Genes involved in cholesterol cascades are linked to brain connectivity in one third of autistic patients

Abstract

The large heterogeneity in the symptomatology and severity of autism spectrum disorder (ASD) is a major drawback for the design of effective therapies. Beyond behavioral phenotypes, subtype stratification strategies that can be applied to large populations are needed, these combining different neurobiological characteristics and based on the large-scale organization of the human brain, as well as neurogenetic fingerprints. Here, we make use of ABIDE, the largest publicly available database of functional neuroimaging in ASD, to which we have applied rigorous data harmonization between the different scanning institutions in order to employ analyses based on consensus clustering and to evaluate the patterns of brain connectivity. As a result, we identified three subtypes of ASD, the first of which was characterized by a mixture of hyper- and hypo-connectivity, stronger network segregation and weaker integration, and it represented approximately 13% of all patients. The second subtype was associated with 31% of the patients, and it was characterized by hyperconnectivity but no topological differences with respect to the group of typically developing controls. The third was the most numerous subtype, assigned to 52% of all patients, and it was characterized by hypoconnectivity, decreased network segregation and increased integration. We also defined a neurobiological signature for each of these subtypes, detailing the connectivity and structures most specific to each subtype. Strikingly, at the behavioral level, none of the neuropsychological scores used in the diagnosis of ASD is capable of differentiating any of the subtypes from the other two. Finally, we use the Allen Human Brain Atlas of gene transcription brain maps to show that subtype 2 has an extraordinary enrichment in biological processes related to the synthesis, regulation and transport of cholesterol and other lipoproteins, one of the mechanisms previously attributed to ASD. We also show that this lipid-susceptible ASD subtype could be represented by the dysfunctionality of the network, unlike the other two subtypes that have more structural alterations in the connectome. Thus, our study provide compelling support for prospects of cholesterol-related therapies in this subset of autistic individuals.

Individual‐based morphological brain network organization and its association with autistic symptoms in young children with autism spectrum disorder

“…This theory assumes an inefficient interregional brain connectivity across the cerebral cortex that results in abnormal information integration at psychological and neural levels in autistic brains and may also explain diverse impairments in social symptoms (Just et al, 2004; Schipul, Keller, & Just, 2011). Other studies also revealed that the overall connectivity class in ASD is highly heterogeneous, and a combination of hyper‐ and hypo‐connectivity seems to coexist across different subtypes of ASD (Maximo & Kana, 2019; Rasero, Jimenez‐Marin, Diez, Hasan, & Cortes, 2020; Yerys et al, 2017) and trajectories of neural development (C. He et al, 2020).…”