Joint contributions of genetic risk and pubertal maturation to internalizing symptoms in adolescents

Adolescence is a developmental period encompassing a wide range of emotional, cognitive, social, and biological changes (Vijayakumar et al., 2018). A steep rise in internalizing disorders such as depression and anxiety is observed during this transition period (Pfeifer & Allen, 2021). Puberty, a biological process which results in reproductive maturity, is thought to play a central role in this increase (Pfeifer & Allen, 2021). While pubertal maturation is often characterized by visible physical changes, it is driven by hormonal fluctuations which influence brain maturation, stress responses, and socioemotional processing (Beck et al., 2023; Dorn & Biro, 2011; McCann et al., 2026; Vijayakumar et al., 2018). Notably, by mid-puberty, the prevalence of internalizing disorders is doubled in females compared to males (Angold et al., 1998; Hayward & Sanborn, 2002; Ullsperger & Nikolas, 2017). The emergence of this sex difference is more closely aligned with pubertal maturation than with chronological age, underscoring puberty as a window of sex-specific vulnerability for internalizing psychopathology (Angold et al., 1998). Youth differ in both the timing and tempo of pubertal development. Whereas pubertal timing reflects an individual’s pubertal status relative to same-age, same-sex peers, pubertal tempo captures the rate at which the individual progresses through puberty over time (Mendle et al., 2010). Pubertal timing is a well-established risk factor for internalizing symptoms, with earlier pubertal timing conferring heightened risk across both sexes (Ullsperger & Nikolas, 2017). Some studies suggest that late pubertal timing may also confer risk, particularly in males, although findings are less robust (Graber, 2013; Kaltiala-Heino et al., 2003; Mendle et al., 2010). In contrast, the associations between pubertal tempo and internalizing symptoms are not clear, as studies have reported mixed findings (Beltz et al., 2014; Cheng et al., 2020; Deardorff et al., 2021; Kowalski et al., 2021; MacSweeney et al., 2025; Marceau et al., 2011; Mendle et al., 2010). For instance, one study reported that faster pubertal tempo is associated with higher internalizing symptoms only in males (Mendle et al., 2010), while another found associations only in females (Kowalski et al., 2021). Given this heterogeneity, pubertal characteristics may not predict internalizing risk alone but rather in interaction with concurrent risk-factors and pre-existing vulnerabilities. One such vulnerability is genetic predisposition to internalizing symptoms, which may help explain why some adolescents are more sensitive to pubertal maturation than others. Twin and genomic studies indicate that internalizing symptoms, particularly anxiety and depressive phenotypes, are moderately heritable (Kendall et al., 2021; Shimada-Sugimoto et al., 2015; Sullivan et al., 2000). Large genome-wide association studies further demonstrate that these traits are associated with thousands of common genetic variants, and polygenic risk scores (PRSs) provide a way to quantify this cumulative genetic signal (Als et al., 2023; Howard et al., 2018; Purves et al., 2020). PRSs for major depressive disorder (MDD), broad depression (DEP), anxiety disorder (ANX), neuroticism (NEU), and attempted suicide (AS) have all been associated with internalizing symptoms in adolescents (Kwong et al., 2021; Loughnan et al., 2022). However, PRSs are seldom examined in the context of puberty, despite puberty being a sensitive window for large-scale, sex-specific shifts in gene expression (Morrison et al., 2014; Peña, 2025). Integrating PRSs with pubertal timing and tempo therefore provides a means of testing whether the association between genetic risk and internalizing symptoms differs across trajectories of pubertal maturation. In the present study, we leverage longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study® (release 6.0) to investigate whether genetic risk and pubertal development interactively contribute to internalizing symptoms across adolescence. Genetic risk will be measured with PRSs for MDD, DEP, ANX, NEU, and AS, to capture distributed genetic liability for internalizing problems. Our primary aim is to test for interactions between internalizing-related PRSs and both pubertal timing and tempo to predict internalizing symptoms within sex, evaluating whether pubertal maturation moderates the associations between genetic vulnerability and symptoms. Next, we will test for sex differences in PRSs to determine whether associations between genetic risk and internalizing symptoms differ by sex, consistent with the possibility that genetic liability is expressed differently in females and males during adolescence. By integrating genomic risk with longitudinal measures of pubertal development in a large cohort, this study provides a novel opportunity to clarify the variability in associations between puberty and internalizing risk.