Autophagy, apoptosis, and neurodevelopmental genes might underlie selective brain region vulnerability in attention-deficit/hyperactivity disorder

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 magnetic resonance imaging (MRI) results from the ADHD ENIGMA Consortium (subcortical MRI n = 3242; cortical MRI n = 4180) along with high-resolution postmortem brain microarray data from Allen Brain Atlas (donors n = 6) from 22 brain regions to investigate our SBRV hypothesis. We performed deconvolution of the bulk transcriptomic data to determine abundances of neuronal and nonneuronal cells in the brain. We 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 smaller brain sizes in ADHD, along with associations to regional abundances of astrocytes and oligodendrocytes. The lack of enrichment of common genetic risk variants for ADHD within implicated gene sets suggests an environmental etiology to these differences. This work provides novel mechanistic clues about SBRV in ADHD.