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.
Highlights
Rafael Romero-Garcia and Varun Warrier contributed to this work.Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Autism Spectrum Conditions ( ‘autism’) are characterized by difficulties in social communication alongside unusually narrow interests and restrictive, repetitive behaviours, a resistance to unexpected change and sensory hypersensitivity [1]
Focusing on cortical thickness (CT), we ask 3 specific questions: (Q1) Which genes and biological pathways are associated with in CT variability (ΔCT) in children with autism? (Q2) What is the spatial expression profile of genes associated with ΔCT? and (Q3) Are these genes enriched for three different classes of risk factors associated with autism: rare, de novo variants, common genetic variants and/or dysregulated genes in the post-mortem cortex? We address these questions by combining analysis of ΔCT in autism, as measured with MRI, with gene expression post-mortem data provided by the Allen Institute for Brain Science (AIBS; [32, 33])
Only PLSR1 was used for subsequent analyses and we only included genes that passed FDR correction (q < 0.05)
Summary
In addition to behavioural and clinical differences, differences in cortical morphology between individuals with autism compared to typical controls have been reported [2,3,4,5]. Recent studies have reported increased cortical volumes in the first years of life with autism compared to controls, with accelerated decline or arrest in growth in adolescents [3, 4]. Studies have separately identified differences in both surface area [6] and CT [7] in children with autism.
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call