Aug 2026· Actas espanolas de psiquiatria· Vol 54 4, pp.
1245-1256
· 0 citations
Medicine
TL;DR
This study indicates a potential causal association between genetically predicted PROG levels and a decreased risk of depression.
Abstract
Background
To investigate the potential causal association between sex hormones and depression, a twosample mendelian randomization (MR) analysis was conducted.
Methods
Summary statistics from Genome-wide Association Study (GWAS) on sex hormones and depression were collected. Sex-specific instruments were used to analyze seven sex hormones, including progesterone (PROG) and bioavailable testosterone (BAT). The inverse variance weighted (IVW) method was employed as the primary analysis, and sensitivity analyses were conducted to assess the robustness of the findings.
Results
The IVW analysis revealed genetically significant association between PROG and depression (odds ratio (OR): 0.95, 95% confidence interval (CI): 0.92-0.98, p = 0.002), which remained significant after Bonferroni correction (p < 0.0036). A nominally significant association was observed for BAT (OR: 0.90, 95% CI: 0.82-1.00, p = 0.049) and depression; however, this association did not survive Bonferroni correction. Upon stratification by gender, these associations were no longer significant (p > 0.05). Furthermore, no substantial associations were observed between depression and other sex hormones, including total testosterone (TT), estradiol (E2), follicle-stimulating hormone, prolactin, and luteinizing hormone (p > 0.05). Leave-one-out analyses and funnel plots (indicating balanced pleiotropy), confirmed the reliability of these findings, supporting the robustness of the results. Significant heterogeneity was observed in seven exposures: E2_Female, TT_Male, TT_Both, BAT_Both, BAT_Male, BAT_Female, and TT_Female. Additionally, Mendelian Randomization Pleiotropy Residual Sum and Outlier (MR-PRESSO) analysis identified outliers for BAT_Both, BAT_Female, E2_Female, TT_Both, and TT_Female; however, excluding these outliers did not alter the results.
Conclusions
This study indicates a potential causal association between genetically predicted PROG levels and a decreased risk of depression. While BAT also suggested a potential protective effect, this association was considered suggestive after multiple testing correction and requires further validation.
Genetic evidence of potential associations between antidepressant use and increased risks of Hashimoto's thyroiditis and hypothyroidism is provided, and support consideration of thyroidfunction monitoring in patients receiving antidepressant treatment, particularly those with pre-existing thyroid risk factors.
Yingxian Ling, Qisong Chen· Actas espanolas de psiquiatr...· 0 citations
INTRODUCTION
Growth Hormone (GH) therapy for deficiency carries potential cancer risks with unclear causality. This Mendelian randomization study investigated the relationship between genetically predicted GH levels and cancer risk across 16 types.
METHODS
We selected genetic variants strongly associated with serum GH levels from published GWAS as instrumental variables. The primary analysis employed inverse-variance weighted MR, supplemented by MR-Egger regression. Sensitivity analyses, including MR-PRESSO and pleiotropy tests, were conducted to evaluate robustness. Mediation analysis was performed to assess the contribution of specific metabolites.
RESULTS
Genetic instruments for GH were derived from genome-wide association studies. Analyses suggested GH may be a risk factor for breast cancer, prostate cancer, and malignant lymphoma, and potentially a protective factor for oral/oropharyngeal cancer and skin cancer. Sensitivity analyses partially supported robustness, though notable limitations were present for some outcomes. Mediation analysis revealed that isovalerylglycine (mediating 34.12%) and the proline/trans-4- hydroxyproline ratio (28.40%) partially explained GH's effect on breast cancer, while the histidine/ glutamine ratio mediated 36.28% of GH's effect on prostate cancer.
DISCUSSION
These findings demonstrate tissue-specific effects of GH on carcinogenesis, partially mediated through metabolic pathways. Results suggest careful risk-benefit assessment in GH therapy and suggest metabolite monitoring could help mitigate cancer risk in susceptible individuals.
CONCLUSION
This Mendelian randomization study provides genetic evidence suggesting a potential causal role of GH exposure and the development of specific cancers, partially mediated by certain metabolites. GH shows both promoting and protective effects depending on the cancer type, with important implications for clinical management. The findings highlight the potential value of exploring risk-stratified approaches in GH replacement therapy and suggest further investigation into metabolic interventions to modulate GH-related cancer risk.
Genetic evidence supporting a causal role for depression in the etiology of late-onset AD is provided, a link not observed for other major psychiatric disorders tested and highlighted the specific importance of managing depression as a potential strategy for mitigating AD risk.
Background: Multiple observational studies have reported associations between greater parity and increased CVD risk. Whether these associations reflect causal effects or are confounded by socioeconomic factors remains unclear. Methods: We investigated associations between number of children ever born (NEB) and 16 cardiometabolic traits in up to 172,122 females and 138,390 males in the UK Biobank, and an independent sample of 53,237 UK Biobank spousal pairs. We additionally conducted sex-stratified two-sample Mendelian randomization (MR) and applied a novel spousal MR framework, in which an individual's spouse's genotype was used as the instrumental variable to estimate the causal effect of NEB on cardiometabolic health outcomes, as an approach to minimize bias from horizontal pleiotropy. Results: NEB was associated with multiple cardiometabolic traits in the multivariable regression, even after adjustment for socioeconomic status, with differences in the strength of association observed between males and females. Traditional MR provided evidence that higher NEB causally increases type 2 diabetes risk in females, body mass index (BMI) in both sexes, female basal metabolic rate (BMR) and male body fat percentage but decreases female blood pressure. Spousal MR corroborated positive effects on female BMI and BMR and additionally suggested inverse causal effects on female HDL cholesterol and ApoA1 and male blood glucose. Conclusion: These findings indicate a possible causal relationship between NEB and long-term cardiometabolic health, although causal effects are likely to be small.
C. Brito Nunes, A. Fraser, G. Moen et al.· medRxiv· 0 citations
BACKGROUND
Antagonistic pleiotropy between fertility and survival suggests testosterone may promote fertility at the expense of survival. We investigated sex-specific effects of testosterone on fertility (offspring number) and lifespan (proxied by maternal and paternal attained age), with blood pressure as a control outcome, adjusted for confounders such as body mass index (BMI) using Mendelian randomization.
METHODS
We identified independent (r2 < 0.001) genetic variants strongly (p < 5e-8) predicting testosterone in men (bioavailable) and women (total) from the largest genome-wide association studies (GWAS), and applied them to the largest available sex-specific GWAS summary statistics for maternal and paternal attained age, participant fertility, and blood pressure adjusted for sex-specific BMI.
RESULTS
Testosterone in men (n = 184,205) was inversely associated with lifespan (-0.74 years per standard deviation increase, 95% confidence interval [CI] -1.32 to -0.16) and was positively associated with fertility (0.03 children, 95% CI: 0.01 to 0.05; n = 209,872) after BMI adjustment. Testosterone was not associated with lifespan or fertility in women. Testosterone was associated with the control outcome in men, i.e. higher diastolic blood pressure after BMI adjustment.
CONCLUSIONS
Our findings in men are consistent with antagonistic pleiotropy, i.e. higher testosterone was associated with greater fertility but shorter lifespan.
Z. Jiesisibieke, C. Schooling· The Aging Male· 0 citations
This study aimed to investigate the genetic causality between cataract (senile and other types) and psychiatric disorders using Mendelian randomization (MR). We performed a bidirectional 2-sample MR analysis using genome-wide association studies summary data. Primary analysis employed inverse-variance weighted, MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses included Cochran Q, MR-pleiotropy residual sum and outlier, MR-Egger intercept, and leave-one-out tests to assess heterogeneity and pleiotropy. Forward MR analysis revealed a suggestive causal effect of other cataract on anxiety (inverse-variance weighted odds ratio [OR] = 0.99, 95% confidence interval: 0.98–1.00, P = .043), though unsupported by other methods. MR-Egger and weighted median suggested potential associations between other cataract and bipolar disorder (P < .05). No significant links were found between senile cataract and psychiatric disorders. Reverse MR analysis showed no consistent causal effects, except for anxiety disorder on other cataract (MR-Egger OR = 8.04, P = .040; weighted median OR = 2.99, P = .047). Sensitivity analyses confirmed robustness despite heterogeneity. This study provides evidence of a potential causal relationship between other cataract and anxiety, though findings were method-dependent. No significant associations were observed for senile cataract or most psychiatric disorders.