Differences in white blood cell proportions between schizophrenia cases and controls are influenced by medication and variations in time of day

Jonelle D Villar; Anne-Kristin Stavrum; Leticia M Spindola; Anja Torsvik; Thomas Bjella; Niels Eiel Steen; Srdjan Djurovic; Ole A Andreassen; Vidar M Steen; Stephanie Le Hellard

doi:10.1038/s41398-023-02507-1

Differences in white blood cell proportions between schizophrenia cases and controls are influenced by medication and variations in time of day

Transl Psychiatry. 2023 Jun 17;13(1):211. doi: 10.1038/s41398-023-02507-1.

Authors

Jonelle D Villar^{1

2}, Anne-Kristin Stavrum^{3

4}, Leticia M Spindola^{3

4}, Anja Torsvik^{3

4}, Thomas Bjella⁵, Niels Eiel Steen⁵, Srdjan Djurovic⁵, Ole A Andreassen⁵, Vidar M Steen^{3

4}, Stephanie Le Hellard^{6

7}

Affiliations

¹ NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway. Jonelle.Villar@uib.no.
² Dr. Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway. Jonelle.Villar@uib.no.
³ NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway.
⁴ Dr. Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
⁵ NORMENT, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁶ NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway. Stephanie.Hellard@uib.no.
⁷ Dr. Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway. Stephanie.Hellard@uib.no.

Abstract

Cases with schizophrenia (SCZ) and healthy controls show differences in white blood cell (WBC) counts and blood inflammation markers. Here, we investigate whether time of blood draw and treatment with psychiatric medications are related to differences in estimated WBC proportions between SCZ cases and controls. DNA methylation data from whole blood was used to estimate proportions of six subtypes of WBCs in SCZ patients (n = 333) and healthy controls (n = 396). We tested the association of case-control status with estimated cell-type proportions and the neutrophil-to-lymphocyte ratio (NLR) in 4 models: with/without adjusting for time of blood draw, and then compared results from blood samples drawn during a 12-h (07:00-19:00) or 7-h (07:00-14:00) period. We also investigated WBC proportions in a subgroup of medication-free patients (n = 51). Neutrophil proportions were significantly higher in SCZ cases (mean=54.1%) vs. controls (mean=51.1%; p = <0.001), and CD8⁺T lymphocyte proportions were lower in SCZ cases (mean=12.1%) vs. controls (mean=13.2%; p = 0.001). The effect sizes in the 12-h sample (07:00-19:00) showed a significant difference between SCZ vs. controls for neutrophils, CD4⁺T, CD8⁺T, and B-cells, which remained significant after adjusting for time of blood draw. In the samples matched for time of blood draw during 07.00-14.00, we also observed an association with neutrophils, CD4⁺T, CD8⁺T, and B-cells that was unaffected by further adjustment for time of blood draw. In the medication-free patients, we observed differences that remained significant in neutrophils (p = 0.01) and CD4⁺T (p = 0.01) after adjusting for time of day. The association of SCZ with NLR was significant in all models (range: p < 0.001 to p = 0.03) in both medicated and unmedicated patients. In conclusion, controlling for pharmacological treatment and circadian cycling of WBC is necessary for unbiased estimates in case-control studies. Nevertheless, the association of WBC with SCZ remains, even after adjusting for the time of day.

MeSH terms

Case-Control Studies
Humans
Leukocytes
Lymphocytes
Neutrophils
Schizophrenia* / genetics

Abstract

MeSH terms

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