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. 2022 Jul 12:13:918584.
doi: 10.3389/fgene.2022.918584. eCollection 2022.

Causal Effect of Age at Menarche on the Risk for Depression: Results From a Two-Sample Multivariable Mendelian Randomization Study

Raphael Hirtz  1   2 , Christine Hars  1 , Roaa Naaresh  2 , Björn-Hergen Laabs  3 , Jochen Antel  2 , Corinna Grasemann  4 , Anke Hinney  2 , Johannes Hebebrand  2 , Triinu Peters  2
Affiliations

Causal Effect of Age at Menarche on the Risk for Depression: Results From a Two-Sample Multivariable Mendelian Randomization Study

Raphael Hirtz et al. Front Genet. .

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.

Keywords: BMI; Mendelian randomization; age at menarche; depression; puberty.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Results of the multiple-SNP Mendelian randomization (MR) analyses regarding the effect of age at menarche (AAM) on the risk for depression. OR = odds ratio, CI = confidence interval, b = unstandardized causal estimate of the change in risk for depression per 1-year change in age of menarche.
FIGURE 2
FIGURE 2
Results of the multivariable MR (MVMR) analyses of the causal effect of age at menarche (AAM) on the risk for depression adjusted for BMI in females, educational attainment, and total white blood cell count calculated using three different methods. OR = odds ratio, CI = confidence interval, b = unstandardized causal estimate of the change in risk for depression per 1-year change in age of menarche.
FIGURE 3
FIGURE 3
Results of the multiple-SNP Mendelian randomization (MR) analysis with robust methods regarding the effect of age at menarche (AAM) on the risk for depression. (a) SNPs associated with BMI were excluded (IV with n = 263 SNPs), (b) SNPs associated with BMI, educational attainment (EdAtt), and white blood cell count (WBC) were excluded (IV with n = 185 SNPs). OR = odds ratio, CI = confidence interval, b = unstandardized causal estimate of the change in risk for depression per 1-year change in age of menarche.
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