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. 2024 Jan 15;95(2):175-186.
doi: 10.1016/j.biopsych.2023.06.010. Epub 2023 Jun 20.

Differences in Intrinsic Gray Matter Connectivity and Their Genomic Underpinnings in Autism Spectrum Disorder

Johanna Leyhausen  1 , Tim Schäfer  2 , Caroline Gurr  2 , Lisa M Berg  2 , Hanna Seelemeyer  2 , Charlotte M Pretzsch  3 , Eva Loth  3 , Bethany Oakley  3 , Jan K Buitelaar  4 , Christian F Beckmann  4 , Dorothea L Floris  5 , Tony Charman  6 , Thomas Bourgeron  7 , Tobias Banaschewski  8 , Emily J H Jones  9 , Julian Tillmann  10 , Chris Chatham  10 ; EU-AIMS LEAP Group; Declan G Murphy  3 , Christine Ecker  11
Collaborators, Affiliations

Differences in Intrinsic Gray Matter Connectivity and Their Genomic Underpinnings in Autism Spectrum Disorder

Johanna Leyhausen et al. Biol Psychiatry. .

Abstract

Background: Autism is a heterogeneous neurodevelopmental condition accompanied by differences in brain connectivity. Structural connectivity in autism has mainly been investigated within the white matter. However, many genetic variants associated with autism highlight genes related to synaptogenesis and axonal guidance, thus also implicating differences in intrinsic (i.e., gray matter) connections in autism. Intrinsic connections may be assessed in vivo via so-called intrinsic global and local wiring costs.

Methods: Here, we examined intrinsic global and local wiring costs in the brain of 359 individuals with autism and 279 healthy control participants ages 6 to 30 years from the EU-AIMS LEAP (Longitudinal European Autism Project). FreeSurfer was used to derive surface mesh representations to compute the estimated length of connections required to wire the brain within the gray matter. Vertexwise between-group differences were assessed using a general linear model. A gene expression decoding analysis based on the Allen Human Brain Atlas was performed to link neuroanatomical differences to putative underpinnings.

Results: Group differences in global and local wiring costs were predominantly observed in medial and lateral prefrontal brain regions, in inferior temporal regions, and at the left temporoparietal junction. The resulting neuroanatomical patterns were enriched for genes that had been previously implicated in the etiology of autism at genetic and transcriptomic levels.

Conclusions: Based on intrinsic gray matter connectivity, the current study investigated the complex neuroanatomy of autism and linked between-group differences to putative genomic and/or molecular mechanisms to parse the heterogeneity of autism and provide targets for future subgrouping approaches.

Keywords: ASD; Imaging genetics; Intrinsic wiring costs; MRI; Neuroimaging.

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Conflict of interest statement

During the past 3 years, JKB has been a consultant to/member of the advisory board of/and/or speaker for Janssen-Cilag BV, Takeda/Shire, Roche, Novartis, Medice, Angelini, and Servier. He is not an employee of any of these companies and is not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, and royalties. TB has served in an advisory or consultancy role for Actelion, Hexal Pharma, Lilly, Medice, Novartis, Oxford Outcomes, Otsuka, PCM Scientific, Shire, and Viforpharma. He received conference support or speaker’s fees from Medice, Novartis, and Shire. He is/has been involved in clinical trials conducted by Shire and Viforpharma. He received royalties from Hogrefe, Kohlhammer, CIP Medien, and Oxford University Press. The current work is unrelated to the above grants and relationships. JT is a consultant for F. Hoffmann–La Roche Ltd. CC is an employee of F. Hoffmann–La Roche Ltd. TC has received research grant support from the Medical Research Council (United Kingdom), the National Institute for Health Research, and 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 to F. Hoffmann-La Roche Ltd. and Servier. He has received royalties from Sage Publications and Guilford Publications. DM has received consultancy fees from Roche and Servier and grant support from the Medical Research Council (United Kingdom), the National Institute for Health Research, and Horizon 2020 and the Innovative Medicines Initiative (European Commission). EJHJ has received funding from Action Medical Research, EU Horizon 2020, the Innovative Medicines Initiative, the Medical Research Council (United Kingdom), MQ: Transforming Mental Health, and the Economic and Social Research Council. SB has served as an author, consultant, or lecturer for Ability Partner, Eli Lilly, Expo Medica, GLGroup, Kompetento, Medice, Prima Publishing Psychiatry, Prophase, Roche, Shire, and System Analytic, and he receives royalties for textbooks and diagnostic tools from Huber/Hogrefe, Kohlhammer, and UTB. AM-L 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 Züurich, Lundbeck A/S, Lundbeck International Neuroscience Foundation, MedinCell, Roche Pharma, Sage Therapeutics, Sumitomo Dainippon Pharma, Synapsis Foundation–Alzheimer Research Switzerland, System Analytics, Techspert.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 Biom ediques August Pi i Sunyer, 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, MerzStiftung, Otsuka Pharmaceuticals, Reunions i Ciencia S.L., Siemens Healthineers, Spanish Society of Psychiatry, Südwestrundfunk Fernsehen, Stern TV, and Vitos Klinikum Kurhessen. SB-C has served as an author, consultant, or lecturer for Ability Partner, Clarion Healthcare, Expo Medica, Eli Lilly, GLGroup, Kompetento, Medice, Prima Publishing Psychiatry, Prophase, Roche, Shire, and System Analytic; he receives royalties for textbooks and diagnostic tools from Huber/Hogrefe, Kohlhammer, and UTB. WS is an employee of F. Hoffmann-La Roche. All other authors report no biomedical financial interests or potential conflicts of interest.

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