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Synaptic and transcriptionally downregulated genes are associated with cortical thickness differences in autism.

Published version
Peer-reviewed

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Authors

Romero-Garcia, Rafael 
Warrier, Varun 
Baron-Cohen, Simon 
Bethlehem, Richard AI  ORCID logo  https://orcid.org/0000-0002-0714-0685

Abstract

Differences in cortical morphology-in particular, cortical volume, thickness and surface area-have been reported in individuals with autism. However, it is unclear what aspects of genetic and transcriptomic variation are associated with these differences. Here we investigate the genetic correlates of global cortical thickness differences (ΔCT) in children with autism. We used Partial Least Squares Regression (PLSR) on structural MRI data from 548 children (166 with autism, 295 neurotypical children and 87 children with ADHD) and cortical gene expression data from the Allen Institute for Brain Science to identify genetic correlates of ΔCT in autism. We identify that these genes are enriched for synaptic transmission pathways and explain significant variation in ΔCT. These genes are also significantly enriched for genes dysregulated in the autism post-mortem cortex (Odd Ratio (OR) = 1.11, Pcorrected  10-14), driven entirely by downregulated genes (OR = 1.87, Pcorrected  10-15). We validated the enrichment for downregulated genes in two independent data sets: Validation 1 (OR = 1.44, Pcorrected = 0.004) and Validation 2 (OR = 1.30; Pcorrected = 0.001). We conclude that transcriptionally downregulated genes implicated in autism are robustly associated with global changes in cortical thickness variability in children with autism.

Description

Keywords

Autism Spectrum Disorder, Autistic Disorder, Brain, Brain Mapping, Cerebral Cortex, Child, Female, Humans, Magnetic Resonance Imaging, Male, Neuroimaging, Synaptic Transmission, Transcriptome

Journal Title

Mol Psychiatry

Conference Name

Journal ISSN

1359-4184
1476-5578

Volume Title

24

Publisher

Springer Science and Business Media LLC
Sponsorship
MRC (1366806)
Medical Research Council (MC_G0802534)
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