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Background: A growing body of neuroimaging studies has reported common neural abnormalities among mental disorders in adults. However, it is unclear whether the distinct disorder-specific mechanisms operate during adolescence despite the overlap among disorders. Methods: We studied a large cohort of more than 11 000 preadolescent (age 9-10 yr) children from the Adolescent Brain and Cognitive Development cohort. We adopted a regrouping approach to compare cortical thickness (CT) alterations and longitudinal changes between healthy controls (n = 4041) and externalizing (n = 1182), internalizing (n = 1959) and thought disorder (n = 347) groups. Genome-wide association study (GWAS) was performed on regional CT across 4468 unrelated European youth. Results: Youth with externalizing or internalizing disorders exhibited increased regional CT compared with controls. Externalizing (p = 8 x [10.sup.-4], Cohen d = 0.10) and internalizing disorders (p = 2 x [10.sup.-3], Cohen d = 0.08) shared thicker CT in the left pars opercularis. The somatosensory and the primary auditory cortex were uniquely affected in externalizing disorders, whereas the primary motor cortex and higher-order visual association areas were uniquely affected in internalizing disorders. Only youth with externalizing disorders showed decelerated cortical thinning from age 10-12 years. The GWAS found 59 genome-wide significant associated genetic variants across these regions. Cortical thickness in common regions was associated with glutamatergic neurons, while internalizing-specific regional CT was associated with astrocytes, oligodendrocyte progenitor cells and GABAergic neurons. Limitations: The sample size of the GWAS was relatively small. Conclusion: Our study provides strong evidence for the presence of specificity in CT, developmental trajectories and underlying genetic underpinnings among externalizing and internalizing disorders during early adolescence. Our results support the neurobiological validity of the regrouping approach that could supplement the use of a dimensional approach in future clinical practice., Introduction During the past 2 decades, long-standing diagnostic categories of mental disorders, based on the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD), have [...]