ESPE2022 Poster Category 1 Pituitary, Neuroendocrinology and Puberty (77 abstracts)
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
1Division of Pediatric Endocrinology and Diabetology, Department of Pediatrics II, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; 2Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; 33Institute of Medical Biometry and Statistics, University Medical Center Schleswig-Holstein - Campus Lübeck, University of Lübeck, Lübeck, Germany; 4Department of Pediatrics, Division of Rare Diseases and CeSER, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
Background: 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.
Methods: 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 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, 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.
Results: 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.
Conclusions: 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.
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