Causal role of immune cells in schizophrenia: Mendelian randomization (MR) study

Abstract

Background Complex immune-brain interactions that affect neural development, survival and function might have causal and therapeutic implications for psychiatric illnesses. However, previous studies examining the association between immune inflammation and schizophrenia (SCZ) have yielded inconsistent findings. Methods Comprehensive two-sample Mendelian randomization (MR) analysis was performed to determine the causal association between immune cell signatures and SCZ in this study. Based on publicly available genetic data, we explored causal associations between 731 immune cell signatures and SCZ risk. A total of four types of immune signatures (median fluorescence intensities (MFI), relative cell (RC), absolute cell (AC), and morphological parameters (MP)) were included. Comprehensive sensitivity analyses were used to verify the robustness, heterogeneity, and horizontal pleiotropy of the results. Results After FDR correction, SCZ had no statistically significant effect on immunophenotypes. It was worth mentioning some phenotypes with unadjusted low P-values, including FSC-A on NKT (β = 0.119, 95% CI = 0.044 ~ 0.194, P = 0.002), DN (CD4-CD8-) NKT %T cell (β = 0.131, 95% CI = 0.054 ~ 0.208, P = 9.03 × 10− 4), and SSC-A on lymphocytes (β = 0.136, 95% CI = 0.059 ~ 0.213, P = 5.43 × 10− 4). The causal effect of SCZ IgD on transitional was estimated to 0.127 (95% CI = 0.051 ~ 0.203, P = 1.09 × 10− 3). SCZ also had a causal effect on IgD+ %B cell (β = 0.130, 95% CI = 0.054 ~ 0.207, P = 8.69 × 10− 4), and DP (CD4+CD8+) %T cell (β = 0.131, 95% CI = 0.054 ~ 0.207, P = 8.05 × 10− 4). Furthermore, four immunophenotypes were identified to be significantly associated with SCZ risk: naive CD4+ %T cell (OR = 0.986, 95% CI = 0.979 ~ 0.992, P = 1.37 × 10− 5), HLA DR on CD14− CD16− (OR = 0.738 (95% CI = 0.642 ~ 0.849, P = 2.00 × 10− 5), CD33dim HLA DR+ CD11b− AC (OR = 0.631, 95% CI = 0.529 ~ 0.753, P = 3.40 × 10− 7) and activated & resting Treg % CD4 Treg (OR = 0.937, 95% CI = 0.906 ~ 0.970, P = 1.96 × 10− 4). Conclusions Our study has demonstrated the close connection between immune cells and SCZ by genetic means, thus providing guidance for future clinical research.

The Relationship Between Circulating Immune Cell Phenotypes and Sepsis: A Mendelian Randomization Study

“…First, we selected SNPs strongly correlated with circulating immune cell phenotypes as IVs. Specifically, we applied a correlation threshold of P < 1 × 10 −5 to identify strongly correlated IVs (19). Second, to guarantee the independence of the selected IVs, we set the linkage disequilibrium (LD) coefficient ( R 2 ) < 0.001 and the maximum LD region span to 10,000 kb, effectively excluding SNPs in LD.…”

Association between human blood metabolome and the risk of coronary heart disease: Mendelian randomization study

“…Firstly, employing PLINK software (version v1.90), we executed a clumping procedure to refine the SNPs selection. This process adhered to a strict linkage disequilibrium (LD) r^2 threshold of less than 0.001, within a 10,000 kb window, 19 ensuring the minimization of confounding genetic linkage.…”

Combination of multidisciplinary approaches reveals potential causal associations between influenza and immune cells: Single-cell RNA sequencing and Mendelian randomization

“…For the data of 731 immune cells, the criteria for the genetic instruments were as follows: P < 5× 10 − 6 , r 2 < 0.001, MAF > 0.01 and kb < 10,000 [32]. For in uenza, we adjusted the signi cance level to P < 5×10 − 8 .The "TwoSampleMR" package was employed to perform UVMR analysis.…”

“…Leukocyte Antigen in humans [32,55]. HLA-DR surface molecules play an important role in the immune response, particularly in assisting in the activation of speci c immune responses [56].…”