The Neurogenetics of Functional Connectivity Alterations in Autism: Insights From Subtyping in 657 Individuals

Javier Rasero; Antonio Jimenez-Marin; Ibai Diez; Roberto Toro; Mazahir T Hasan; Jesus M Cortes

doi:10.1016/j.biopsych.2023.04.014

The Neurogenetics of Functional Connectivity Alterations in Autism: Insights From Subtyping in 657 Individuals

Biol Psychiatry. 2023 Nov 15;94(10):804-813. doi: 10.1016/j.biopsych.2023.04.014. Epub 2023 Apr 22.

Authors

Javier Rasero¹, Antonio Jimenez-Marin², Ibai Diez³, Roberto Toro⁴, Mazahir T Hasan⁵, Jesus M Cortes⁶

Affiliations

¹ Cognitive Axon Laboratory, Department of Psychology, Carnegie Mellon University, Pittsburgh, Pennsylvania. Electronic address: jrasero.daparte@gmail.com.
² Computational Neuroimaging Laboratory, Biocruces-Bizkaia Health Research Institute, Barakaldo, Spain; Biomedical Research Doctorate Program, University of the Basque Country, Leioa, Spain.
³ Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
⁴ Institut Pasteur, Université de Paris, Département de neuroscience, Paris, France.
⁵ Laboratory of Brain Circuits Therapeutics, Achucarro Basque Center for Neuroscience, Leioa, Spain; Ikerbasque, The Basque Foundation for Science, Bilbao, Spain.
⁶ Computational Neuroimaging Laboratory, Biocruces-Bizkaia Health Research Institute, Barakaldo, Spain; Ikerbasque, The Basque Foundation for Science, Bilbao, Spain; Department of Cell Biology and Histology, University of the Basque Country, Leioa, Spain.

PMID: 37088169
DOI: 10.1016/j.biopsych.2023.04.014

Abstract

Background: There is little consensus and controversial evidence on anatomical alterations in the brains of people with autism spectrum disorder (ASD), due in part to the large heterogeneity present in ASD, which in turn is a major drawback for developing therapies. One strategy to characterize this heterogeneity in ASD is to cluster large-scale functional brain connectivity profiles.

Methods: A subtyping approach based on consensus clustering of functional brain connectivity patterns was applied to a population of 657 autistic individuals with quality-assured neuroimaging data. We then used high-resolution gene transcriptomic data to characterize the molecular mechanism behind each subtype by performing enrichment analysis of the set of genes showing a high spatial similarity with the profiles of functional connectivity alterations between each subtype and a group of typically developing control participants.

Results: Two major stable subtypes were found: subtype 1 exhibited hypoconnectivity (less average connectivity than typically developing control participants) and subtype 2, hyperconnectivity. The 2 subtypes did not differ in structural imaging metrics in any of the analyzed regions (68 cortical and 14 subcortical) or in any of the behavioral scores (including IQ, Autism Diagnostic Interview, and Autism Diagnostic Observation Schedule). Finally, only subtype 2, comprising about 43% of ASD participants, led to significant enrichments after multiple testing corrections. Notably, the dominant enrichment corresponded to excitation/inhibition imbalance, a leading well-known primary mechanism in the pathophysiology of ASD.

Conclusions: Our results support a link between excitation/inhibition imbalance and functional connectivity alterations, but only in one ASD subtype, overall characterized by brain hyperconnectivity and major alterations in somatomotor and default mode networks.

Keywords: Allen Human Brain Atlas; Autism; Excitation/inhibition balance; Hyperconnectivity; Subtyping.

MeSH terms

Autism Spectrum Disorder* / diagnostic imaging
Autism Spectrum Disorder* / genetics
Autistic Disorder*
Brain / diagnostic imaging
Brain Mapping / methods
Humans
Magnetic Resonance Imaging / methods
Neural Pathways / diagnostic imaging

Associated data

figshare/10.6084/m9.figshare.21901821