Shared Genetic Loci Between Schizophrenia and White Blood Cell Counts Suggest Genetically Determined Systemic Immune Abnormalities

Nils Eiel Steen; Zillur Rahman; Attila Szabo; Guy F L Hindley; Nadine Parker; Weiqiu Cheng; Aihua Lin; Kevin S O'Connell; Mashhood A Sheikh; Alexey Shadrin; Shahram Bahrami; Sandeep Karthikeyan; Eva Z Hoseth; Anders M Dale; Pål Aukrust; Olav B Smeland; Thor Ueland; Oleksandr Frei; Srdjan Djurovic; Ole A Andreassen

doi:10.1093/schbul/sbad082

Shared Genetic Loci Between Schizophrenia and White Blood Cell Counts Suggest Genetically Determined Systemic Immune Abnormalities

Schizophr Bull. 2023 Sep 7;49(5):1345-1354. doi: 10.1093/schbul/sbad082.

Authors

Nils Eiel Steen^{1

2}, Zillur Rahman^{1

2}, Attila Szabo^{1

3}, Guy F L Hindley^{1

4}, Nadine Parker^{1

2}, Weiqiu Cheng^{1

2}, Aihua Lin¹, Kevin S O'Connell^{1

2}, Mashhood A Sheikh^{5

6}, Alexey Shadrin^{1

2}, Shahram Bahrami^{1

2}, Sandeep Karthikeyan^{1

2}, Eva Z Hoseth^{1

7}, Anders M Dale^{8

9

10}, Pål Aukrust^{5

6

11}, Olav B Smeland^{1

2}, Thor Ueland^{5

6

12}, Oleksandr Frei^{1

13}, Srdjan Djurovic^{14

15}, Ole A Andreassen^{1

2

3}

Affiliations

¹ NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
² Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
³ K.G. Jebsen Centre for Neurodevelopmental Disorders, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁴ Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁵ Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
⁶ Faculty of Medicine, University of Oslo, Oslo, Norway.
⁷ Division of Mental Health, Helse Møre Romsdal HF, Kristiansund, Norway.
⁸ Department of Radiology, University of California, San Diego, La Jolla, CA, USA.
⁹ Department of Cognitive Sciences, University of California, San Diego, La Jolla, CA, USA.
¹⁰ Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
¹¹ Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
¹² K.G. Jebsen-Thrombosis Research and Expertise Center (TREC), University of Tromsø, Tromsø, Norway.
¹³ Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway.
¹⁴ NORMENT Centre, Department of Clinical Science, University of Bergen, Bergen, Norway.
¹⁵ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.

Abstract

Background: Immune mechanisms are indicated in schizophrenia (SCZ). Recent genome-wide association studies (GWAS) have identified genetic variants associated with SCZ and immune-related phenotypes. Here, we use cutting edge statistical tools to identify shared genetic variants between SCZ and white blood cell (WBC) counts and further understand the role of the immune system in SCZ.

Study design: GWAS results from SCZ (patients, n = 53 386; controls, n = 77 258) and WBC counts (n = 56 3085) were analyzed. We applied linkage disequilibrium score regression, the conditional false discovery rate method and the bivariate causal mixture model for analyses of genetic associations and overlap, and 2 sample Mendelian randomization to estimate causal effects.

Study results: The polygenicity for SCZ was 7.5 times higher than for WBC count and constituted 32%-59% of WBC count genetic loci. While there was a significant but weak positive genetic correlation between SCZ and lymphocytes (rg = 0.05), the conditional false discovery rate method identified 383 shared genetic loci (53% concordant effect directions), with shared variants encompassing all investigated WBC subtypes: lymphocytes, n = 215 (56% concordant); neutrophils, n = 158 (49% concordant); monocytes, n = 146 (47% concordant); eosinophils, n = 135 (56% concordant); and basophils, n = 64 (53% concordant). A few causal effects were suggested, but consensus was lacking across different Mendelian randomization methods. Functional analyses indicated cellular functioning and regulation of translation as overlapping mechanisms.

Conclusions: Our results suggest that genetic factors involved in WBC counts are associated with the risk of SCZ, indicating a role of immune mechanisms in subgroups of SCZ with potential for stratification of patients for immune targeted treatment.

Keywords: inflammation; leucocyte; pleiotropy; polygenicity; psychosis; severe mental disorder.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Leukocyte Count
Phenotype
Polymorphism, Single Nucleotide
Schizophrenia* / genetics

Grants and funding

R01 EB000790/EB/NIBIB NIH HHS/United States