Interindividual Differences in Cortical Thickness and Their Genomic Underpinnings in Autism Spectrum Disorder

EU-AIMS LEAP group

doi:10.1176/appi.ajp.2021.20050630

Interindividual Differences in Cortical Thickness and Their Genomic Underpinnings in Autism Spectrum Disorder

EU-AIMS LEAP group

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

40 Citations (Scopus)

Abstract

Objective: Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions. Methods: The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6–30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features. Results: In addition to significant between-group differences in “core” ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals’ total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission. Conclusions: The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.

Original language	English
Pages (from-to)	242-254
Number of pages	13
Journal	American Journal of Psychiatry
Volume	179
Issue number	3
DOIs	https://doi.org/10.1176/appi.ajp.2021.20050630
Publication status	Published - Mar 2022

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10.1176/appi.ajp.2021.20050630

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@article{58cd8cc6c2274efba7807d05fc9382b9,

title = "Interindividual Differences in Cortical Thickness and Their Genomic Underpinnings in Autism Spectrum Disorder",

abstract = "Objective: Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions. Methods: The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6–30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features. Results: In addition to significant between-group differences in “core” ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals{\textquoteright} total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission. Conclusions: The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.",

author = "{EU-AIMS LEAP group} and Christine Ecker and Pretzsch, {Charlotte M.} and Anke Bletsch and Caroline Mann and Tim Schaefer and Sara Ambrosino and Julian Tillmann and Afsheen Yousaf and Andreas Chiocchetti and Lombardo, {Michael V.} and Varun Warrier and Nico Bast and Carolin Moessnang and Sarah Baumeister and Flavio Dell{\textquoteright}Acqua and Floris, {Dorothea L.} and Mariam Zabihi and Andre Marquand and Freddy Cliquet and Claire Leblond and Clara Moreau and Nick Puts and Tobias Banaschewski and Jones, {Emily J.H.} and Luke Mason and Sven B{\"o}lte and Andreas Meyer-Lindenberg and Persico, {Antonio M.} and Sarah Durston and Simon Baron-Cohen and Will Spooren and Eva Loth and Freitag, {Christine M.} and Tony Charman and Guillaume Dumas and Thomas Bourgeron and Beckmann, {Christian F.} and Buitelaar, {Jan K.} and Murphy, {Declan G.M.} and Jumana Ahmad and Michael Brammer and Daisy Crawley and Jessica Faulkner and Hannah Hayward and Lythgoe, {David J.} and Bethany Oakley and Barbara Ruggeri and {San Jos{\'e} C{\'a}ceres}, Antonia and Emily Simonoff and Williams, {Steve C.R.}",

note = "Funding Information: This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 115300 for the project EU-AIMS and no. 777394 for the project AIMS-2-TRIALS. This Joint Undertaking receives support from the European Union{\textquoteright}s Horizon 2020 research and innovation programme, the European Federation of Pharmaceutical Industries and Associates, Autism Speaks, Autistica, and SFARI. Dr. Ecker gratefully acknowledges support from the German Research Foundation under the Heisenberg Programme (EC480/1-1 and EC480/2-1). Dr. Murphy acknowledges support from the NIHR Maudsley Biomedical Research Centre. Funding Information: Dr. Tillmann has served as a consultant for Hoffmann–La Roche. Dr. Banaschewski has served as an adviser or consultant for Actelion, ADHS Digital, Eli Lilly, Hexal Pharma, Infectopharm, Lundbeck, Medice, Neurim Pharmaceuticals, Novartis, Oberberg GmbH, Otsuka, Oxford Outcomes, PCM Scientific, Roche, Shire, Takeda, and Vifor Pharma; he has received conference support or speaking fees from Medice, Novartis, Shire, and Takeda; he has been involved in clinical trials conducted by Shire and Vifor Pharma; and he has received royalties from CIP Medien, Hogrefe, Kohl-hammer, and Oxford University Press. Dr. Jones has received funding from Action Medical Research, EU Horizon 2020, the Innovative Medicines Initiative, the Medical Research Council (UK), MQ: Transforming Mental Health, and the Economic and Social Research Council. Dr. B{\"o}lte has served as an author, consultant, or lecturer for Ability Partner, Eli Lilly, Expo Medica, GLGroup, Kompetento, Medice, Prima Psychiatry, Prophase, Roche, Shire, and System Analytic, and he receives royalties for textbooks and diagnostic tools from Huber/Hogrefe, Kohlhammer, and UTB. Dr. Meyer-Lindenberg has served as a consultant for the Agence Nationale de la Recherche, the American Association for the Advancement of Science, Atheneum Partners, Blueprint Partnership, Boehringer Ingelheim, the Brain Mind Institute, BrainsWay, the Catania International Summer School of Neuroscience, Daimler und Benz Stiftung, Elsevier, the Fondation FondaMental, Janssen-Cilag, Hoffmann–La Roche, ICARE Schizophrenia, K.G. Jebsen Foundation, L.E.K. Consulting, The LOOP Z{\"u}rich, Lundbeck A/S, Lundbeck International Neuroscience Foundation, MedinCell, Roche Pharma, Sage Therapeutics, Sumitomo Dainippon Pharma, Synapsis Foundation–Alzheimer Research Switzerland, System Analytics, Tech-spert.io, Thieme Verlag, and von Behring R{\"o}ntgen Stiftung, and he has received speaking fees from BAG Psychiatrie Oberbayern, Biotest AG, Boehringer Ingelheim, Fama Public Relations, Forum Werkstatt Karlsruhe, Institut d{\textquoteright}Investigacions Biom{\`e}diques August Pi i Sunyer (IDIBAPS), the International Society of Psychiatric Genetics, Janssen-Cilag, Klinik f{\"u}r Psychiatrie und Psychotherapie, Klinikum Christophsbad, G{\"o}ppingen, Lilly Deutschland, Lundbeck SAS France, Luzerner Psychiatrie, LVR Klinikum D{\"u}sseldorf, LWL Psychiatrie Verbund Westfalen-Lippe, Med Update GmbH, Merz-Stiftung, Otsuka Pharmaceuticals, Reunions i Ciencia S.L., Siemens Healthineers, Spanish Society of Psychiatry, S{\"u}dwestrundfunk Fernsehen, Stern TV, and Vitos Klinikum Kurhessen. Dr. Baron-Cohen has served as an author, consultant, or lecturer for Ability Partner, Clarion Healthcare, Expo Medica, Eli Lilly, GLGroup, Kompetento, Medice, Prima Psychiatry, Prophase, Roche, Shire, and System Analytic; he receives royalties for textbooks and diagnostic tools from Huber/Hogrefe, Kohl-hammer, and UTB. Dr. Spooren is an employee of F. Hoffmann–La Roche. Dr. Freitag receives royalties for books on autism spectrum disorder, ADHD, and major depressive disorder. Dr. Charman has received research grant support from the Medical Research Council (UK), the National Institute for Health Research, Horizon 2020 and the Innovative Medicines Initiative (European Commission), MQ, Autistica, FP7 (European Commission), the Charles Hawkins Fund, and the Waterloo Foundation; he has served as a consultant for F. Hoffmann–La Roche and Servier; and he has received royalties from Guilford Publications and Sage Publications. Dr. Beckmann is co-founder of SBGneuro. Dr. Buitelaar has served as a consultant, advisory board member, and/or speaker for Angelini, Janssen Cilag BV, Novartis, Medice, Roche, Servier, and Takeda/Shire. Dr. Murphy has received honoraria from Roche and Servier, and he has received grant support from the Medical Research Council (UK), the National Institute for Health Research, and Horizon 2020 and the Innovative Medicines Initiative (European Commission). The other authors report no financial relationships with commercial interests. Publisher Copyright: {\textcopyright} 2022 American Psychiatric Association. All rights reserved.",

year = "2022",

month = mar,

doi = "10.1176/appi.ajp.2021.20050630",

language = "English",

volume = "179",

pages = "242--254",

journal = "American Journal of Psychiatry",

issn = "0002-953X",

publisher = "American Psychiatric Publishing Inc.",

number = "3",

}

TY - JOUR

T1 - Interindividual Differences in Cortical Thickness and Their Genomic Underpinnings in Autism Spectrum Disorder

AU - EU-AIMS LEAP group

AU - Ecker, Christine

AU - Pretzsch, Charlotte M.

AU - Bletsch, Anke

AU - Mann, Caroline

AU - Schaefer, Tim

AU - Ambrosino, Sara

AU - Tillmann, Julian

AU - Yousaf, Afsheen

AU - Chiocchetti, Andreas

AU - Lombardo, Michael V.

AU - Warrier, Varun

AU - Bast, Nico

AU - Moessnang, Carolin

AU - Baumeister, Sarah

AU - Dell’Acqua, Flavio

AU - Floris, Dorothea L.

AU - Zabihi, Mariam

AU - Marquand, Andre

AU - Cliquet, Freddy

AU - Leblond, Claire

AU - Moreau, Clara

AU - Puts, Nick

AU - Banaschewski, Tobias

AU - Jones, Emily J.H.

AU - Mason, Luke

AU - Bölte, Sven

AU - Meyer-Lindenberg, Andreas

AU - Persico, Antonio M.

AU - Durston, Sarah

AU - Baron-Cohen, Simon

AU - Spooren, Will

AU - Loth, Eva

AU - Freitag, Christine M.

AU - Charman, Tony

AU - Dumas, Guillaume

AU - Bourgeron, Thomas

AU - Beckmann, Christian F.

AU - Buitelaar, Jan K.

AU - Murphy, Declan G.M.

AU - Ahmad, Jumana

AU - Brammer, Michael

AU - Crawley, Daisy

AU - Faulkner, Jessica

AU - Hayward, Hannah

AU - Lythgoe, David J.

AU - Oakley, Bethany

AU - Ruggeri, Barbara

AU - San José Cáceres, Antonia

AU - Simonoff, Emily

AU - Williams, Steve C.R.

N1 - Funding Information: This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 115300 for the project EU-AIMS and no. 777394 for the project AIMS-2-TRIALS. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme, the European Federation of Pharmaceutical Industries and Associates, Autism Speaks, Autistica, and SFARI. Dr. Ecker gratefully acknowledges support from the German Research Foundation under the Heisenberg Programme (EC480/1-1 and EC480/2-1). Dr. Murphy acknowledges support from the NIHR Maudsley Biomedical Research Centre. Funding Information: Dr. Tillmann has served as a consultant for Hoffmann–La Roche. Dr. Banaschewski has served as an adviser or consultant for Actelion, ADHS Digital, Eli Lilly, Hexal Pharma, Infectopharm, Lundbeck, Medice, Neurim Pharmaceuticals, Novartis, Oberberg GmbH, Otsuka, Oxford Outcomes, PCM Scientific, Roche, Shire, Takeda, and Vifor Pharma; he has received conference support or speaking fees from Medice, Novartis, Shire, and Takeda; he has been involved in clinical trials conducted by Shire and Vifor Pharma; and he has received royalties from CIP Medien, Hogrefe, Kohl-hammer, and Oxford University Press. Dr. Jones has received funding from Action Medical Research, EU Horizon 2020, the Innovative Medicines Initiative, the Medical Research Council (UK), MQ: Transforming Mental Health, and the Economic and Social Research Council. Dr. Bölte has served as an author, consultant, or lecturer for Ability Partner, Eli Lilly, Expo Medica, GLGroup, Kompetento, Medice, Prima Psychiatry, Prophase, Roche, Shire, and System Analytic, and he receives royalties for textbooks and diagnostic tools from Huber/Hogrefe, Kohlhammer, and UTB. Dr. Meyer-Lindenberg has served as a consultant for the Agence Nationale de la Recherche, the American Association for the Advancement of Science, Atheneum Partners, Blueprint Partnership, Boehringer Ingelheim, the Brain Mind Institute, BrainsWay, the Catania International Summer School of Neuroscience, Daimler und Benz Stiftung, Elsevier, the Fondation FondaMental, Janssen-Cilag, Hoffmann–La Roche, ICARE Schizophrenia, K.G. Jebsen Foundation, L.E.K. Consulting, The LOOP Zürich, Lundbeck A/S, Lundbeck International Neuroscience Foundation, MedinCell, Roche Pharma, Sage Therapeutics, Sumitomo Dainippon Pharma, Synapsis Foundation–Alzheimer Research Switzerland, System Analytics, Tech-spert.io, Thieme Verlag, and von Behring Röntgen Stiftung, and he has received speaking fees from BAG Psychiatrie Oberbayern, Biotest AG, Boehringer Ingelheim, Fama Public Relations, Forum Werkstatt Karlsruhe, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), the International Society of Psychiatric Genetics, Janssen-Cilag, Klinik für Psychiatrie und Psychotherapie, Klinikum Christophsbad, Göppingen, Lilly Deutschland, Lundbeck SAS France, Luzerner Psychiatrie, LVR Klinikum Düsseldorf, LWL Psychiatrie Verbund Westfalen-Lippe, Med Update GmbH, Merz-Stiftung, Otsuka Pharmaceuticals, Reunions i Ciencia S.L., Siemens Healthineers, Spanish Society of Psychiatry, Südwestrundfunk Fernsehen, Stern TV, and Vitos Klinikum Kurhessen. Dr. Baron-Cohen has served as an author, consultant, or lecturer for Ability Partner, Clarion Healthcare, Expo Medica, Eli Lilly, GLGroup, Kompetento, Medice, Prima Psychiatry, Prophase, Roche, Shire, and System Analytic; he receives royalties for textbooks and diagnostic tools from Huber/Hogrefe, Kohl-hammer, and UTB. Dr. Spooren is an employee of F. Hoffmann–La Roche. Dr. Freitag receives royalties for books on autism spectrum disorder, ADHD, and major depressive disorder. Dr. Charman has received research grant support from the Medical Research Council (UK), the National Institute for Health Research, Horizon 2020 and the Innovative Medicines Initiative (European Commission), MQ, Autistica, FP7 (European Commission), the Charles Hawkins Fund, and the Waterloo Foundation; he has served as a consultant for F. Hoffmann–La Roche and Servier; and he has received royalties from Guilford Publications and Sage Publications. Dr. Beckmann is co-founder of SBGneuro. Dr. Buitelaar has served as a consultant, advisory board member, and/or speaker for Angelini, Janssen Cilag BV, Novartis, Medice, Roche, Servier, and Takeda/Shire. Dr. Murphy has received honoraria from Roche and Servier, and he has received grant support from the Medical Research Council (UK), the National Institute for Health Research, and Horizon 2020 and the Innovative Medicines Initiative (European Commission). The other authors report no financial relationships with commercial interests. Publisher Copyright: © 2022 American Psychiatric Association. All rights reserved.

PY - 2022/3

Y1 - 2022/3

N2 - Objective: Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions. Methods: The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6–30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features. Results: In addition to significant between-group differences in “core” ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals’ total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission. Conclusions: The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.

AB - Objective: Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions. Methods: The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6–30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features. Results: In addition to significant between-group differences in “core” ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals’ total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission. Conclusions: The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.

UR - http://www.scopus.com/inward/record.url?scp=85121656447&partnerID=8YFLogxK

U2 - 10.1176/appi.ajp.2021.20050630

DO - 10.1176/appi.ajp.2021.20050630

M3 - Article

C2 - 34503340

AN - SCOPUS:85121656447

SN - 0002-953X

VL - 179

SP - 242

EP - 254

JO - American Journal of Psychiatry

JF - American Journal of Psychiatry

IS - 3

ER -

Interindividual Differences in Cortical Thickness and Their Genomic Underpinnings in Autism Spectrum Disorder

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