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

CIBERSAM group

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

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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 (n_cases = 169 and n_controls = 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
Early online date	21 Mar 2024
DOIs	https://doi.org/10.1016/j.biopsych.2024.03.011
Publication status	Published - 1 Sept 2024

Bibliographical note

Publisher Copyright:
© 2024 Society of Biological Psychiatry

Funding

This work was supported by Spanish Ministry of Science , Innovation and Universities Instituto de Salud Carlos III (Grant Nos. SAM16PE07CP1 , PI16/02012 , PI17/00997 , PI19/01024 , and PI20/00721 ), cofinanced by European Regional Development Funds from the European Commission, \u201CA way of making Europe,\u201D CIBERSAM (Centro de Investigaci\u00F3n Biom\u00E9dica en Red de Salud Menta); Madrid Regional Government (Grant No. B2017/BMD-3740 AGES-CM-2 ), European Union Structural Funds; the European Union Seventh Framework Program (Grant Nos. 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 the European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (Grant No. 115916, Project PRISM, and Grant No. 777394, Project AIMS-2-TRIALS), Fundaci\u00F3n Familia Alonso, Fundaci\u00F3n Alicia Koplowitz, and Fundaci\u00F3n Mutua Madrile\u00F1a. CMD-C holds a Juan Rod\u00E9s Grant from Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (Grant No. JR19/00024). JG-P held a Sara Borrell grant during the development of the research from Instituto de Salud Carlos III (Grant No. CD20/00118). CA has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion, and Takeda. CMD-C has received honoraria from AbbVie, Sanofi, and Exeltis. BC-F has received honoraria (advisory board and educational lectures) and travel expenses from Takeda, Menarini, Angelini, Teva, Otsuka, Lundbeck, and Johnson & Johnson. He has also received unrestricted research grants from Lundbeck. XG received a grant from Fundaci\u00F3n Instituto Roche. All other authors report no biomedical financial interests or potential conflicts of interest.

Funders	Funder number
Fundación Familia Alonso
Instituto de Salud Carlos III
Fundación Alicia Koplowitz
European Commission
Fundación Instituto Roche
Centro de Investigación Biomédica en Red de Salud Mental
Fundación Mutua Madrileña
FP7 Health
European Regional Development Fund
Seventh Framework Programme	FP7-4-HEALTH-2009-2.2.1-2-241909, FP7- HEALTH-2013-2.2.1-2-603196
Innovative Medicines Initiative	115916, AIMS-2-TRIALS, 777394
Ministerio de Ciencia e Innovación	CD20/00118, JR19/00024
Ministerio de Ciencia, Innovación y Universidades	PI17/00997, PI19/01024, PI20/00721, SAM16PE07CP1, PI16/02012
Madrid Regional Government	B2017/BMD-3740 AGES-CM-2

Keywords

Brain imaging
Cortical thinning
Genetics
Schizophrenia
Transcriptomics

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10.1016/j.biopsych.2024.03.011

Accelerated Cortical Thinning in Schizophrenia Is Associated With Rare and Common Predisposing Variation to Schizophrenia and Neurodevelopmental DisordersFinal published version, 3.61 MBLicence: Article 25fa Dutch Copyright Act

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@article{5ac487bc253b4f44ab9eaabf7beb417b,

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 = "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}anas and Julio Bobes and Ana Gonz{\'a}lez-Pinto and B. Crespo-Facorro and L. 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 Lourdes Fa{\~n}anas and \{Rosa de la Cruz\}, Araceli and B{\'a}rbara Arias and Pinto, \{Ana Gonz{\'a}lez\} and B. Crespo-Facorro and L. Martorell and Gerard Muntan{\'e} and Escart{\'i}, \{Mar{\'i}a Jos{\'e}\} and Olga Rivero and Mara Parellada and Carmen Moreno and Celso Arango and Elizabeth Buimer and \{van Haren\}, Neeltje and Wiepke Cahn and Michael O'Donovan and Kahn, \{Ren{\'e} S.\} and Pol, \{Hilleke Hulshoff\} and Joost Janssen and Hugo Schnack and \{CIBERSAM group\}",

note = "Publisher Copyright: {\textcopyright} 2024 Society of Biological Psychiatry",

year = "2024",

month = sep,

day = "1",

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

language = "English",

volume = "96",

pages = "376--389",

journal = "Biological psychiatry",

issn = "0006-3223",

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TY - JOUR

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

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 - Fañanas, Lourdes

AU - Bobes, Julio

AU - González-Pinto, Ana

AU - Crespo-Facorro, B.

AU - Martorell, L.

AU - Arrojo, Manuel

AU - Vilella, Elisabet

AU - Gutiérrez-Zotes, Alfonso

AU - Perez-Rando, Marta

AU - Moltó, María Dolores

AU - Fañanas, Lourdes

AU - Rosa de la Cruz, Araceli

AU - Arias, Bárbara

AU - Pinto, Ana González

AU - Crespo-Facorro, B.

AU - Martorell, L.

AU - Muntané, Gerard

AU - Escartí, María José

AU - Rivero, Olga

AU - Parellada, Mara

AU - Moreno, Carmen

AU - Arango, Celso

AU - Buimer, Elizabeth

AU - van Haren, Neeltje

AU - Cahn, Wiepke

AU - O'Donovan, Michael

AU - Kahn, René S.

AU - Pol, Hilleke Hulshoff

AU - Janssen, Joost

AU - Schnack, Hugo

AU - CIBERSAM group

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

UR - https://www.scopus.com/pages/publications/85192488593

UR - https://www.scopus.com/inward/citedby.url?scp=85192488593&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2024.03.011

DO - 10.1016/j.biopsych.2024.03.011

M3 - Article

C2 - 38521159

AN - SCOPUS:85192488593

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

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