Interindividual Differences in Cortical Thickness and Their Genomic Underpinnings in Autism Spectrum Disorder

Abstract

Objective. Autism Spectrum Disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. However, the link between biological pathways and differences in brain anatomy, which may pave the way towards targeted therapeutic interventions, remains poorly understood.Methods. Our study examined neurodevelopmental differences in cortical thickness (CT) and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 270 typically developing controls (aged 6-30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). We also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups, which differed in the severity and pattern of sensory features.Results. In addition to significant between-group differences in 'core' ASD brain regions (i.e. fronto-temporal and cingulate regions), we found that ASD individuals manifested as neuroanatomical outliers within the neurotypical CT range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals' total (i.e. accumulated) degree of neuroanatomical atypicality was significantly correlated with the higher polygenic scores for ASD, and other psychiatric conditions, and scaled with measures of symptom severity. Differences in CT deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission.Conclusions. Our findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping. shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, and royalties. Sven Bölte discloses that he has in the last 5 years acted as an author, consultant or lecturer for Shire, Medice, Roche,

Longitudinal Changes in Cortical Thickness in Adolescents with Autism Spectrum Disorder and Their Association with Restricted and Repetitive Behaviors

“…A recent study by Romero-Garcia et al (2019) demonstrated that differences in cortical thickness (CT) during childhood were robustly associated with genes involved in synaptic transmission pathways, which are known to be downregulated in the postmortem ASD cortex [ 42 , 66 ]. Similar results were also recently reported by our group when examining CT differences in ASD in a large and clinically heterogeneous sample [ 67 ]. The present results converge with these previous findings, as we observed an enrichment for genes and coexpressed modules that are known to be downregulated in ASD.…”

Variation in glutamate and GABA genes and their association with brain structure and chemistry in autism

“…Despite many reports of group differences in cortical thickness (60,61), we did not show any significant differences between autistic and control participants in our study. However, we found that regions where GABAergic - but not glutamatergic - genes were increasingly expressed in the normative brain showed larger differences in cortical thickness between our autism and control participants.…”

From Genes to Therapy in Autism Spectrum Disorder

“…Interestingly, the observed differences in cortical thinning correlated with synaptic genes [ 21 ]. These findings echo previous observations, indicating an association between synaptic genes and differences in cortical thickness in individuals with ASD [ 22 , 23 ]. Bieneck et al, reported altered cortical thinning predominantly in fronto-temporal brain regions and the cingulate cortex in individuals with ASD [ 21 ].…”