Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, England; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, England.
Institute for Mental Health, University of Birmingham, Birmingham, England; Early Intervention Service, Birmingham Womens and Childrens NHS Foundation Trust, Birmingham, England.
Brain Behav Immun. 2021 Oct;97:176-185. doi: 10.1016/j.bbi.2021.07.009. Epub 2021 Jul 16.
Schizophrenia, bipolar disorder and depression are associated with inflammation. However, it is unclear whether associations of immunological proteins/traits with these disorders are likely to be causal, or could be explained by reverse causality/residual confounding.
We used bi-directional two-sample Mendelian randomization (MR) and multi-variable MR (MVMR) analysis to examine evidence of causality, specificity and direction of association of 20 immunological proteins/traits (pro-inflammatory cytokines: interleukin (IL)-6, tumour necrosis factor (TNF)-α, IL-12, IL-16, IL-17, IL-18; anti-inflammatory cytokines: IL-1 receptor antagonist (RA), IL-10, IL-13; chemokines: IL-8, monocyte chemo-attractant protein-1 (MCP-1); lymphoid growth-factors: soluble (s) IL-2Rα, IL-4, IL-7, IL-9; myeloid growth-factor: IL-5; acute phase protein: C-Reactive Protein (CRP); immune cells: neutrophils, lymphocytes; neurotrophic factor: brain derived neurotrophic factor (BDNF)) with schizophrenia, major depression and bipolar disorder.
Genetically-predicted IL-6 was associated with increased risk of schizophrenia in univariable MR (OR = 1.24; 95% C.I., 1.05-1.47) and with major depression in MVMR (OR = 1.08; 95% C.I., 1.03-1.12). These results survived Bonferroni-correction. Genetically-predicted sIL-2Rα (OR = 1.07; 95% C.I., 1.01-1.12) and IL-9 (OR = 1.06; 95% C.I., 1.01-1.11) were associated with increased schizophrenia risk. Genetically-predicted BDNF (OR = 0.97; 95% C.I., 0.94-1.00) and MCP-1 (OR = 0.96; 95% C.I., 0.91-0.99) were associated with reduced schizophrenia risk. However, these findings did not survive correction for multiple testing. The CRP-schizophrenia association attenuated completely after taking into account IL-6 and sIL-2Rα in MVMR (OR = 1.02; 95% C.I., 0.81-1.28). No significant associations were observed for bipolar disorder. Evidence from bidirectional MR did not support reverse causality.
We report evidence in support of potential causal associations of several immunological proteins/traits with schizophrenia, and of IL-6 with depression. Some of the findings did not survive correction for multiple testing and so replication in larger samples is required. Experimental studies are also required to further examine causality, mechanisms, and treatment potential for these immunological proteins/pathways for schizophrenia and depression.
精神分裂症、双相情感障碍和抑郁症与炎症有关。然而，目前尚不清楚免疫蛋白/特征与这些疾病之间的关联是否可能具有因果关系，或者是否可以用反向因果关系/残余混杂来解释。
我们使用双向两样本孟德尔随机化（MR）和多变量 MR（MVMR）分析来检验 20 种免疫蛋白/特征（促炎细胞因子：白细胞介素（IL）-6、肿瘤坏死因子（TNF）-α、IL-12、IL-16、IL-17、IL-18；抗炎细胞因子：IL-1 受体拮抗剂（RA）、IL-10、IL-13；趋化因子：IL-8、单核细胞趋化蛋白-1（MCP-1）；淋巴生长因子：可溶性（s）IL-2Rα、IL-4、IL-7、IL-9；髓样生长因子：IL-5；急性期蛋白：C 反应蛋白（CRP）；免疫细胞：中性粒细胞、淋巴细胞；神经营养因子：脑源性神经营养因子（BDNF））与精神分裂症、重度抑郁症和双相情感障碍之间因果关系、特异性和关联方向的证据。
单变量 MR 中，遗传预测的 IL-6 与精神分裂症风险增加相关（OR=1.24；95%置信区间，1.05-1.47），MVMR 中与重度抑郁症相关（OR=1.08；95%置信区间，1.03-1.12）。这些结果经过 Bonferroni 校正后仍然存在。遗传预测的 sIL-2Rα（OR=1.07；95%置信区间，1.01-1.12）和 IL-9（OR=1.06；95%置信区间，1.01-1.11）与精神分裂症风险增加相关。遗传预测的 BDNF（OR=0.97；95%置信区间，0.94-1.00）和 MCP-1（OR=0.96；95%置信区间，0.91-0.99）与精神分裂症风险降低相关。然而，这些发现并未经过多次测试校正。MVMR 中考虑到 IL-6 和 sIL-2Rα 后，CRP 与精神分裂症的关联完全减弱（OR=1.02；95%置信区间，0.81-1.28）。双向 MR 未发现与双相情感障碍相关的证据。反向因果关系的证据并不支持。
我们报告了支持几种免疫蛋白/特征与精神分裂症之间潜在因果关系的证据，以及 IL-6 与抑郁症之间的证据。其中一些发现未经过多次测试校正，因此需要在更大的样本中进行复制。还需要进行实验研究，以进一步研究这些免疫蛋白/途径对精神分裂症和抑郁症的因果关系、机制和治疗潜力。
