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Mendelian randomization of risk factors for premenstrual disorders
Yihui Yang1, Bowen Tang2, Elgeta Hysaj2
1Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. yihui.yang.2@ki.se.
Abstract:
The causal role of established risk factors for premenstrual disorders (PMDs) remains unclear. We used Mendelian randomization (MR) to assess causality for eight known-risk factors identified through a literature review. Summary statistics for these risk factors were from genome-wide association studies (GWAS) with sample size ranging from 129,017 to 1.2 million, and for PMDs from a GWAS of 72,297 participants. Findings were validated using one-sample MR in LifeGene cohort (n = 5674-5937). In two-sample MR, genetic liability to smoking initiation (OR = 1.25 (1.10-1.43)), earlier menarche (OR = 0.94 (0.89-0.98) per year), and higher BMI (OR = 1.19 (1.05-1.34) per kg/m2) were associated with PMD risk. No causal association was indicated for anemia, childhood abuse, childhood asthma, diabetes, and endometriosis. In one-sample MR, point estimates for BMI (OR = 1.10 (0.88-1.38) per kg/m²) and earlier menarche (OR = 0.98 (0.83-1.15) per year) were directionally consistent with the two-sample MR findings, but the confidence intervals included null effects. However, a null association was observed for smoking (OR = 0.94 (0.77-1.16)). The two-sample MR supports causal role of earlier menarche, higher BMI, and smoking in risk of PMDs. The lack of replication in one-sample MR highlights the need for triangulating evidence from future well-powered and methodologically comparable studies to strengthen these findings.
Insights
Mendelian randomization suggests earlier menarche, higher BMI, and smoking increase premenstrual disorder (PMD) risk. Further studies are needed to confirm these causal links for PMD development.
Area of Science:
- Reproductive Health
- Genetic Epidemiology
- Psychiatry
Background:
- The causal factors contributing to premenstrual disorders (PMDs) are not fully understood.
- Established risk factors require causal validation to inform prevention and treatment strategies.
Purpose of the Study:
- To investigate the causal relationships between eight established risk factors and premenstrual disorders (PMDs) using Mendelian randomization.
- To assess the potential causal roles of factors including smoking, menarche timing, BMI, anemia, childhood abuse, asthma, diabetes, and endometriosis in PMD risk.
Main Methods:
- Employed two-sample Mendelian randomization (MR) utilizing large genome-wide association study (GWAS) summary statistics for risk factors and PMDs.
- Validated findings using one-sample MR in the LifeGene cohort to assess robustness of associations.
- Analyzed genetic liability to smoking initiation, age at menarche, body mass index (BMI), anemia, childhood abuse, asthma, diabetes, and endometriosis.
Main Results:
- Two-sample MR indicated that genetic liability to smoking initiation (OR=1.25), earlier menarche (OR=0.94 per year), and higher BMI (OR=1.19 per kg/m²) are causally associated with increased PMD risk.
- No causal associations were detected for anemia, childhood abuse, childhood asthma, diabetes, or endometriosis.
- One-sample MR results were directionally consistent for BMI and earlier menarche but did not reach statistical significance, and smoking showed a null association, highlighting potential limitations or heterogeneity.
Conclusions:
- Mendelian randomization provides evidence supporting a causal role for earlier menarche, higher BMI, and smoking in the risk of developing premenstrual disorders (PMDs).
- The lack of consistent replication in the one-sample MR analysis underscores the need for future large-scale, methodologically rigorous studies to confirm these findings and elucidate PMD etiology.
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