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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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 languageEnglish
Pages (from-to)175-186
Number of pages12
JournalBiological psychiatry
Issue number2
Early online date20 Jun 2023
Publication statusPublished - 15 Jan 2024


  • ASD
  • neuroimaging
  • structural MRI
  • intrinsic wiring costs
  • imaging genetics


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