Spatial organization of cells and variable expression of autophagy, apoptosis, and neurodevelopmental genes might underlie selective brain region vulnerability in Attention-Deficit/Hyperactivity Disorder

Abstract

Genetically influenced changes in brain organization occur over the course of development. Large-scale brain imaging studies by the ENIGMA Consortium identified structural changes associated with attention-deficit/hyperactivity disorder (ADHD). It is not clear why some brain regions are impaired and others spared by the etiological risks for ADHD. We hypothesized that spatial variation in brain cell organization and/or pathway expression levels contribute to selective brain region vulnerability (SBRV) in ADHD. In this study, we used the largest available collection of imaging results from the ADHD ENIGMA Consortium along with high-resolution postmortem brain microarray data from Allen Brain Atlas from 22 sub-cortical and cortical brain regions to investigate our selective brain region vulnerability (SBRV) hypothesis. We performed deconvolution of the bulk transcriptomic data to determine abundances of neuronal and non-neuronal cells in the brain. We then assessed the relationships between gene set expression levels, cell abundance, and standardized effect sizes representing regional changes in brain sizes in cases of ADHD. Our analysis yielded significant correlations between apoptosis, autophagy, and neurodevelopment genes with reductions in regional brain sizes in ADHD, along with associations to regional abundances of dopaminergic neurons, astrocytes, oligodendrocytes, and neural progenitor cells. This works provides novel mechanistic insights into SBRV in ADHD.

Structural Brain Imaging Studies Offer Clues about the Effects of the Shared Genetic Etiology among Neuropsychiatric Disorders

“…In the lower left region of Figure 3 Our prior studies of SBRV in ADHD implicated the regulation of genes in apoptosis, autophagy and neurodevelopment pathways in ADHD (21,22). Neurodevelopmental pathways had also been implicated in the cross-disorder analysis of the Psychiatric Genomics Consortium (3), which suggests that cross-disorder similarities in these pathways may account for cross disorder similarities in SBRV.…”

“…ENIGMA has also reported significant case vs. control differences in sMRI phenotypes for: attention-deficit/hyperactivity disorder (ADHD) (9,10), autism spectrum disorder (ASD) (11), bipolar disorder (BD) (12,13), common epilepsy syndromes (14), major depressive disorder (MDD) (15,16), obsessive compulsive disorder (OCD) (17,18) and schizophrenia (SCZ) (19,20). Each of these disorders shows a pattern of what we have termed selective brain region vulnerability (SBRV) (21,22). By this, we mean that some brain regions may be more vulnerable to the genetic and environmental risk factors associated with each disorder.…”

Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure

“…These correlations were strong and significant in children with ADHD, but not in adults. In a subsequent analysis that also included cortical data from ENIGMA-ADHD, the same group found that ADHD-associated volumetric reductions were associated with apoptosis, autophagy, and neurodevelopment gene pathways and with regional abundances of dopaminergic neurons, astrocytes, oligodendrocytes, and neural progenitor cells (Hess, Radonji c, Patak, Glatt, & Faraone, 2019). These data suggest that the selective brain region vulnerability seen in ADHD may be due to differences in the cellular composition and constitutive gene expression between regions, which do and do not show ADHD-associated volumetric changes.…”