Adolescents' genetic risks tied to psychotic symptoms

Study reveals genetic links between attention deficits, functional brain connectivity, and early psychosis risk in adolescents.

In a recent study published in Nature Mental Health, researchers examine the relationships between neuropsychiatric and cognitive polygenic scores (PGSs), attention-related phenotypes, and psychosis spectrum symptoms.

Attention deficits and schizophrenia risk

Adolescence, which is a critical period characterized by cognitive changes and brain network reorganization, is considered a risk period for psychosis. Recent studies indicate that PGSs for neurodevelopmental disorders and attention-deficit hyperactivity disorder (ADHD) are associated with sub-threshold psychotic symptoms during adolescence. Conversely, PGS for SCZ is weakly associated with psychopathology in adolescence and childhood.

About the study

In the present study, researchers investigate the relationships between attentional variability, genetic risk, sub-clinical psychotic-like experiences (PLEs), and attention-related functional brain architecture in early adolescence.

Data were obtained from 11,855 children from the adolescent brain cognitive development study, which monitored individuals between nine and eleven years of age at baseline for 10 years. Individuals with symptoms aligning with psychosis-spectrum disorders were included in the study.

Study participants completed seven tasks across executive function, working memory, attention, episodic memory, language abilities, and processing speed. Timed-reaction-time tasks, including the dimensional change card sort, Flanker, and pattern comparison processing speed tasks, were also used. Inter-individual variability (IIV) was examined for each task in relation to PGSs and PLEs and was aggregated to generate a composite, cross-task IIV score.

Higher scores indicated increased inattentiveness. The prodromal questionnaire brief child version (PQ-BC) was used to assess PLEs.

A summary score for PQ-BC distress was calculated as a measure of PLEs. All study participants underwent brain magnetic resonance imaging (MRI). Within- and between-network functional connectivity (FC) was determined using pairwise correlations.

Only attention-related functional networks were assessed for associations, such as the default mode network (DMN)-task-positive network (TPN) anticorrelation and within-network FC of DMN and TPNs. TPNs included cingulo-opercular network (CON) and dorsal attention network (DAN). Summary statistics from recent genome-wide association studies of psychiatric phenotypes were acquired from a database.

Psychiatric phenotypes included ADHD, SCZ, autism spectrum disorder (ASD), Tourette’s syndrome (TS), and major depressive disorder (MDD). Only ADHD and SCZ PGSs were individually tested, whereas a broad neurodevelopmental (Neurodev) PGS was calculated using summary statistics of TS, ASD, and MDD. Associations were tested using linear mixed-effects models.

Study findings

Altered FC and greater IIV were associated with more severe PLEs. Greater IIV was associated with increased PLE severity, according to the PQ-BC distress score. A weaker anticorrelation between DMN and DAN, as well as between DMN and CON, was significantly associated with the severity of PLEs.

A significant association between PLE severity and weaker FC within DMN, DAN, and CON was detected. Higher PGSs for IIV, Neurodev, and ADHD, as well as lower cognitive PGS associated with increased IIV, were also observed.

However, SCZ PGS was not associated with IIV. Comparatively, lower cognitive PGS and higher PGSs for ADHD, SCZ, and Neurodev were associated with more severe PLEs.

PGSs were not associated with the DAN-DMN anticorrelation or within-network FC of the DAN. Notably, IIV-mediated associations between cognitive, Neurodev, and ADHD PGSs and PLEs were involved in 4-16% of these relationships.

The associations between cognitive, ADHD, and Neurodev PGSs and PLEs weakened over time. However, no significant interaction was observed between time and PGS for SCZ.

Conclusions

Associations between cognitive, Neurodev, and ADHD PGSs and PLE severity weakened over time, whereas those between SCZ PGS and PLEs remained consistent. Overall, the study findings indicate that genetic predisposition to neurodevelopmental disorders, which may present as subthreshold psychotic symptoms in early adolescence, is partially mediated by attentional lapses.

Journal reference:

• Chang, S. E., Hughes, D. E., Zhu, J., et al. (2024). Attention-mediated genetic influences on psychotic symptomatology in adolescence. Nature Mental Health. doi:10.1038/s44220-024-00338-7