Background: Substance use disorders (SUDs) are moderately to highly heritable and develop in stages that typically begin in adolescence or young adulthood. The predominant use of cross-sectional adult samples to study SUDs and their genetic liability leaves it unclear whether their correlates may plausibly reflect predispositional risk and/or arise as a consequence of exposure. Methods: We conducted a phenome-wide association study (PheWAS) of polygenic scores (PGSs) for SUDs (i.e., problematic alcohol use, tobacco use disorder, cannabis use disorder [CUD], opioid use disorder [OUD], and a general addiction risk factor) in children ages 8 to 13 years ( n European ancestry = 5556; n African American ancestry = 1584) enrolled in the Adolescent Brain Cognitive Development (ABCD) Study. Up to 1697 phenotypes were examined across several domains, including mental health, substance use, physical health, cognition, and screen media. Results: The PheWAS yielded 309 significant associations with the SUD PGS, particularly among mental health, sleep, screen time, and caffeine consumption phenotypes. Most associations remained significant in substance-naïve participants. The CUD PGS had the largest number of associations and was particularly associated with externalizing behavior in both genetic ancestry subsamples. OUD PGS associations were enriched for cognitive and neighborhood environmental phenotypes. Neuroimaging phenotypes (e.g., resting-state functional connectivity) partially accounted for associations between the SUD PGS and screen time phenotypes. Conclusions: Genetic liability to SUDs is expressed during childhood as potentially modifiable risk factors that could be targeted to attenuate its expression in adolescence and adulthood.
Background: Major depressive disorder (MDD) is associated with widespread molecular abnormalities in the brain; however, the contribution of ribosome-centered regulatory mechanisms remains poorly understood. Ribosomal RNA (rRNA) 2′-O-methylation (Nm) is the most abundant and evolutionarily conserved RNA modification and has emerged as a determinant of ribosome heterogeneity and translational control. However, the rRNA Nm landscape has not been examined in psychiatric illness. Here, we used RiboMeth-seq to map site-specific rRNA Nm in the MDD brain. Methods: RiboMeth-seq was performed in the dorsolateral prefrontal cortex of individuals with MDD ( n = 17) and matched nonpsychiatric control subjects ( n = 20) using an Illumina NextSeq2000 in 50-bp single-end mode. Specific RiboMeth-seq scores were calculated in ±2 nucleotide intervals for all RNA positions and extracted for the positions of known Nm residues in target RNA. Results: The overall distribution of ribose methylation scores was highly similar between groups, indicating the preservation of the global rRNA Nm landscape in MDD. At the same time, we identified 8 significantly altered Nm sites, including 4 in 28S rRNA (Am2802, Cm2848, Cm3866, and Gm4593) and 4 in 18S rRNA (Um172, Am576, Am1031, and Gm1490). These selective changes occurred in the absence of widespread remodeling, supporting a model in which MDD is associated with targeted modification of functionally relevant ribosomal positions rather than a generalized disruption of ribosome integrity. Conclusions: Our findings identify rRNA Nm as a previously unrecognized layer of molecular alteration in MDD and suggest that site-specific variation in ribosome composition may contribute to aberrant translational regulation in the depressed brain.
Background Older adults with remitted major depressive disorder or mild cognitive impairment (MCI) are at an increased risk for Alzheimer’s dementia (AD). Cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) slows cognitive decline in this population; however, its effects on gray matter macro- and microstructure have not been characterized. We investigated whether CR+tDCS alters cortical structure and whether baseline factors such as brain structure moderate potential changes. Methods Participants from the PACt-MD (Prevention of Alzheimer's Dementia with CR plus tDCS in Mild Cognitive Impairment and Depression) trial received active or sham CR+sham tDCS for 8 weeks and were followed for 2 to 7 years. Gray matter macrostructure (cortical thickness and surface area) was measured via T1-weighted magnetic resonance imaging at baseline, after acute treatment (N = 181), and at study completion (n = 102). Microstructure was assessed using neurite orientation dispersion and density imaging (NODDI). Mixed-effects models examined treatment effects and moderation by baseline factors across brain regions. Results No effects of CR+tDCS were observed on gray matter macro- or microstructure. Baseline cortical thickness moderated temporal lobe thickness changes, strongest in the entorhinal cortex over follow-up (pFDR = .010). Baseline NODDI measures moderated microstructural changes, strongest in the rostral middle frontal orientation dispersion index after acute treatment (pFDR < .001). There were no moderation effects of diagnosis or APOE status. Conclusions CR+tDCS does not produce uniform structural changes but interacts with baseline macro- and microstructure to shape longitudinal trajectories. Findings support the potential for precision approaches in preventive interventions for older adults at risk for AD.
