Associations of immunological proteins/traits with schizophrenia, major depression and bipolar disorder: A bi-directional two-sample mendelian randomization study.
Associations of immunological proteins/traits with schizophrenia, major depression and bipolar disorder: A bi-directional two-sample mendelian randomization study.
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DOI：
10.1016/j.bbi.2021.07.009
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Khandaker GM
中科院分区：
文献类型：
--
作者：
Perry BI;Upthegrove R;Kappelmann N;Jones PB;Burgess S;Khandaker GM
精神分裂症、双相情感障碍和抑郁症与炎症有关。然而，尚不清楚免疫蛋白/特征与这些疾病的关联是否可能是因果关系，或者可以通过反向因果关系/残留混杂来解释。我们使用双向两样本孟德尔随机化 (MR) 和多变量 MR (MVMR) 分析来检查 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 IL-2Rα、IL-4、IL-7、IL-9；急性期蛋白：C 反应蛋白 (CRP)；免疫细胞：中性粒细胞、淋巴细胞(BDNF)) 与精神分裂症、重度抑郁症和双相情感障碍。基因预测的 IL-6 在单变量 MR 中与精神分裂症风险增加相关（OR=1.24；95% C.I.，1.05-1.47），在 MVMR 中与重度抑郁症风险增加相关（OR=1.08；95% C.I.，1.03-1.12）。这些结果经受了 Bonferroni 校正。基因预测的 sIL-2Rα（OR=1.07；95% C.I.，1.01-1.12）和 IL-9（OR=1.06；95% C.I.，1.01-1.11）与精神分裂症风险增加相关。基因预测的 BDNF（OR=0.97；95% C.I.，0.94-1.00）和 MCP-1（OR=0.96；95% C.I.，0.91-0.99）与精神分裂症风险降低相关。然而，这些发现并没有经过多次测试的修正。在 MVMR 中考虑 IL-6 和 sIL-2Rα 后，CRP 与精神分裂症的关联完全减弱（OR=1.02；95% C.I.，0.81-1.28）。没有观察到双相情感障碍的显着关联。双向 MR 的证据不支持反向因果关系。我们报告的证据支持几种免疫蛋白/特征与精神分裂症以及 IL-6 与抑郁症之间的潜在因果关系。一些发现无法通过多次测试的校正，因此需要在更大的样本中进行复制。还需要实验研究来进一步检查这些免疫蛋白/途径对精神分裂症和抑郁症的因果关系、机制和治疗潜力。
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.
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影响因子：
11
作者：
Khandaker, Golam M.;Zuber, Verena;Burgess, Stephen
通讯作者：
Burgess, Stephen
影响因子：
7.7
作者：
Bowden J;Del Greco M F;Minelli C;Davey Smith G;Sheehan NA;Thompson JR
通讯作者：
Thompson JR
影响因子：
25.8
作者：
Khandaker GM;Pearson RM;Zammit S;Lewis G;Jones PB
通讯作者：
Jones PB
影响因子：
15.8
作者：
Danesh, John;Kaptoge, Stephen;Mann, Andrea G.;Sarwar, Nadeem;Wood, Angela;Angleman, Sara B.;Wensley, Frances;Higgins, Julian P. T.;Lennon, Lucy;Eiriksdottir, Gudny;Rumley, Ann;Whincup, Peter H.;Lowe, Gordon D. O.;Gudnason, Vilmundur
通讯作者：
Gudnason, Vilmundur
DOI：
10.1016/s2665-9913(20)30345-3
发表时间：
2020-11
期刊：
The Lancet. Rheumatology
影响因子：
--
作者：
Bovijn J;Lindgren CM;Holmes MV
通讯作者：
Holmes MV