and targeted exercise recommendations, particularly for women with early menopause predisposition.

Genetic nurture and direct genetic transmission effects on body mass index across age

Genetic trade-offs in fertility and longevity explain the maintenance of disease-associated alleles in humans

Genetic variants that increase the risk for complex diseases persist in human populations, despite adverse effects on health and longevity. Life-history theory predicts that such alleles can be maintained by trade-offs arising from pleiotropy, yet direct genomic evidence has been limited. We asked whether disease-associated variants persist because they enhance reproduction, despite costs to health and lifespan. By analysing genome-wide data across 62 diseases, longevity and fertility, we show that disease-risk alleles are, on average, associated with reduced longevity and increased fertility. Moreover, the subset of alleles that increase both fertility and disease risk appear to have been favoured by natural selection over the past 50,000 years. Using Mendelian randomization, we detect a causal effect of genetic liability to disease on longevity, but no robust evidence for a causal effect on fertility; importantly, these estimates remain stable after adjusting for socioeconomic factors. At the individual level, we compared offspring numbers between affected and unaffected individuals with high polygenic disease risk. For most diseases, affected individuals had more children than unaffected ones. But for early-onset diseases, the pattern reverses, indicating reproductive costs of early morbidity. Together, these results support antagonistic pleiotropy and help explain the persistence of disease-risk alleles in human populations. Despite their detrimental health effects, disease loci persist in human populations. This study shows that disease-risk alleles are generally associated with reduced longevity and increased fertility, while alleles that increase both fertility and disease risk have been favoured by natural selection.