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Genetic susceptibility for major depressive disorder associates with trajectories of depressive symptoms across childhood and adolescence

By Alexandre A. Lussier, Matt Hawrilenko, Min-Jung Wang, Karmel W Choi, Janine Cerutti, Yiwen Zhu, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Erin C Dunn

Posted 06 Mar 2020
medRxiv DOI: 10.1101/2020.03.02.19007088

BackgroundDepression that onsets during childhood and adolescence is associated with worse illness course and outcomes. However, the genetic factors that influence risk for early-onset depression remain mostly unknown. Using data collected over thirteen years, we examined whether polygenic risk scores (PRS) capturing genetic risk for major depressive disorder (MDD) were associated with early-onset depressive symptoms, as assessed from childhood to adolescence. MethodsData came from the Avon Longitudinal Study of Parents and Children, a prospective, longitudinal birth cohort (analytic sample=7,308 youth). We analyzed the relationship between genetic susceptibility to depression and three time-dependent measures of depressive symptoms across ages 4-16.5 (trajectories, onset, and cumulative burden of symptoms). Trajectories were constructed using a growth mixture model with structured residuals. Symptom onset and cumulative burden were assessed using the intercept and area under the trajectory curves, respectively. PRS were generated using MDD summary statistics from the Psychiatric Genomics Consortium. We used MAGMA to identify gene-level associations with these measures. ResultsYouth were classified into six classes of depressive symptom trajectories: high/renitent (26.5% of youth), high/reversing (5.8%), childhood decrease (6.1%), late childhood peak (3%), adolescent spike (2.5%), and minimal symptoms (56.1%). PRS could discriminate between youth in the "high" classes compared to the minimal symptoms and childhood decrease classes. Two genes (SIX5; DMPK) were nominally associated with both onset and cumulative burden. ConclusionsThis study highlights a role for genetic factors in shaping depressive symptoms across childhood and adolescence, particularly among youths with generally high or low symptoms, regardless of age-independent responding.

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