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

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

Publication Date

11-18-2022

Journal

Schizophrenia Bulletin

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.

Keywords

SNP, polygenic risk score, gene expression, functional connectivity, working memory

Comments

Supplementary Materials

PMID: 35988022