Age-Dependent Effects of Schizophrenia Genetic Risk on Cortical Thickness and Cortical Surface Area: Evaluating Evidence for Neurodevelopmental and Neurodegenerative Models of Schizophrenia

Risk for schizophrenia peaks during early adulthood, a critical period for brain development. Although several influential theoretical models have been proposed for the developmental relationship between brain pathology and clinical onset, to our knowledge, no study has directly evaluated the predictions of these models for schizophrenia developmental genetic effects on brain structure. To address this question, we introduce a framework to estimate the effects of schizophrenia genetic variation on brain structure phenotypes across the life span. Five-hundred and six participants, including 30 schizophrenia probands, 200 of their relatives (aged 12-85 years) from 32 families with at least two first-degree schizophrenia relatives, and 276 unrelated controls, underwent MRI to assess regional cortical thickness (CT) and cortical surface area (CSA). Genetic variance decomposition analyses were conducted to distinguish among schizophrenia neurogenetic effects that are most salient before schizophrenia peak age-of-risk (i. e., early neurodevelopmental effects), after peak age-of-risk (late neurodevelopmental effects), and during the later plateau of age-of-risk (neurodegenerative effects). Genetic correlations between schizophrenia and cortical traits suggested early neurodevelopmental effects for frontal and insula CSA, late neurodevelopmental effects for overall CSA and frontal, parietal, and occipital CSA, and possible neurodegenerative effects for temporal CT and parietal CSA. Importantly, these developmental neurogenetic effects were specific to schizophrenia and not found with nonpsychotic depression. Our findings highlight the potentially dynamic nature of schizophrenia genetic effects across the lifespan and emphasize the utility of integrating neuroimaging methods with developmental behavior genetic approaches to elucidate the nature and timing of risk-conferring processes in psychopathology. General Scientific Summary This study informs neurodevelopmental models of schizophrenia by showing that schizophrenia genetic risk appears to impact frontal and insula regions before peak age of onset, extend more broadly to frontal, parietal, and occipital regions after peak age of onset, and to a limited extent, parahippocampal and parietal regions during the later plateau of age of onset. Overall, schizophrenia genetic effects may influence different aspects of brain structure before peak, after peak, and during the plateau of schizophrenia age of onset, particularly for cortical surface area compared with cortical thickness phenotypes.

Automated summary

This study investigates the effects of schizophrenia genetic variation on brain structure phenotypes across the lifespan. The results suggest that schizophrenia genetic risk impacts different brain regions at different developmental stages, with frontal and insula regions being affected before the peak age of onset, and frontal, parietal, occipital regions being affected after the peak age of onset. These findings highlight the dynamic nature of schizophrenia genetic effects and the importance of integrating neuroimaging methods with developmental behavior genetic approaches in understanding risk processes in psychopathology.