Accelerated Cortical Thinning in Schizophrenia Is Associated With Rare and Common Predisposing Variation to Schizophrenia and Neurodevelopmental Disorders

CIBERSAM group; Javier González-Peñas; Clara Alloza; Rachel Brouwer; Covadonga M Díaz-Caneja; Javier Costas; Noemí González-Lois; Ana Guil Gallego; Lucía de Hoyos; Xaquín Gurriarán; Álvaro Andreu-Bernabeu; Rafael Romero-García; Lourdes Fañanás; Julio Bobes; Ana González-Pinto; Benedicto Crespo-Facorro; Lourdes Martorell; Manuel Arrojo; Elisabet Vilella; Alfonso Gutiérrez-Zotes; Marta Perez-Rando; María Dolores Moltó

doi:10.1016/j.biopsych.2024.03.011

Accelerated Cortical Thinning in Schizophrenia Is Associated With Rare and Common Predisposing Variation to Schizophrenia and Neurodevelopmental Disorders

CIBERSAM group, Javier González-Peñas^*, Clara Alloza, Rachel Brouwer, Covadonga M Díaz-Caneja, Javier Costas, Noemí González-Lois, Ana Guil Gallego, Lucía de Hoyos, Xaquín Gurriarán, Álvaro Andreu-Bernabeu, Rafael Romero-García, Lourdes Fañanás, Julio Bobes, Ana González-Pinto, Benedicto Crespo-Facorro, Lourdes Martorell, Manuel Arrojo, Elisabet Vilella, Alfonso Gutiérrez-ZotesMarta Perez-Rando, María Dolores Moltó

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: Schizophrenia is a highly heritable disorder characterized by increased cortical thinning throughout the life span. 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 with healthy control participants from a large longitudinal sample (ncases = 169 and ncontrols = 298, ages 16-70 years). We studied the correlation between gene expression data from the Allen Human Brain Atlas and accelerated thinning estimates across cortical regions. Finally, we explored the functional and genetic underpinnings of the genes that contribute most to accelerated thinning.

RESULTS: We found a global pattern of accelerated cortical thinning in individuals with schizophrenia compared with healthy control participants. Genes underexpressed in cortical regions that exhibit 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.

Original language	English
Pages (from-to)	376-389
Number of pages	14
Journal	Biological Psychiatry
Volume	96
Issue number	5
DOIs	https://doi.org/10.1016/j.biopsych.2024.03.011
Publication status	Published - 1 Sept 2024
Externally published	Yes

Bibliographical note

Funding

This work was supported by the Spanish Ministry of Science, Innovation and Universities. Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI17/00997, PI19/01024, PI20/00721), co-financed by ERDF Funds from the European Commission, \u201CA way of making Europe\u201D, CIBERSAM. Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds. European Union Seventh Framework Program under grant agreements FP7-4-HEALTH-2009-2.2.1-2-241909 (Project EU-GEI), FP7- HEALTH-2013-2.2.1-2-603196 (Project PSYSCAN), and FP7- HEALTH-2013-2.2.1-2-602478 (Project METSY); and European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement No 115916, Project PRISM, and grant agreement No 777394, Project AIMS-2-TRIALS), Fundaci\u00F3n Familia Alonso, Fundaci\u00F3n Alicia Koplowitz, and Fundaci\u00F3n Mutua Madrile\u00F1a. CM D\u00EDaz-Caneja holds a Juan Rod\u00E9s Grant from Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (JR19/00024). J.G-P holded a Sara Borrell Grant during the development of the research from Instituto de Salud Carlos III (CD20/00118).

Funders	Funder number
Ministry of Science, Innovation and Universities	JR19/00024
Instituto de Salud Carlos III	SAM16PE07CP1, PI16/02012, PI17/00997, PI19/01024, PI20/00721, CD20/00118
European Commission
(Centro de Investigación Biomédica en Red de Salud Menta
Madrid Regional Government	B2017/BMD-3740 AGES-CM-2
European Union Seventh Framework Program	FP7-4-HEALTH-2009-2.2.1-2-241909, FP7- HEALTH-2013-2.2.1-2-603196, FP7- HEALTH-2013-2.2.1-2-602478
Innovative Medicines Initiatives	115916, Project PRISM, 777394, Project AIMS-2-TRIALS
Fundación Familia Alonso
Fundación Alicia Koplowitz
Fundación Mutua Madrileña

Keywords

Brain imaging
Cortical thinning
Genetics
Schizophrenia
Transcriptomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.biopsych.2024.03.011

Cite this

CIBERSAM group, González-Peñas, J., Alloza, C., Brouwer, R., Díaz-Caneja, C. M., Costas, J., González-Lois, N., Gallego, A. G., de Hoyos, L., Gurriarán, X., Andreu-Bernabeu, Á., Romero-García, R., Fañanás, L., Bobes, J., González-Pinto, A., Crespo-Facorro, B., Martorell, L., Arrojo, M., Vilella, E., ... Moltó, M. D. (2024). Accelerated Cortical Thinning in Schizophrenia Is Associated With Rare and Common Predisposing Variation to Schizophrenia and Neurodevelopmental Disorders. Biological Psychiatry, 96(5), 376-389. https://doi.org/10.1016/j.biopsych.2024.03.011

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title = "Accelerated Cortical Thinning in Schizophrenia Is Associated With Rare and Common Predisposing Variation to Schizophrenia and Neurodevelopmental Disorders",

abstract = "BACKGROUND: Schizophrenia is a highly heritable disorder characterized by increased cortical thinning throughout the life span. 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 with healthy control participants from a large longitudinal sample (ncases = 169 and ncontrols = 298, ages 16-70 years). We studied the correlation between gene expression data from the Allen Human Brain Atlas and accelerated thinning estimates across cortical regions. Finally, we explored the functional and genetic underpinnings of the genes that contribute most to accelerated thinning.RESULTS: We found a global pattern of accelerated cortical thinning in individuals with schizophrenia compared with healthy control participants. Genes underexpressed in cortical regions that exhibit 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.",

keywords = "Brain imaging, Cortical thinning, Genetics, Schizophrenia, Transcriptomics",

author = "{CIBERSAM group} and Javier Gonz{\'a}lez-Pe{\~n}as and Clara Alloza and Rachel Brouwer and D{\'i}az-Caneja, {Covadonga M} and Javier Costas and Noem{\'i} Gonz{\'a}lez-Lois and Gallego, {Ana Guil} and {de Hoyos}, Luc{\'i}a and Xaqu{\'i}n Gurriar{\'a}n and {\'A}lvaro Andreu-Bernabeu and Rafael Romero-Garc{\'i}a and Lourdes Fa{\~n}an{\'a}s and Julio Bobes and Ana Gonz{\'a}lez-Pinto and Benedicto Crespo-Facorro and Lourdes Martorell and Manuel Arrojo and Elisabet Vilella and Alfonso Guti{\'e}rrez-Zotes and Marta Perez-Rando and Molt{\'o}, {Mar{\'i}a Dolores} and Elizabeth Buimer and {van Haren}, Neeltje and Wiepke Cahn and Michael O'Donovan and Kahn, {Ren{\'e} S} and Celso Arango and Pol, {Hilleke Hulshoff} and Joost Janssen and Hugo Schnack",

year = "2024",

month = sep,

day = "1",

doi = "10.1016/j.biopsych.2024.03.011",

language = "English",

volume = "96",

pages = "376--389",

journal = "Biological Psychiatry",

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CIBERSAM group, González-Peñas, J, Alloza, C, Brouwer, R, Díaz-Caneja, CM, Costas, J, González-Lois, N, Gallego, AG, de Hoyos, L, Gurriarán, X, Andreu-Bernabeu, Á, Romero-García, R, Fañanás, L, Bobes, J, González-Pinto, A, Crespo-Facorro, B, Martorell, L, Arrojo, M, Vilella, E, Gutiérrez-Zotes, A, Perez-Rando, M & Moltó, MD 2024, 'Accelerated Cortical Thinning in Schizophrenia Is Associated With Rare and Common Predisposing Variation to Schizophrenia and Neurodevelopmental Disorders', Biological Psychiatry, vol. 96, no. 5, pp. 376-389. https://doi.org/10.1016/j.biopsych.2024.03.011

TY - JOUR

T1 - Accelerated Cortical Thinning in Schizophrenia Is Associated With Rare and Common Predisposing Variation to Schizophrenia and Neurodevelopmental Disorders

AU - CIBERSAM group

AU - González-Peñas, Javier

AU - Alloza, Clara

AU - Brouwer, Rachel

AU - Díaz-Caneja, Covadonga M

AU - Costas, Javier

AU - González-Lois, Noemí

AU - Gallego, Ana Guil

AU - de Hoyos, Lucía

AU - Gurriarán, Xaquín

AU - Andreu-Bernabeu, Álvaro

AU - Romero-García, Rafael

AU - Fañanás, Lourdes

AU - Bobes, Julio

AU - González-Pinto, Ana

AU - Crespo-Facorro, Benedicto

AU - Martorell, Lourdes

AU - Arrojo, Manuel

AU - Vilella, Elisabet

AU - Gutiérrez-Zotes, Alfonso

AU - Perez-Rando, Marta

AU - Moltó, María Dolores

AU - Buimer, Elizabeth

AU - van Haren, Neeltje

AU - Cahn, Wiepke

AU - O'Donovan, Michael

AU - Kahn, René S

AU - Arango, Celso

AU - Pol, Hilleke Hulshoff

AU - Janssen, Joost

AU - Schnack, Hugo

PY - 2024/9/1

Y1 - 2024/9/1

N2 - BACKGROUND: Schizophrenia is a highly heritable disorder characterized by increased cortical thinning throughout the life span. 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 with healthy control participants from a large longitudinal sample (ncases = 169 and ncontrols = 298, ages 16-70 years). We studied the correlation between gene expression data from the Allen Human Brain Atlas and accelerated thinning estimates across cortical regions. Finally, we explored the functional and genetic underpinnings of the genes that contribute most to accelerated thinning.RESULTS: We found a global pattern of accelerated cortical thinning in individuals with schizophrenia compared with healthy control participants. Genes underexpressed in cortical regions that exhibit 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.

AB - BACKGROUND: Schizophrenia is a highly heritable disorder characterized by increased cortical thinning throughout the life span. 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 with healthy control participants from a large longitudinal sample (ncases = 169 and ncontrols = 298, ages 16-70 years). We studied the correlation between gene expression data from the Allen Human Brain Atlas and accelerated thinning estimates across cortical regions. Finally, we explored the functional and genetic underpinnings of the genes that contribute most to accelerated thinning.RESULTS: We found a global pattern of accelerated cortical thinning in individuals with schizophrenia compared with healthy control participants. Genes underexpressed in cortical regions that exhibit 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.

KW - Brain imaging

KW - Cortical thinning

KW - Genetics

KW - Schizophrenia

KW - Transcriptomics

U2 - 10.1016/j.biopsych.2024.03.011

DO - 10.1016/j.biopsych.2024.03.011

M3 - Article

C2 - 38521159

SN - 0006-3223

VL - 96

SP - 376

EP - 389

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 5

ER -

Accelerated Cortical Thinning in Schizophrenia Is Associated With Rare and Common Predisposing Variation to Schizophrenia and Neurodevelopmental Disorders

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

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Cite this