Hippocampal volume decrease is a structural hallmark of schizophrenia (SCZ), and convergent evidence from postmortem and imaging studies suggests that it may be explained by changes in the cytoarchitecture of the cornu ammonis 4 (CA4) and dentate gyrus (DG) subfields. Increasing evidence indicates that aerobic exercise increases hippocampal volume in CA subfields and improves cognition in SCZ patients. Previous studies showed that the effects of exercise on the hippocampus might be connected to the polygenic burden of SCZ risk variants. However, little is known about cell type-specific genetic contributions to these structural changes. In this secondary analysis, we evaluated the modulatory role of cell type-specific SCZ polygenic risk scores (PRS) on volume changes in the CA1, CA2/3, and CA4/DG subfields over time. We studied 20 multi-episode SCZ patients and 23 healthy controls who performed aerobic exercise, and 21 multi-episode SCZ patients allocated to a control intervention (table soccer) for 3 months. Magnetic resonance imaging-based assessments were performed with FreeSurfer at baseline and after 3 months. The analyses showed that the polygenic burden associated with oligodendrocyte precursor cells (OPC) and radial glia (RG) significantly influenced the volume changes between baseline and 3 months in the CA4/DG subfield in SCZ patients performing aerobic exercise. A higher OPC- or RG-associated genetic risk burden was associated with a less pronounced volume increase or even a decrease in CA4/DG during the exercise intervention. We hypothesize that SCZ cell type-specific polygenic risk modulates the aerobic exercise-induced neuroplastic processes in the hippocampus.

Executive functions are metacognitive capabilities that control and coordinate mental processes. In the transdiagnostic PsyCourse Study, comprising patients of the affective-to-psychotic spectrum and controls, we investigated the genetic basis of the time course of two core executive subfunctions: set-shifting (Trail Making Test, part B (TMT-B)) and updating (Verbal Digit Span backwards) in 1338 genotyped individuals. Time course was assessed with four measurement points, each 6 months apart. Compared to the initial assessment, executive performance improved across diagnostic groups. We performed a genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with performance change over time by testing for SNP-by-time interactions using linear mixed models. We identified nine genome-wide significant SNPs for TMT-B in strong linkage disequilibrium with each other on chromosome 5. These were associated with decreased performance on the continuous TMT-B score across time. Variant rs150547358 had the lowest P value = 7.2 × 10-10 with effect estimate beta = 1.16 (95% c.i.: 1.11, 1.22). Implementing data of the FOR2107 consortium (1795 individuals), we replicated these findings for the SNP rs150547358 (P value = 0.015), analyzing the difference of the two available measurement points two years apart. In the replication study, rs150547358 exhibited a similar effect estimate beta = 0.85 (95% c.i.: 0.74, 0.97). Our study demonstrates that longitudinally measured phenotypes have the potential to unmask novel associations, adding time as a dimension to the effects of genomics.

Cognitive deficits are a core feature of psychiatric disorders like schizophrenia and bipolar disorder. Evidence supports a genome-wide polygenic score (GPS) for educational attainment (GPSEDU) can be used to explain variability in cognitive performance. We aimed to identify different cognitive domains associated with GPSEDU in a transdiagnostic clinical cohort of chronic psychiatric patients with known cognitive deficits. Bipolar and schizophrenia patients from the PsyCourse cohort (N = 730; 43% female) were used. Likewise, we tested whether GPSs for schizophrenia (GPSSZ) and bipolar disorder (GPSBD) were associated with cognitive outcomes. GPSEDU explained 1.5% of variance in the backward verbal digit span, 1.9% in the number of correctly recalled words of the Verbal Learning and Memory Test, and 1.1% in crystallized intelligence. These effects were robust to the influences of treatment and diagnosis. No significant associations between GPSSZ or GPSBD with cognitive outcomes were found. Furthermore, these risk scores did not confound the effect of GPSEDU on cognitive outcomes. GPSEDU explains a small fraction of cognitive performance in adults with psychiatric disorders, specifically for domains related to linguistic learning and working memory. Investigating such a proxy-phenotype longitudinally, could give intriguing insight into the disease course, highlighting at what time genes play a more influential role on cognitive performance. Better understanding the origin of these deficits might help identify those patients at risk for lower levels of functioning and poor social outcomes. Polygenic estimates may in the future be part of predictive models for more personalized interventions.