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
