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.
Highlights
Schizophrenia (SCZ) has a broad genetic architecture, characterized by thousands of common genetic variants[1] and rare pathogenic copy number variations (CNVs).[2]
After correcting for FWE using TFCE correction (PCORRECTED < .05), we found no effect of SCZ-Risk profile scores (RPS) group in the choice decision contrast
In a series of linear regression models, we found no evidence for association between SCZ-RPS related blood oxygen level-dependent (BOLD) in any of the clusters identified within the whole brain or ROI analysis (P > .1, in all cases)
Summary
Schizophrenia (SCZ) has a broad genetic architecture, characterized by thousands of common genetic variants (single nucleotide polymorphisms; SNPs)[1] and rare pathogenic copy number variations (CNVs).[2] These loci demonstrate biological convergence on central nervous system pathways such as voltage-gated calcium channel signaling, fragile X mental retardation protein (FMRP) gene targets, and excitatory/inhibitory synaptic neurotransmission.[3] SCZ polygenicity confers susceptibility to other psychiatric disorders, suggesting a shared, common etiology.[4] While the cumulative (polygenic) effects of currently identified risk alleles explain approximately 7% of SCZ liability, these risk profile scores (RPS) do not yet offer predictive utility.[1] SCZ-RPS are useful in identifying causal antecedents that predict disease risk such as reduced cognitive ability,[5] increased substance use[6,7] and higher incidence for specific SCZ symptom dimensions.[8] SCZ loci show genetic overlap with a number of polygenic, heritable traits, including personality, education and socioeconomic status.[9,10,11,12] SCZ-RPS has been combined with neuroimaging measures to identify disturbances in brain structure and function that reflect mechanisms of SCZ disease pathogenesis. Behavioral and neural measures of cognition (eg, using functional magnetic resonance imaging [fMRI]) may reflect disease susceptibility.[13,14,15,16,17] These imaging SCZ-RPS studies support theories that cognitive dysfunction is a risk factor for SCZ, while at least
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