RDoC Mechanisms of Transdiagnostic Polygenic Risk for Trajectories of Depression: From Early Adolescence to Adulthood

Abstract

There is substantial heterogeneity in the development of depression across early adolescence into adulthood. Yet, little is known about the risk factors underlying individual differences in the development of depression. For instance, despite the discovery of genetic variants for depression, there is also significant genetic overlap between depression and other mental disorders. Thus, depression may have etiologically complex (i.e., transdiagnostic) origins when accounting for its heterogeneous developmental presentations. This study examined the association between a transdiagnostic polygenic score for psychopathology (p-factor PGS) and depressive trajectories, spanning early adolescence into adulthood, in the National Longitudinal Study of Adolescent to Adult Health. We also examined whether the Research Domains Criteria (RDoC) negative valence (i.e., negative emotionality), positive valence (i.e., novelty seeking), and cognitive systems (i.e., picture vocabulary) could explain how the p-factor PGS eventuates into the various pathways of depressive development. Four trajectories of depression were identified: low depression (78.9%), low increasing (7.3%), high declining (8.2%), and early adult peaked (5.7%). The p-factor PGS was only associated with the trajectory that showed increasing depression over time -low increasing. There was also a specific indirect effect by which the association of p-factor PGS on early adult peaked and high declining depression was partially mediated by negative emotionality, but not by picture vocabulary or novelty seeking.Our findings reinforce the crucial role of development in genetically-informed RDoC models of depression, as there appear to be distinct correlates and risk factors that underlie the various developmental pathways of depression. Clinical implications were also discussed.General Scientific Summary: There are individual differences in how depression symptoms progress over time, but little is known about the risk factors that underlie these various patterns of development. This study suggests that there are distinct correlates and risk factors that underlie the various developmental pathways of depression. We found that transdiagnostic polygenic risks for psychopathology are directly associated with worsening patterns of adolescent to adult depression and indirectly associated with the less severe patterns of depression via negative emotionality.

Enhancing the Discriminatory Power of ADHD and Autism Spectrum Disorder Polygenic Scores in Clinical and Non-Clinical Samples

“…The issue of whether or not psychiatric PGS models can be made to be more developmentally sensitive is critical to address in future studies, as emerging studies have shown that psychiatric PGS may be better in predicting certain trajectories of psychopathology over others (38).…”

“…Given the potential for confounding due to mixed-informant effects (i.e., adult self-report vs. parent-report of children’s psychiatric disorders), as well as the limited power to detect effects in the adult subsamples for PNC and SPARK, we limited our PGS association analyses to children. The issue of whether or not psychiatric PGS models can be made to be more developmentally sensitive is critical to address in future studies, as emerging studies have shown that psychiatric PGS may be better in predicting certain trajectories of psychopathology over others (38).…”

The need to grow: Developmental considerations and challenges for modern psychiatric taxonomies.

“…The empirical articles in this special section highlight key strengths of the developmental psychology research tradition, including the use of multiple informants (e.g., Liu et al, 2022), longitudinal designs (e.g., Li et al, 2022), and multiple-measure assessments of key constructs. Although we appreciate that not every biobehavioral study of psychopathology can afford to implement each of these strategies, the manifestation of psychopathology over the life span shows remarkable diagnostic heterogeneity and transitions among the spectra (internalizing, externalizing, and thought problems; Caspi et al, 2020).…”

“…We examine this agenda from the perspective of another modern approach to psychiatric classification: the Hierarchical Taxonomy of Psychopathology (HiTOP; Kotov et al, 2017). Building on four of the contributions to this special section (Damme et al, 2022;Li et al, 2022;Liu et al, 2022;Petersen & LeBeau, 2022), we highlight three areas for advancing developmental integration within broadband psychiatric frameworks: (a) the importance of structural models of personality and psychopathology, (b) the value of improving measurement and assessment, and (c) the opportunities offered to such frameworks by stronger integration of developmental context. We articulate ways in which the HiTOP model advances our understanding of mental health and its development beyond the RDoC approach, as well as areas in which developmental integration is lacking in both HiTOP and RDoC frameworks.…”

Integrating development into the Research Domain Criteria (RDoC) framework: Introduction to the special section.

“…Li et al (2022) embrace the emphasis of the RDoC framework on transdiagnostic processes in their examination of associations between a polygenic score (PGS) for general psychopathology (the p factor) and multiple RDoC dimensions, including negative emotionality (an index that spans acute threat, potential threat, sustained threat, loss, and frustrative nonreward, the negative valence domain constructs), novelty seeking (an index of reward responsiveness, a positive valence domain construct), and picture vocabulary (an index of language, a cognitive domain construct), measured using self-report questionnaires and performance on a neurocognitive test. They find that the transdiagnostic PGS predicted depression trajectories during the transition from adolescence into early adulthood, as well as suggestive evidence of a specific indirect association for negative emotionality (but not novelty seeking or picture vocabulary).…”