Structural and Functional Neuroimaging of Polygenic Risk for Schizophrenia: A Recall-by-Genotype–Based Approach

Abstract

Risk profile scores (RPS) derived from genome-wide association studies (GWAS) explain a considerable amount of susceptibility for schizophrenia (SCZ). However, little is known about how common genetic risk factors for SCZ influence the structure and function of the human brain, largely due to the constraints of imaging sample sizes. In the current study, we use a novel recall-by-genotype (RbG) methodological approach, where we sample young adults from a population cohort (Avon Longitudinal Study of Parents and Children: N genotyped = 8365) based on their SCZ-RPS. We compared 197 healthy individuals at extremes of low (N = 99) or high (N = 98) SCZ-RPS with behavioral tests, and structural and functional magnetic resonance imaging (fMRI). We first provide methodological details that will inform the design of future RbG studies for common SCZ genetic risk. We further provide an between group analysis of the RbG individuals (low vs high SCZ-RPS) who underwent structural neuroimaging data (T1-weighted scans) and fMRI data during a reversal learning task. While we found little evidence for morphometric differences between the low and high SCZ-RPS groups, we observed an impact of SCZ-RPS on blood oxygen level-dependent (BOLD) signal during reward processing in the ventral striatum (PFWE-VS-CORRECTED = .037), a previously investigated broader reward-related network (PFWE-ROIS-CORRECTED = .008), and across the whole brain (PFWE-WHOLE-BRAIN-CORRECTED = .013). We also describe the study strategy and discuss specific challenges of RbG for SCZ risk (such as SCZ-RPS related homoscedasticity). This study will help to elucidate the behavioral and imaging phenotypes that are associated with SCZ genetic risk.

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 ).…”

Endophenotype Potential of Nucleus Accumbens Functional Connectivity: Effects of Polygenic Risk for Schizophrenia Interacting with Childhood Adversity

“…Several studies have combined a PGRS of SCZ with task fMRI and rsfMRI (for review, see Dezhina et al [32]). Here, more consistent findings were correlations between the PGRS and ventral striatal activation during choice behaviour [33] and reward processing [34,35]. Wang et al [36] investigated PGRS effects on resting state FC of the insula, finding both positively and negatively associated regions.…”

Reliability of Static and Dynamic Network Metrics in the Resting-State: A MEG-Beamformed Connectivity Analysis

“…It is highly recommend to access the reliability of any metric derived from any neuroimaging modality in a repeat scan protocol in healthy control population before applying it to a larger disease group where the cost of scanning is too high (diffusion MRI: Dimitriadis et al, 2017d ). Additionally, we will expand this analysis in future efforts to identify disease status alone including clinical variables related to genetic risk (Lancaster et al, 2018 ), expected treatment response and prognosis.…”