Assessing causal links between age at menarche and adolescent mental health: a Mendelian randomisation study

Abstract

Background: The timing of puberty may have an important impact on adolescent mental health. In particular, earlier age at menarche has been associated with elevated rates of depression in adolescents. Previous research suggests that this relationship may be causal, but replication and an investigation of whether this effect extends to other mental health domains is warranted.

Methods: In this Registered Report, we triangulated evidence from different causal inference methods using a new wave of data (N = 13,398) from the Norwegian Mother, Father, and Child Cohort Study. We combined multiple regression, one- and two-sample Mendelian randomisation (MR), and negative control analyses (using pre-pubertal symptoms as outcomes) to assess the causal links between age at menarche and different domains of adolescent mental health.

Results: Our results supported the hypothesis that earlier age at menarche is associated with elevated depressive symptoms in early adolescence based on multiple regression (β = - 0.11, 95% CI [- 0.12, - 0.09], p_one-tailed < 0.01). One-sample MR analyses suggested that this relationship may be causal (β = - 0.07, 95% CI [- 0.13, 0.00], p_one-tailed = 0.03), but the effect was small, corresponding to just a 0.06 standard deviation increase in depressive symptoms with each earlier year of menarche. There was also some evidence of a causal relationship with depression diagnoses during adolescence based on one-sample MR (OR = 0.74, 95% CI [0.54, 1.01], p_one-tailed = 0.03), corresponding to a 29% increase in the odds of receiving a depression diagnosis with each earlier year of menarche. Negative control and two-sample MR sensitivity analyses were broadly consistent with this pattern of results. Multivariable MR analyses accounting for the genetic overlap between age at menarche and childhood body size provided some evidence of confounding. Meanwhile, we found little consistent evidence of effects on other domains of mental health after accounting for co-occurring depression and other confounding.

Conclusions: We found evidence that age at menarche affected diagnoses of adolescent depression, but not other domains of mental health. Our findings suggest that earlier age at menarche is linked to problems in specific domains rather than adolescent mental health in general.

Keywords: Age at menarche; Depression; MBRN; Mendelian randomisation; MoBa.

Fig. 1

Overview of the Registered Report process

Fig. 2

Directed acyclic graph illustrating the Mendelian randomisation design. G_j is the jth genetic variant, with direct effect γ_j on exposure X, and direct effect α_j on outcome Y; θ is the estimated causal effect of the exposure on the outcome; ϕ_j is the relationship between confounders U and G_j; dotted lines represent possible violations of the MR assumptions

Fig. 3

Observational and causal links between age at menarche and depression. A Standardised betas of age at menarche predicting adolescent depressive symptoms, based on linear regressions unadjusted and adjusted for covariates and symptoms at age 8, one-sample Mendelian randomisation (MR), and negative control MR with 8-year depressive symptoms as the outcome. B Standardised odds ratios of age at menarche predicting depression diagnoses during adolescence, based on logistic regressions unadjusted and adjusted for covariates, and one-sample MR. In both panels, the orange dashed line represents the smallest effect size of interest for the observational analysis; the blue dashed line represents the smallest effect size of interest for the MR. NB: 95% confidence intervals are presented to show the precision of the estimates, but all statistical tests for depression outcomes were pre-specified to be one-tailed, meaning that the visual interpretation of the CIs in relation to the point null and smallest effect sizes of interest differs from the test result (described in text) in places

Fig. 4

Two-sample MR sensitivity analyses of age at menarche and depressive symptoms. MR sensitivity analyses showing broadly consistent directions of effect (except for MR-Egger), with an earlier age at menarche related to elevated adolescent depressive symptoms. MR, Mendelian randomisation; SNP, single nucleotide polymorphism

Fig. 5

Observational and causal links between age at menarche and other domains. A Standardised betas for age at menarche predicting symptoms in other domains of mental health in adolescence, based on linear regressions unadjusted and adjusted for covariates, concurrent depressive symptoms (age 14) and pre-pubertal symptoms (age 8), one-sample Mendelian randomisation (MR), and negative control MR with 8-year symptoms as outcomes. B Standardised odds ratios of age at menarche predicting diagnoses in other domains of mental health during adolescence (ages 10–17), based on logistic regressions unadjusted and adjusted for covariates, adolescent (ages 10–17) depression diagnoses and childhood diagnoses for each domain (ages 0–8), and one-sample MR. In both panels, the orange dashed line represents the smallest effect size of interest for the observational analysis; the blue dashed line represents the smallest effect size of interest for the MR; 95% confidence intervals are presented. ANX, anxiety; CD, conduct disorder; ODD, oppositional defiant disorder; ADHD, attention-deficit hyperactivity disorder; DBD, disruptive behaviour disorder