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Accelerated cortical thinning in schizophrenia is associated with rare and common predisposing variation to schizophrenia and neurodevelopmental disorders

González-Peñas, Javier, Alloza, Clara, Brouwer, Rachel, Díaz-Caneja, Covadonga M, Costas, Javier, González-Lois, Noemi, Gallego, Ana Guil, de Hoyos, Lucia, Gurriarán, Xaquín, Andreu-Bernabeu, Álvaro, Romero-García, Rafael, Fananas, Lourdes, Bobes, Julio, Gonzales Pinto, Ana, Crespo-Facorro, Benedicto, Martorell, Lourdes, Arrojo, Manuel, Vilella, Elisabet, Guitiérrez-Zotes, Alfonso, Perez-Rando, Marta, Moltó, María Dolores, CIBERSAM group, Buimer, Elizabeth, van Haren, Neeltje, Cahn, Wiepke, O'Donovan, Michael ORCID:, Kahn, Rene, Arango, Celso, Hulshoff Pol, Hilleke, Janssen, Joost and Schnack, Hugo 2024. Accelerated cortical thinning in schizophrenia is associated with rare and common predisposing variation to schizophrenia and neurodevelopmental disorders. Biological Psychiatry 10.1016/j.biopsych.2024.03.011
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Background: Schizophrenia is a highly heritable disorder characterized by increased cortical thinning throughout the lifespan. Studies have reported a shared genetic basis between schizophrenia and cortical thickness. However, no genes whose expression is related to abnormal cortical thinning in schizophrenia have been identified. Methods: We conducted linear mixed models to estimate the rates of accelerated cortical thinning across 68 regions from the Desikan-Killiany atlas in individuals with schizophrenia compared to healthy controls from a large longitudinal sample (NCases = 169 and NControls = 298, aged 16-70 years). We studied the correlation between gene expression data from the Allen Human Brain Atlas and accelerated thinning estimates across cortical regions. We finally explored the functional and genetic underpinnings of the genes most contributing to accelerated thinning. Results: We described a global pattern of accelerated cortical thinning in individuals with schizophrenia compared to healthy controls. Genes underexpressed in cortical regions exhibiting this accelerated thinning were downregulated in several psychiatric disorders and were enriched for both common and rare disrupting variation for schizophrenia and neurodevelopmental disorders. In contrast, none of these enrichments were observed for baseline cross-sectional cortical thickness differences. Conclusions: Our findings suggest that accelerated cortical thinning, rather than cortical thickness alone, serves as an informative phenotype for neurodevelopmental disruptions in schizophrenia. We highlight the genetic and transcriptomic correlates of this accelerated cortical thinning, emphasizing the need for future longitudinal studies to elucidate the role of genetic variation and the temporal-spatial dynamics of gene expression in brain development and aging in schizophrenia.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Elsevier
ISSN: 0006-3223
Date of First Compliant Deposit: 19 March 2024
Date of Acceptance: 5 March 2024
Last Modified: 28 Mar 2024 18:07

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