Sex-dependent association study of complement C4 gene with treatment-resistant schizophrenia and hospitalization frequency

Kowsar Teymouri; Mahbod Ebrahimi; Cheng C Chen; Venuja Sriretnakumar; Ayeshah G Mohiuddin; Arun K Tiwari; Jennie G Pouget; Clement C Zai; James L Kennedy

doi:10.1016/j.psychres.2024.116202

Sex-dependent association study of complement C4 gene with treatment-resistant schizophrenia and hospitalization frequency

Psychiatry Res. 2024 Sep 23:342:116202. doi: 10.1016/j.psychres.2024.116202. Online ahead of print.

Authors

Kowsar Teymouri¹, Mahbod Ebrahimi¹, Cheng C Chen¹, Venuja Sriretnakumar², Ayeshah G Mohiuddin², Arun K Tiwari³, Jennie G Pouget⁴, Clement C Zai⁵, James L Kennedy⁶

Affiliations

¹ Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
² Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
³ Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
⁴ Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
⁵ Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
⁶ Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Electronic address: jim.kennedy@camh.ca.

PMID: 39342786
DOI: 10.1016/j.psychres.2024.116202

Abstract

The complement component 4 (C4) gene, codes for two isotypes, C4A and C4B, and can exist in long or short forms (C4L and C4S). The C4AL variant has been associated with elevated schizophrenia (SCZ) risk. Here, we investigated the relationship between C4 variation and clinical outcomes in SCZ. N = 434 adults with SCZ or schizoaffective disorder were included in this retrospective study. A three-step genotyping workflow was performed to determine C4 copy number variants. These variants were tested for association with clinical outcome measures, including treatment-resistant SCZ (TRS), number of hospitalizations (NOH), and symptom severity (PANSS). Sex and ancestry stratified analyses were performed. We observed a marginally significant association between C4S and TRS in males only, and a negative association between C4S and NOH in the total sample. C4AS had negative association with NOH in males and non-Europeans. Lastly, C4A copy numbers and C4A predicted brain expression showed negative association with NOH in males only. Our study provides further support for sex-specific effect of C4 on SCZ clinical outcomes, and also suggests that C4S and C4AS might have a protective effect against increased severity. C4 could potentially serve as a genetic biomarker in the future, however, more research is required.

Keywords: Clinical subtypes; Clozapine; Immune system; PANSS; Symptom severity.