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

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

doi:10.1093/schbul/sbac088

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

Schizophr Bull. 2022 Nov 18;48(6):1306-1317. doi: 10.1093/schbul/sbac088.

Authors

Jiayu Chen¹, Zening Fu¹, Juan R Bustillo^{2

3}, Nora I Perrone-Bizzozero^{2

3}, Dongdong Lin¹, Jose Canive³, Godfrey D Pearlson^{4

5}, Julia M Stephen⁶, Andrew R Mayer⁶, Steven G Potkin⁷, Theo G M van Erp⁸, Peter Kochunov⁹, L Elliot Hong⁹, Bhim M Adhikari⁹, Ole A Andreassen^{10

11}, Ingrid Agartz^{10

11

12}, Lars T Westlye^{10

13}, Jing Sui^{1

14}, Yuhui Du^{1

15}, Fabio Macciardi⁷, Faith M Hanlon⁶, Rex E Jung¹⁶, Jessica A Turner¹⁷, Jingyu Liu^{1

18}, Vince D Calhoun^{1

17}

Affiliations

¹ Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University, Georgia Institute of Technology, and Emory University, Atlanta, GA, USA.
² Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.
³ Department of Psychiatry and Behavioral Sciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.
⁴ Olin Neuropsychiatry Research Center, Institute of Living, Hartford, CT, USA.
⁵ Department of Psychiatry and Neuroscience, Yale University, New Haven, CT, USA.
⁶ The Mind Research Network, Albuquerque, NM, USA.
⁷ Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine, CA, USA.
⁸ Department of Psychiatry and Human Behavior, Clinical Translational Neuroscience Laboratory, School of Medicine, University of California, Irvine, CA, USA.
⁹ Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, USA.
¹⁰ Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research (NORMENT), Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹¹ Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
¹² Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
¹³ Department of Psychology, University of Oslo, Oslo, Norway.
¹⁴ Brainnetome Center and National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
¹⁵ School of Computer and Information Technology, Shanxi University, Taiyuan, China.
¹⁶ Department of Psychology, University of New Mexico, Albuquerque, NM, USA.
¹⁷ Psychology Department and Neuroscience Institute, Georgia State University, Atlanta, GA, USA.
¹⁸ Department of Computer Science, Georgia State University, Atlanta, GA, USA.

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; functional connectivity; gene expression; polygenic risk score; working memory.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Bipolar Disorder* / diagnostic imaging
Bipolar Disorder* / genetics
Cognition
Cognition Disorders*
Humans
Schizophrenia* / diagnostic imaging
Schizophrenia* / genetics
Transcriptome

Abstract

Publication types

MeSH terms

Grants and funding