Polygenic risk has an impact on the structural plasticity of hippocampal subfields during aerobic exercise combined with cognitive remediation in multi-episode schizophrenia

Abstract

Preliminary studies suggest that, besides improving cognition, aerobic exercise might increase hippocampal volume in schizophrenia patients; however, results are not consistent. Individual mechanisms of volume changes are unknown but might be connected to the load of risk genes. Genome-wide association studies have uncovered the polygenic architecture of schizophrenia. The secondary analysis presented here aimed to determine the modulatory role of schizophrenia polygenic risk scores (PRSs) on volume changes in the total hippocampus and cornu ammonis (CA) 1, CA2/3, CA4/dentate gyrus (DG) and subiculum over time. We studied 20 multi-episode schizophrenia patients and 23 healthy controls who performed aerobic exercise (endurance training) combined with cognitive remediation for 3 months and 21 multi-episode schizophrenia patients allocated to a control intervention (table soccer) combined with cognitive remediation. Magnetic resonance imaging-based assessments were performed at baseline and after 3 months with FreeSurfer. No effects of PRSs were found on total hippocampal volume change. Subfield analyses showed that the volume changes between baseline and 3 months in the left CA4/DG were significantly influenced by PRSs in schizophrenia patients performing aerobic exercise. A larger genetic risk burden was associated with a less pronounced volume increase or a decrease in volume over the course of the exercise intervention. Results of exploratory enrichment analyses reinforced the notion of genetic risk factors modulating biological processes tightly related to synaptic ion channel activity, calcium signaling, glutamate signaling and regulation of cell morphogenesis. We hypothesize that a high polygenic risk may negatively influence neuroplasticity in CA4/DG during aerobic exercise in schizophrenia.

Figure 1

Scatterplot showing the relationship between the optimal schizophrenia polygenic risk score (PRS; x axis, standardized) and the change from baseline (V1) in the volume of the hippocampal subfields CA1 (left panel), CA2/3 (middle panel) and CA4/dentate gyrus (right panel) after 3 months of aerobic exercise (V3) (y axis, corrected residuals). Positive values in the y axis indicate a gain in volume after 3 months; positive values in the x axis, a higher genetic risk burden. Regression line and 95% confidence intervals are also shown.

Figure 2

Results of the formal enrichment analyses summarizing the Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) or Reactome pathways enriched in this study with a Bonferroni-corrected adjusted P-value<0.05. Red line: nominal significance threshold (0.05) of corrected P-values.