Differences in Intrinsic Gray-Matter connectivity and their genomic underpinnings in Autism Spectrum Disorder

Leyhausen, J. and Schäfer, T. and Gurr, C. and Berg, L.M. and Seelemeyer, H. and Pretzsch, C.M. and Loth, E. and Oakley, B. and Buitelaar, J.K. and Beckmann, C.F. and Florise, D.L. and Charman, T. and Bourgeron, T. and Banaschewski, T. and Jones, Emily J.H. and Tillmann, J. and Chatham, C. and The EU-AIMS LEAP Group and Murphy, D. and Ecker, C. (2023) Differences in Intrinsic Gray-Matter connectivity and their genomic underpinnings in Autism Spectrum Disorder. Biological Psychiatry , ISSN 0006-3223.

Abstract

Background: Autism is a heterogenous 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 N=359 autistic individuals and N=279 controls, aged 7-31 years from the EU-AIMS Longitudinal European Autism Project (LEAP). FreeSurfer was used to derive surface mesh representations to compute the estimated length of connections required to wire the brain within the gray-matter. Vertex-wise between-group differences were assessed using a general linear model. A gene expression decoding analysis based on the Allan 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 previously implicated in the etiology of autism at the genetic and transcriptomic level. Conclusion: Based on intrinsic gray-matter connectivity, the 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.

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