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Causal Effect of Age at Menarche on the Risk for Depression: Results From a Two-Sample Multivariable Mendelian
Raphael Hirtz1,2, Christine Hars1, Roaa Naaresh2
1Division of Pediatric Endocrinology and Diabetology, Department of Pediatrics II, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Abstract:
A fair number of epidemiological studies suggest that age at menarche (AAM) is associated with depression, but the reported effect sizes are small, and there is evidence of residual confounding. Moreover, previous Mendelian randomization (MR) studies to avoid inferential problems inherent to epidemiological studies have provided mixed findings. To clarify the causal relationship between age at menarche and broadly defined depression risk, we used 360 genome-wide significantly AAM-related single-nucleotide polymorphisms (SNPs) as instrumental variable and data from the latest GWAS for the broadly defined depression risk on 807,553 individuals (246,363 cases and 561,190 controls). Multiple methods to account for heterogeneity of the instrumental variable (penalized weighted median, MR Lasso, and contamination mixture method), systematic and idiosyncratic pleiotropy (MR RAPS), and horizontal pleiotropy (MR PRESSO and multivariable MR using three methods) were used. Body mass index, education attainment, and total white blood count were considered pleiotropic phenotypes in the multivariable MR analysis. In the univariable [inverse-variance weighted (IVW): OR = 0.96, 95% confidence interval = 0.94-0.98, p = 0.0003] and multivariable MR analysis (IVW: OR = 0.96, 95% confidence interval = 0.94-0.99, p = 0.007), there was a significant causal effect of AAM on depression risk. Thus, the present study supports conclusions from previous epidemiological studies implicating AAM in depression without the pitfalls of residual confounding and reverse causation. Considering the adverse consequences of an earlier AAM on mental health, this finding should foster efforts to address risk factors that promote an earlier AAM.
Insights
Earlier age at menarche (AAM) is causally linked to increased depression risk. This genetic study confirms epidemiological findings, highlighting AAM as a factor in mental health. Addressing earlier AAM may improve well-being.
Area of Science:
- Reproductive Health
- Psychiatric Genetics
- Epidemiology
Background:
- Epidemiological studies suggest an association between age at menarche (AAM) and depression, but findings are limited by small effect sizes and confounding.
- Previous Mendelian randomization (MR) studies have yielded inconsistent results regarding the causal link between AAM and depression.
Purpose of the Study:
- To clarify the causal relationship between age at menarche and broadly defined depression risk using a robust genetic approach.
- To overcome limitations of observational studies, such as residual confounding and reverse causation.
Main Methods:
- Utilized 360 genome-wide significant AAM-related single-nucleotide polymorphisms (SNPs) as instrumental variables.
- Employed data from a large genome-wide association study (GWAS) on depression risk (N=807,553).
- Applied multiple MR methods (penalized weighted median, MR Lasso, MR-RAPS, MR-PRESSO, multivariable MR) to ensure result validity and account for pleiotropy, considering BMI, education, and white blood cell count.
Main Results:
- A significant inverse causal effect of AAM on depression risk was observed in both univariable (IVW: OR=0.96, P=0.0003) and multivariable MR analyses (IVW: OR=0.96, P=0.007).
- Each unit increase in AAM was associated with a reduced odds of depression.
- Robustness checks confirmed the primary findings, indicating a reliable causal link.
Conclusions:
- This study provides strong evidence supporting a causal effect of age at menarche on depression risk.
- Findings align with epidemiological observations but are free from confounding and reverse causation biases.
- Interventions aimed at addressing factors contributing to an earlier AAM may positively impact mental health and reduce depression prevalence.
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