Impact on the Onset of Psychosis of a Polygenic Schizophrenia-Related Risk Score and Changes in White Matter Volume

Abstract

Background: Reductions in the volume of brain white matter are a common feature in schizophrenia and bipolar disorder while the association between white matter and polygenic schizophrenia-related risk is unclear. To look at the intermediate state between health and the full-blown disorder, we investigated this aspect in groups of patients before and after the onset of psychosis. Methods: On a 3 Tesla scanner, total and regional white matter volumes were investigated by structural magnetic resonance imaging (MRI) in the following groups: 37 at-risk mental state patients (ARMS), including 30 with no transition to psychosis (ARMS-NT) and 7 with a transition to psychosis (ARMS-T) pooled with 25 first episode psychosis (FEP) patients. These T₁-weighted images were automatically processed with the FreeSurfer software and compared with an odds-ratio-weighted polygenic schizophrenia-related risk score (PSRS) based on the publicly available top white matter single-nucleotide polymorphisms. Results: We found no association, only a trend, between PSRS and white matter volume over all groups (β = 0.24, p = 0.07, 95% confidence interval = [-0.02 – 0.49]). However, a higher PSRS was significantly associated with a higher probability of being assigned to the ARMS-T + FEP group rather than to the ARMS-NT group (β = 0.70, p = 0.02, 95% confidence interval = [0.14 – 1.33]); there was no such association with white matter volume. Additionally, a positive association was found between PSRS and the Brief Psychiatric Rating Scale (BPRS) total score for the pooled ARMS-NT/ARMS-T+FEP sample and for the ARMS-T + FEP group also, but none for the ARMS-NT group only. Conclusion: These findings suggest that at-risk mental state patients with a transition and first-episode psychosis patients have a higher genetic risk for schizophrenia than at-risk mental state patients with no transition to psychosis; this risk was associated with psychopathological symptoms. Further analyses may allow polygenic schizophrenia-related risk scores to be used as biomarkers to predict psychosis.

Schizophrenia Polygenic Risk and Brain Structural Changes in Methamphetamine-Associated Psychosis in a South African Population

“…In particular, polygenic risk scores for schizophrenia may not be associated with measures of brain volume in healthy individuals or in those with psychotic disorders. This explanation is consistent with findings from previous research in populations of largely European ancestry ( Reus et al, 2017 ; Harrisberger et al, 2018 ; Lancaster et al, 2018 ; Simões et al, 2020 ). For example, no associations between PRS for schizophrenia and for bipolar disorder with either subcortical volume or WM microstructure, were found in the United Kingdom Biobank ( Reus et al, 2017 ).…”

Prevention of Psychosis

“…The main limitations of this study were that the meta-analyses had heterogeneous quality (eResults in the Supplement) and that the literature search approach may have favored the selection of more commonly and readily studied domains that are more likely to be included in a meta-analysis. We cannot exclude the possibility that some promising advancements in the CHR-P field, despite having sufficient data, do not (yet) have a corresponding eligible meta-analysis, such as polygenic risk scores . However, in the current era, this possibility is becoming increasingly less likely, with meta-analyses being performed frequently, to the point that multiple meta-analyses are available for the same topic .…”

“…We cannot exclude the possibility that some promising advancements in the CHR-P field, despite having sufficient data, do not (yet) have a corresponding eligible metaanalysis, such as polygenic risk scores. 96 However, in the current era, this possibility is becoming increasingly less likely, with metaanalyses being performed frequently, to the point that multiple metaanalyses are available for the same topic. [97][98][99] In any case, for most putative domains that are difficult to study (or uncommonly studied), the current grade of evidence is unlikely to be remarkable, given the limited data.…”

Translational Potential of Neuroimaging Genomic Analyses to Diagnosis and Treatment in Mental Disorders

“…Although not yet clinically useful [199,200], PRS is one of the most commonly explored multivariate genetic markers and has shown some potential in the context of prodromal research to predict transition from high risk to psychosis [201,202]. This may enable stratifying individuals into groups of high and low risk of transition and delivery of treatment accordingly [203].…”