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

Author:

Chen Jiayu1,Fu Zening1,Bustillo Juan R23,Perrone-Bizzozero Nora I23,Lin Dongdong1,Canive Jose3,Pearlson Godfrey D45,Stephen Julia M6ORCID,Mayer Andrew R6ORCID,Potkin Steven G7,van Erp Theo G M8,Kochunov Peter9,Elliot Hong L9,Adhikari Bhim M9,Andreassen Ole A1011,Agartz Ingrid101112,Westlye Lars T1013ORCID,Sui Jing114,Du Yuhui115,Macciardi Fabio7,Hanlon Faith M6,Jung Rex E16ORCID,Turner Jessica A17ORCID,Liu Jingyu118,Calhoun Vince D117

Affiliation:

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

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.

Funder

National Institutes of Health

Publisher

Oxford University Press (OUP)

Subject

Psychiatry and Mental health

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