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

Johanna Leyhausen; Tim Schäfer; Caroline Gurr; Lisa m. Berg; Hanna Seelemeyer; Charlotte m. Pretzsch; Eva Loth; Bethany Oakley; Jan k. Buitelaar; Christian f. Beckmann; Dorothea l. Floris; Tony Charman; Thomas Bourgeron; Tobias Banaschewski; Emily j.h. Jones; Julian Tillmann; Chris Chatham; Declan g. Murphy; Christine Ecker; Jumana Ahmad; Sara Ambrosino; Bonnie Auyeung; Tobias Banaschewski; Simon Baron-Cohen; Sarah Baumeister; Christian f. Beckmann; Sven Bölte; Thomas Bourgeron; Carsten Bours; Michael Brammer; Daniel Brandeis; Claudia Brogna; Yvette De bruijn; Jan k. Buitelaar; Bhismadev Chakrabarti; Tony Charman; Ineke Cornelissen; Daisy Crawley; Flavio Dell’acqua; Guillaume Dumas; Sarah Durston; Christine Ecker; Jessica Faulkner; Vincent Frouin; Pilar Garcés; David Goyard; Lindsay Ham; Hannah Hayward; Joerg Hipp; Rosemary Holt; Mark h. Johnson; Emily j.h. Jones; Prantik Kundu; Meng-Chuan Lai; Xavier liogier D’ardhuy; Michael v. Lombardo; Eva Loth; David j. Lythgoe; René Mandl; Andre Marquand; Luke Mason; Maarten Mennes; Andreas Meyer-Lindenberg; Carolin Moessnang; Nico Bast; Declan g. Murphy; Bethany Oakley; Laurence O’dwyer; Marianne Oldehinkel; Bob Oranje; Gahan Pandina; Antonio m. Persico; Barbara Ruggeri; Amber Ruigrok; Jessica Sabet; Roberto Sacco; Antonia San josé cáceres; Emily Simonoff; Will Spooren; Julian Tillmann; Roberto Toro; Heike Tost; Jack Waldman; Steve c.r. Williams; Caroline Wooldridge; Marcel p. Zwiers

doi:10.1016/j.biopsych.2023.06.010

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

Johanna Leyhausen, Tim Schäfer, Caroline Gurr, Lisa m. Berg, Hanna Seelemeyer, Charlotte m. Pretzsch, Eva Loth, Bethany Oakley, Jan k. Buitelaar, Christian f. Beckmann, Dorothea l. Floris, Tony Charman, Thomas Bourgeron, Tobias Banaschewski, Emily j.h. Jones, Julian Tillmann, Chris Chatham, Declan g. Murphy, Christine Ecker, Jumana AhmadSara Ambrosino, Bonnie Auyeung, Tobias Banaschewski, Simon Baron-Cohen, Sarah Baumeister, Christian f. Beckmann, Sven Bölte, Thomas Bourgeron, Carsten Bours, Michael Brammer, Daniel Brandeis, Claudia Brogna, Yvette De bruijn, Jan k. Buitelaar, Bhismadev Chakrabarti, Tony Charman, Ineke Cornelissen, Daisy Crawley, Flavio Dell’acqua, Guillaume Dumas, Sarah Durston, Christine Ecker, Jessica Faulkner, Vincent Frouin, Pilar Garcés, David Goyard, Lindsay Ham, Hannah Hayward, Joerg Hipp, Rosemary Holt, Mark h. Johnson, Emily j.h. Jones, Prantik Kundu, Meng-Chuan Lai, Xavier liogier D’ardhuy, Michael v. Lombardo, Eva Loth, David j. Lythgoe, René Mandl, Andre Marquand, Luke Mason, Maarten Mennes, Andreas Meyer-Lindenberg, Carolin Moessnang, Nico Bast, Declan g. Murphy, Bethany Oakley, Laurence O’dwyer, Marianne Oldehinkel, Bob Oranje, Gahan Pandina, Antonio m. Persico, Barbara Ruggeri, Amber Ruigrok, Jessica Sabet, Roberto Sacco, Antonia San josé cáceres, Emily Simonoff, Will Spooren, Julian Tillmann, Roberto Toro, Heike Tost, Jack Waldman, Steve c.r. Williams, Caroline Wooldridge, Marcel p. Zwiers

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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.

Original language	English
Pages (from-to)	175-186
Number of pages	12
Journal	Biological psychiatry
Volume	95
Issue number	2
Early online date	20 Jun 2023
DOIs	https://doi.org/10.1016/j.biopsych.2023.06.010
Publication status	Published - 15 Jan 2024

Keywords

ASD
neuroimaging
structural MRI
intrinsic wiring costs
imaging genetics

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10.1016/j.biopsych.2023.06.010

Differences in Intrinsic Gray-Matter_LEYHAUSEN_2023_GREEN AAMAccepted author manuscript, 440 KB

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Leyhausen, J., Schäfer, T., Gurr, C., Berg, L. M., Seelemeyer, H., Pretzsch, C. M., Loth, E., Oakley, B., Buitelaar, J. K., Beckmann, C. F., Floris, D. L., Charman, T., Bourgeron, T., Banaschewski, T., Jones, E. J. H., Tillmann, J., Chatham, C., Murphy, D. G., Ecker, C., ... Zwiers, M. P. (2024). Differences in Intrinsic Gray Matter Connectivity and Their Genomic Underpinnings in Autism Spectrum Disorder. Biological psychiatry, 95(2), 175-186. https://doi.org/10.1016/j.biopsych.2023.06.010

@article{a45c8de97404400da0f1d7a54986fa89,

title = "Differences in Intrinsic Gray Matter Connectivity and Their Genomic Underpinnings in Autism Spectrum Disorder",

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, neuroimaging, structural MRI, intrinsic wiring costs, imaging genetics",

author = "Johanna Leyhausen and Tim Sch{\"a}fer and Caroline Gurr and Berg, {Lisa m.} and Hanna Seelemeyer and Pretzsch, {Charlotte m.} and Eva Loth and Bethany Oakley and Buitelaar, {Jan k.} and Beckmann, {Christian f.} and Floris, {Dorothea l.} and Tony Charman and Thomas Bourgeron and Tobias Banaschewski and Jones, {Emily j.h.} and Julian Tillmann and Chris Chatham and Murphy, {Declan g.} and Christine Ecker and Jumana Ahmad and Sara Ambrosino and Bonnie Auyeung and Tobias Banaschewski and Simon Baron-Cohen and Sarah Baumeister and Beckmann, {Christian f.} and Sven B{\"o}lte and Thomas Bourgeron and Carsten Bours and Michael Brammer and Daniel Brandeis and Claudia Brogna and {De bruijn}, Yvette and Buitelaar, {Jan k.} and Bhismadev Chakrabarti and Tony Charman and Ineke Cornelissen and Daisy Crawley and Flavio Dell{\textquoteright}acqua and Guillaume Dumas and Sarah Durston and Christine Ecker and Jessica Faulkner and Vincent Frouin and Pilar Garc{\'e}s and David Goyard and Lindsay Ham and Hannah Hayward and Joerg Hipp and Rosemary Holt and Johnson, {Mark h.} and Jones, {Emily j.h.} and Prantik Kundu and Meng-Chuan Lai and D{\textquoteright}ardhuy, {Xavier liogier} and Lombardo, {Michael v.} and Eva Loth and Lythgoe, {David j.} and Ren{\'e} Mandl and Andre Marquand and Luke Mason and Maarten Mennes and Andreas Meyer-Lindenberg and Carolin Moessnang and Nico Bast and Murphy, {Declan g.} and Bethany Oakley and Laurence O{\textquoteright}dwyer and Marianne Oldehinkel and Bob Oranje and Gahan Pandina and Persico, {Antonio m.} and Barbara Ruggeri and Amber Ruigrok and Jessica Sabet and Roberto Sacco and {San jos{\'e} c{\'a}ceres}, Antonia and Emily Simonoff and Will Spooren and Julian Tillmann and Roberto Toro and Heike Tost and Jack Waldman and Williams, {Steve c.r.} and Caroline Wooldridge and Zwiers, {Marcel p.}",

note = "Funding Information: This work was supported by the Innovative Medicines Initiative 2 Joint Undertaking for the projects EU-AIMS (Grant No. 115300) and AIMS-2-TRIALS (Grant No. 777394). This joint undertaking receives support from the European Union{\textquoteright}s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations and AUTISM SPEAKS, Autistica, and Simons Foundation Autism Research Initiative. CE gratefully acknowledges support from the German Research Foundation under the Heisenberg Programme (EC480/1-1 and EC480/2-1). DGM also acknowledges support from the National Institute of Health and Care Research Maudsley Biomedical Research Centre. DLF is supported by funding from the European Union{\textquoteright}s Horizon 2020 research and innovation programme under Marie Sk{\l}odowska-Curie (Grant No. 101025785). CE received funding from Horizon Europe (Grant No. 101057385) and from UK Research and Innovation under the U.K. government{\textquoteright}s Horizon Europe funding guarantee (Grant No. 10039383) (R2D2-MH). Funding Information: 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{\textquoteright}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 Z{\"u}urich, 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 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 ediques August Pi i Sunyer, 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, MerzStiftung, Otsuka Pharmaceuticals, Reunions i Ciencia S.L., Siemens Healthineers, Spanish Society of Psychiatry, S{\"u}dwestrundfunk 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. Publisher Copyright: {\textcopyright} 2023 Society of Biological Psychiatry",

year = "2024",

month = jan,

day = "15",

doi = "10.1016/j.biopsych.2023.06.010",

language = "English",

volume = "95",

pages = "175--186",

journal = "Biological psychiatry",

issn = "0006-3223",

publisher = "Elsevier",

number = "2",

}

Leyhausen, J, Schäfer, T, Gurr, C, Berg, LM, Seelemeyer, H, Pretzsch, CM , Loth, E , Oakley, B, Buitelaar, JK, Beckmann, CF, Floris, DL, Charman, T, Bourgeron, T, Banaschewski, T, Jones, EJH, Tillmann, J, Chatham, C, Murphy, DG , Ecker, C , Ahmad, J, Ambrosino, S, Auyeung, B, Banaschewski, T, Baron-Cohen, S, Baumeister, S, Beckmann, CF, Bölte, S, Bourgeron, T, Bours, C, Brammer, M, Brandeis, D, Brogna, C, De bruijn, Y, Buitelaar, JK, Chakrabarti, B, Charman, T, Cornelissen, I, Crawley, D, Dell’acqua, F, Dumas, G, Durston, S, Ecker, C , Faulkner, J, Frouin, V, Garcés, P, Goyard, D, Ham, L, Hayward, H, Hipp, J, Holt, R, Johnson, MH, Jones, EJH, Kundu, P, Lai, M-C, D’ardhuy, XL, Lombardo, MV, Loth, E , Lythgoe, DJ, Mandl, R, Marquand, A , Mason, L, Mennes, M, Meyer-Lindenberg, A, Moessnang, C, Bast, N, Murphy, DG , Oakley, B, O’dwyer, L, Oldehinkel, M, Oranje, B, Pandina, G, Persico, AM, Ruggeri, B, Ruigrok, A, Sabet, J, Sacco, R, San josé cáceres, A , Simonoff, E, Spooren, W, Tillmann, J, Toro, R, Tost, H, Waldman, J, Williams, SCR, Wooldridge, C & Zwiers, MP 2024, 'Differences in Intrinsic Gray Matter Connectivity and Their Genomic Underpinnings in Autism Spectrum Disorder', Biological psychiatry, vol. 95, no. 2, pp. 175-186. https://doi.org/10.1016/j.biopsych.2023.06.010

TY - JOUR

T1 - Differences in Intrinsic Gray Matter Connectivity and Their Genomic Underpinnings in Autism Spectrum Disorder

AU - Leyhausen, Johanna

AU - Schäfer, Tim

AU - Gurr, Caroline

AU - Berg, Lisa m.

AU - Seelemeyer, Hanna

AU - Pretzsch, Charlotte m.

AU - Loth, Eva

AU - Oakley, Bethany

AU - Buitelaar, Jan k.

AU - Beckmann, Christian f.

AU - Floris, Dorothea l.

AU - Charman, Tony

AU - Bourgeron, Thomas

AU - Banaschewski, Tobias

AU - Jones, Emily j.h.

AU - Tillmann, Julian

AU - Chatham, Chris

AU - Murphy, Declan g.

AU - Ecker, Christine

AU - Ahmad, Jumana

AU - Ambrosino, Sara

AU - Auyeung, Bonnie

AU - Banaschewski, Tobias

AU - Baron-Cohen, Simon

AU - Baumeister, Sarah

AU - Beckmann, Christian f.

AU - Bölte, Sven

AU - Bourgeron, Thomas

AU - Bours, Carsten

AU - Brammer, Michael

AU - Brandeis, Daniel

AU - Brogna, Claudia

AU - De bruijn, Yvette

AU - Buitelaar, Jan k.

AU - Chakrabarti, Bhismadev

AU - Charman, Tony

AU - Cornelissen, Ineke

AU - Crawley, Daisy

AU - Dell’acqua, Flavio

AU - Dumas, Guillaume

AU - Durston, Sarah

AU - Ecker, Christine

AU - Faulkner, Jessica

AU - Frouin, Vincent

AU - Garcés, Pilar

AU - Goyard, David

AU - Ham, Lindsay

AU - Hayward, Hannah

AU - Hipp, Joerg

AU - Holt, Rosemary

AU - Johnson, Mark h.

AU - Jones, Emily j.h.

AU - Kundu, Prantik

AU - Lai, Meng-Chuan

AU - D’ardhuy, Xavier liogier

AU - Lombardo, Michael v.

AU - Loth, Eva

AU - Lythgoe, David j.

AU - Mandl, René

AU - Marquand, Andre

AU - Mason, Luke

AU - Mennes, Maarten

AU - Meyer-Lindenberg, Andreas

AU - Moessnang, Carolin

AU - Bast, Nico

AU - Murphy, Declan g.

AU - Oakley, Bethany

AU - O’dwyer, Laurence

AU - Oldehinkel, Marianne

AU - Oranje, Bob

AU - Pandina, Gahan

AU - Persico, Antonio m.

AU - Ruggeri, Barbara

AU - Ruigrok, Amber

AU - Sabet, Jessica

AU - Sacco, Roberto

AU - San josé cáceres, Antonia

AU - Simonoff, Emily

AU - Spooren, Will

AU - Tillmann, Julian

AU - Toro, Roberto

AU - Tost, Heike

AU - Waldman, Jack

AU - Williams, Steve c.r.

AU - Wooldridge, Caroline

AU - Zwiers, Marcel p.

N1 - Funding Information: This work was supported by the Innovative Medicines Initiative 2 Joint Undertaking for the projects EU-AIMS (Grant No. 115300) and AIMS-2-TRIALS (Grant No. 777394). This joint undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations and AUTISM SPEAKS, Autistica, and Simons Foundation Autism Research Initiative. CE gratefully acknowledges support from the German Research Foundation under the Heisenberg Programme (EC480/1-1 and EC480/2-1). DGM also acknowledges support from the National Institute of Health and Care Research Maudsley Biomedical Research Centre. DLF is supported by funding from the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie (Grant No. 101025785). CE received funding from Horizon Europe (Grant No. 101057385) and from UK Research and Innovation under the U.K. government’s Horizon Europe funding guarantee (Grant No. 10039383) (R2D2-MH). Funding Information: 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. Publisher Copyright: © 2023 Society of Biological Psychiatry

PY - 2024/1/15

Y1 - 2024/1/15

N2 - 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.

AB - 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.

KW - ASD

KW - neuroimaging

KW - structural MRI

KW - intrinsic wiring costs

KW - imaging genetics

UR - http://www.scopus.com/inward/record.url?scp=85168350197&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2023.06.010

DO - 10.1016/j.biopsych.2023.06.010

M3 - Article

SN - 0006-3223

VL - 95

SP - 175

EP - 186

JO - Biological psychiatry

JF - Biological psychiatry

IS - 2

ER -

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

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