Bidirectional two-sample Mendelian randomization study of differential white blood cell counts and schizophrenia

• Published in: Brain, behavior, and immunity behavior, and immunity, 2024-05, Vol.118, p.22-30
• Main Authors: Leung, Perry B.M., Liu, Zipeng, Zhong, Yuanxin, Tubbs, Justin D., Di Forti, Marta, Murray, Robin M., So, Hon-Cheong, Sham, Pak C., Lui, Simon S.Y.
• Format: Article
• Language: English
• Subjects: Immune system; Mendelian randomization; Neuroinflammation; Schizophrenia; White blood cell count
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2024.02.015

•Multiple mendelian randomization (MR) methods examined the directions of genetically-predicted relationships between schizophrenia and white cell counts.•Bidirectional genetic genetically-predicted relationships for elevated lymphocyte counts and schizophrenia risk were supported by most MR methods.•Genetically-predicted liability to schizophrenia is associated with elevated lymphocyte, monocyte and neutrophil counts.•Genetically-predicted elevation of lymphocyte, eosinophil, and monocyte counts may contribute to the development of schizophrenia, consistent with the vulnerability-stress-inflammation model.•The SNP of rs13195636 located in the MHC region appears highly influential in MR results, shared by schizophrenia and white cell counts. Schizophrenia and white blood cell counts (WBC) are both complex and polygenic traits. Previous evidence suggests that increased WBC are associated with higher all-cause mortality, and other studies have found elevated WBC in first-episode psychosis and chronic schizophrenia. However, these observational findings may be confounded by antipsychotic exposures and their effects on WBC. Mendelian randomization (MR) is a useful method for examining the directions of genetically-predicted relationships between schizophrenia and WBC. We performed a two-sample MR using summary statistics from genome-wide association studies (GWAS) conducted by the Psychiatric Genomics Consortium Schizophrenia Workgroup (N = 130,644) and the Blood Cell Consortium (N = 563,946). The MR methods included inverse variance weighted (IVW), MR Egger, weighted median, MR-PRESSO, contamination mixture, and a novel approach called mixture model reciprocal causal inference (MRCI). False discovery rate was employed to correct for multiple testing. Multiple MR methods supported bidirectional genetically-predicted relationships between lymphocyte count and schizophrenia: IVW (b = 0.026; FDR p-value = 0.008), MR Egger (b = 0.026; FDR p-value = 0.008), weighted median (b = 0.013; FDR p-value = 0.049), and MR-PRESSO (b = 0.014; FDR p-value = 0.010) in the forward direction, and IVW (OR = 1.100; FDR p-value = 0.021), MR Egger (OR = 1.231; FDR p-value