No Relationship between Male Pubertal Timing and Depression – New Insights from Epidemiology and Mendelian Randomization

Abstract

BackgroundIn males, the relationship between pubertal timing and depression is understudied and less consistent than in females, likely for reasons of unmeasured confounding. To clarify this relationship, a combined epidemiological and genetic approach was chosen to exploit the methodological advantages of both approaches.MethodsData from 2,026 males from a nationwide study (KiGGS) were used to investigate the non-/linear relationship between pubertal timing defined by the age at voice break and major depressive disorder (MDD), considering a multitude of potential confounders and their interactions with pubertal timing. This analysis was complemented by Mendelian Randomization (MR), which is robust to inferential problems inherent to epidemiological studies. We used 71 single nucleotide polymorphisms related to pubertal timing in males as instrumental variable to clarify its causal relationship with MDD based on data from 807,553 individuals (246,363 cases and 561,190 controls) by univariable and multivariable MR, including BMI as pleiotropic phenotype.ResultsUnivariable MR indicated a causal effect of pubertal timing on MDD risk (inverse-variance weighted: OR=0.93, 95%-CI [0.87–0.99)], p=.03). However, this was not confirmed by multivariable MR (inverse-variance weighted: OR=0.95, 95%-CI [0.88–1.02)], p=.13), consistent with the epidemiological approach (OR=1.01, 95%-CI [0.81–1.26], p=.93). Instead, the multivariable MR study indicated a causal relationship of BMI with MDD by two of three methods.ConclusionsPubertal timing is not related to MDD risk in males. Considering the adverse health outcomes of higher BMI levels, our findings support the rationale for preventive measures to address obesity and its related risk factors.

The causal role of male pubertal timing for the development of externalizing and internalizing traits: results from Mendelian randomization studies

“…), increased body weight has consistently been associated with earlier puberty in boys [25,26]. In addition, body weight is associated with internalizing and externalizing problems [27], suggesting it may serve as a pleiotropic pathway, which is supported by a previous MR study [15]. To analyze whether our results were affected by body weightrelated pleiotropy, effect estimates of MPT on psychological outcomes were calculated, adjusting Male puberty timing and psychological traits for BMI (IVW BMIcorr).…”

“…However, this conclusion rests on a limited number of studies, as noted by the authors of this meta-analysis [2]. Further, a recent large combined epidemiological and MR study including the most comprehensive set of confounders to date, found no evidence of a relationship between (either early or late) MPT and major depressive disorder (MDD) in males [15]. This finding suggests that previous studies may have been affected by confounding, which could also extend to other domains of internalizing traits.…”

“…Thus, this largescale GWAS is less dependent on a specific assessment of MPT and provides a more reliable tool to investigate the causal effect of male pubertal timing on psychopathologies. In a previous MR study, this GWAS was utilized to analyze the effect of MPT on depression but did not find robust evidence for a relationship between both [15]. However, further psychopathologies in males have not been addressed by MR studies so far, despite reasonable evidence for extensive associations of MPT with externalizing and internalizing traits and disorders in epidemiological studies [2].…”