Genome-Transcriptome-Functional Connectivity-Cognition Link Differentiates Schizophrenia From Bipolar Disorder

Overview

Journal Schizophr Bull

Publisher Oxford University Press

Specialty Psychiatry

Date 2022 Aug 21

PMID 35988022

Authors

Jiayu Chen

Zening Fu

Juan R Bustillo

Nora I Perrone-Bizzozero

Dongdong Lin

Jose Canive

Godfrey D Pearlson

Julia M Stephen

Andrew R Mayer

Steven G Potkin

Theo G M van Erp

Peter Kochunov

L Elliot Hong

Bhim M Adhikari

Ole A Andreassen

Ingrid Agartz

Lars T Westlye

Jing Sui

Yuhui Du

Fabio Macciardi

Faith M Hanlon

Rex E Jung

Jessica A Turner

Jingyu Liu

Vince D Calhoun

Affiliations

Soon will be listed here.

Abstract

Background And Hypothesis: Schizophrenia (SZ) and bipolar disorder (BD) share genetic risk factors, yet patients display differential levels of cognitive impairment. We hypothesized a genome-transcriptome-functional connectivity (frontoparietal)-cognition pathway linked to SZ-versus-BD differences, and conducted a multiscale study to delineate this pathway.

Study Designs: Large genome-wide studies provided single nucleotide polymorphisms (SNPs) conferring more risk for SZ than BD, and we identified their regulated genes, namely SZ-biased SNPs and genes. We then (a) computed the polygenic risk score for SZ (PRSSZ) of SZ-biased SNPs and examined its associations with imaging-based frontoparietal functional connectivity (FC) and cognitive performances; (b) examined the spatial correlation between ex vivo postmortem expressions of SZ-biased genes and in vivo, SZ-related FC disruptions across frontoparietal regions; (c) investigated SZ-versus-BD differences in frontoparietal FC; and (d) assessed the associations of frontoparietal FC with cognitive performances.

Study Results: PRSSZ of SZ-biased SNPs was significantly associated with frontoparietal FC and working memory test scores. SZ-biased genes' expressions significantly correlated with SZ-versus-BD differences in FC across frontoparietal regions. SZ patients showed more reductions in frontoparietal FC than BD patients compared to controls. Frontoparietal FC was significantly associated with test scores of multiple cognitive domains including working memory, and with the composite scores of all cognitive domains.

Conclusions: Collectively, these multiscale findings support the hypothesis that SZ-biased genetic risk, through transcriptome regulation, is linked to frontoparietal dysconnectivity, which in turn contributes to differential cognitive deficits in SZ-versus BD, suggesting that potential biomarkers for more precise patient stratification and treatment.

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