Cytokines and schizophrenia revisited: a two-sample multi-marker Mendelian randomization approach

Background Schizophrenia is a complex mental disorder with recent evidence suggesting a critical immune component underpinning its pathophysiology. Two-sample Mendelian randomization (MR) provided an opportunity to probe the immune changes in schizophrenia by harnessing the increasing availability of summary-level data from large GWAS consortia. Objective To map the extensive immune response of schizophrenia in terms of cytokines/chemokines and to explore the effect of cytokines induced by schizophrenia (SCZ-induced cytokines) on the brain structure and function Sources and methods Using the summary-level data generated from GWAS of schizophrenia, cytokines in the peripheral blood and imaging-derived phenotypes (IDPs), we performed two rounds of two-sample MR analysis; the identified cytokines from first round of analysis (schizophrenia => cytokines) were modeled for its underlying structure and subsequent clustering analysis further grouped SCZ-induced cytokines based on their genetic similarities. The multi-phenotype summary statistics of each cytokine module were then used as instrumental variables (IVs) for the second round of MR analysis to detect their effect on brain structure and function. Results The first round of MR analysis identified nine cytokines, the highlight of which includes IL18 (OR = 1.292, P = 8.37 × 10−42) and TNFa (OR = 0.721, P = 7.33 × 10−6), to be causally associated with schizophrenia. These SCZ-induced cytokines could be clustered into three modules. The second round of MR analysis (cytokine module => IDPs) indicated that module B (SCGFb-IP10-CTACK-IL6) significantly increased the level of IDPs including IDP\_T1\_SIENAX\_peripheral\_grey\_normalised\_volume (β = 0.0453, P = 4.40×1010), IDP\_dMRI\_TBSS\_MD\_Posterior\_corona\_radiata_R (β= 0.0584, P = 8.89× 10−16) and IDP\_dMRI\_TBSS\_MD\_Cingulum\_hippocampus\_R (β = 0.0563, P = 9.88× 10−15), with module C (IL18-GROa-TNFa) increasing the level of IDP\_dMRI\_TBSS\_L2\_Posterior\_thalamic\_radiation_R (β= 0.0341, P = 2.67× 10−6). Conclusion Our study, for the first time, mapped the causal link from schizophrenia to the comprehensive immune responses, and the findings suggest immune networks play a role in pathophysiology of schizophrenia by mediating the deviations of total gray matter volume and white matter fibers possibly in the mesolimbic system.