Why is there selective subcortical vulnerability in ADHD? Clues from postmortem brain gene expression data

Abstract

Sub-cortical volumetric differences were associated with attention-deficit/hyperactivity disorder (ADHD) in a recent multi-site, mega-analysis of 1713 ADHD persons and 1529 controls. As there was a wide range of effect sizes among the sub-cortical volumes, it is possible that selective neuronal vulnerability has a role in these volumetric losses. To address this possibility, we used data from Allen Brain Atlas to investigate variability in gene expression profiles between subcortical regions of typically developing brains. We tested the hypothesis that the expression of genes in a set of curated ADHD candidate genes and five a priori selected, biological pathways would be associated with the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) findings. Across the subcortical regions studied by ENIGMA, gene expression profiles for three pathways were significantly correlated with ADHD-associated volumetric reductions: apoptosis, oxidative stress and autophagy. These correlations were strong and significant for children with ADHD, but not for adults. Although preliminary, these data suggest that variability of structural brain anomalies in ADHD can be explained, in part, by the differential vulnerability of these regions to mechanisms mediating apoptosis, oxidative stress and autophagy.

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.…”

Genetics of attention deficit hyperactivity disorder

“…These findings challenge the idea that the core of ADHD's pathophysiology rests within the machinery of catecholaminergic transmission. Instead, it is possible that the catecholaminergic dysregulation believed to underlie ADHD is a secondary compensation to ADHD's primary etiology (see discussion by Hess et al [151]). …”

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

“…The latest version of the Gene Ontology (GO) database was downloaded via R package GO.db (version 3.7.0) (8) to retrieve the most up-to-date annotations for the following gene sets of interest that had previously been implicated in ADHD and that we hypothesized might be involved in SBRV: apoptosis, autophagy, neurotransmission, neurodevelopment, and reactive oxygen species (9–12). A total of 1,313 unique HGNC genes were identified including 43 ADHD candidate genes designated in our previous study (7). 1,288 of these had expression data in the Allen Brain Atlas.…”

“…We postulate that mechanisms underlying SBRV explain why some brain regions show structural brain changes associated with ADHD while others do not (2, 6). Previously, we found that autophagy, apoptosis, and oxidative stress pathways were associated with smaller sub-cortical brain region volumes in ADHD and suggested that they may mediate SBRV (7). The present work builds on our previous study by including newly released data from the ENIGMA-ADHD working group for cortical brain regions.…”