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Background: Children with neurodevelopmental disorders are at increased risk of developing depression. Irritability predicts depression in the general population and is common in children with neurodevelopmental disorders. Thus, it is possible that irritability in children with neurodevelopmental disorders contributes to the link with later depression. This study aimed to (1) examine the association between childhood neurodevelopmental difficulties and adolescent depression and (2) test whether irritability explains this association.Methods: Children with any neurodevelopmental difficulty at age 7-9 (n=1697) and a selected, comparison group without any neurodevelopmental difficulty (n=3177) were identified from a prospective, UK population-based cohort, the Avon Longitudinal Study of Parents and Children. Neurodevelopmental difficulties were defined as a score in the bottom 5% of the sample on at least one measure of cognitive ability, communication, autism spectrum symptoms, attention-deficit/hyperactivity symptoms, reading or motor co-ordination. The Development and Well Being Assessment measured parent-reported child irritability at age 7, parent-reported adolescent depression at ages 10 and 13, and self-reported depression at age 15. Depression measures were combined, deriving an outcome of Major Depressive Disorder (MDD) in adolescence. Logistic regression examined the association between childhood neurodevelopmental difficulties and adolescent MDD, controlling for gender. Path analysis estimated the proportion of this association explained by irritability. Analyses were repeated for individual neurodevelopmental problems.Results: Childhood neurodevelopmental difficulties were associated with adolescent MDD (OR=2.11, 95% CI=1.24,3.60, p=0.006). Childhood irritability statistically accounted for 42% of this association. On examining each neurodevelopmental difficulty separately, autistic, communication and ADHD problems were each associated with depression, with irritability explaining 29%-51% of these links.Conclusions: Childhood irritability appears to be a key contributor to the link between childhood neurodevelopmental difficulties and adolescent MDD. High rates of irritability in children with autistic and ADHD difficulties may explain elevated rates of depression in the neurodevelopmental group.

Key Points Question Do neuropsychiatric disorder genetic risk variants influence developmental trajectories of depression in youth? Findings In this population-based study including 7543 adolescents, distinct depression trajectory classes were identified. A later-adolescence–onset class (17.3% of the sample) showed a typical depression trajectory and was associated with major depressive disorder risk alleles, and an early-adolescence–onset class (9.0%) showed clinically significant symptoms at age 12 years and was associated with schizophrenia and attention-deficit hyperactivity disorder genetic risk, childhood attention-deficit hyperactivity disorder, and neurodevelopmental traits. Meaning Depression in youth is heterogeneous; findings are consistent with emerging evidence for a neurodevelopmental component to some cases of depression and that this component is more likely when onset is very early., Importance Depression often first manifests in adolescence. Thereafter, individual trajectories vary substantially, but it is not known what shapes depression trajectories in youth. Adult studies suggest that genetic risk for schizophrenia, a psychiatric disorder with a neurodevelopmental component, may contribute to an earlier onset of depression. Objective To test the hypothesis that there are distinct trajectories of depressive symptoms and that genetic liability for neurodevelopmental psychiatric disorders (eg, schizophrenia, attention deficit/hyperactivity disorder [ADHD]), as well as for major depressive disorder (MDD), contribute to early-onset depression. Design, Setting, and Participants The Avon Longitudinal Study of Parents and Children is an ongoing, prospective, longitudinal, population-based cohort that has been collecting data since September 6, 1990, including data on 7543 adolescents with depressive symptoms at multiple time points. The present study was conducted between November 10, 2017, and August 14, 2018. Main Outcomes and Measures Trajectories based on self-reported depressive symptoms dichotomized by the clinical cutpoint; MDD, schizophrenia, and ADHD polygenic risk score (PRS) were predictors. Results In 7543 adolescents with depression data on more than 1 assessment point between a mean (SD) age of 10.64 (0.25) years and 18.65 (0.49) years (3568 [47.3%] male; 3975 [52.7%] female), 3 trajectory classes were identified: persistently low (73.7%), later-adolescence onset (17.3%), and early-adolescence onset (9.0%). The later-adolescence–onset class was associated with MDD genetic risk only (MDD PRS: odds ratio [OR], 1.27; 95% CI, 1.09-1.48; P = .003). The early-adolescence–onset class was also associated with MDD genetic risk (MDD PRS: OR, 1.24; 95% CI, 1.06-1.46; P = .007) but additionally with genetic risk for neurodevelopmental disorders (schizophrenia PRS: OR, 1.22; 95% CI, 1.04-1.43; P = .01; ADHD PRS: OR, 1.32; 95% CI, 1.13-1.54; P, This population-based study examines the association between genetic risk variants for neuropsychiatric disorders and the age at onset and trajectories of depression in children.