PMID- 34280516 OWN - NLM STAT- MEDLINE DCOM- 20210922 LR - 20220716 IS - 1090-2139 (Electronic) IS - 0889-1591 (Print) IS - 0889-1591 (Linking) VI - 97 DP - 2021 Oct TI - Associations of immunological proteins/traits with schizophrenia, major depression and bipolar disorder: A bi-directional two-sample mendelian randomization study. PG - 176-185 LID - S0889-1591(21)00273-7 [pii] LID - 10.1016/j.bbi.2021.07.009 [doi] AB - BACKGROUND: 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. METHODS: 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)-alpha, 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-2Ralpha, 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. RESULTS: 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-2Ralpha (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-2Ralpha 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. CONCLUSIONS: 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. CI - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Perry, Benjamin I AU - Perry BI AD - Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, England; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, England. Electronic address: bip20@medschl.cam.ac.uk. FAU - Upthegrove, Rachel AU - Upthegrove R AD - Institute for Mental Health, University of Birmingham, Birmingham, England; Early Intervention Service, Birmingham Womens and Childrens NHS Foundation Trust, Birmingham, England. FAU - Kappelmann, Nils AU - Kappelmann N AD - Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany; International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany. FAU - Jones, Peter B AU - Jones PB AD - Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, England; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, England. FAU - Burgess, Stephen AU - Burgess S AD - MRC Biostatistics Unit, University of Cambridge, Cambridge, England. FAU - Khandaker, Golam M AU - Khandaker GM AD - Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, England; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, England; MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England; Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England; Avon and Wiltshire Mental Health Partnership NHS Trust, Bristol England. LA - eng GR - RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom GR - 204623/WT_/Wellcome Trust/United Kingdom GR - DRF-2018-11-ST2-018/DH_/Department of Health/United Kingdom GR - MC_UU_00002/7/MRC_/Medical Research Council/United Kingdom GR - WT_/Wellcome Trust/United Kingdom GR - RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom GR - 201486/WT_/Wellcome Trust/United Kingdom GR - 204623/Z/16/Z/WT_/Wellcome Trust/United Kingdom GR - MC_PC_17213/MRC_/Medical Research Council/United Kingdom GR - MR/S037675/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210716 PL - Netherlands TA - Brain Behav Immun JT - Brain, behavior, and immunity JID - 8800478 SB - IM CIN - Brain Behav Immun. 2022 Jan;99:130-131. PMID: 34600087 MH - *Bipolar Disorder/genetics MH - Depression MH - *Depressive Disorder, Major/genetics MH - Humans MH - Mendelian Randomization Analysis MH - *Schizophrenia/genetics PMC - PMC7612947 MID - EMS146248 OTO - NOTNLM OT - Immune system OT - Inflammation OT - Mendelian randomization OT - bipolar disorder OT - depression OT - schizophrenia EDAT- 2021/07/20 06:00 MHDA- 2021/09/23 06:00 PMCR- 2022/07/02 CRDT- 2021/07/19 20:13 PHST- 2021/02/11 00:00 [received] PHST- 2021/06/18 00:00 [revised] PHST- 2021/07/12 00:00 [accepted] PHST- 2021/07/20 06:00 [pubmed] PHST- 2021/09/23 06:00 [medline] PHST- 2021/07/19 20:13 [entrez] PHST- 2022/07/02 00:00 [pmc-release] AID - S0889-1591(21)00273-7 [pii] AID - 10.1016/j.bbi.2021.07.009 [doi] PST - ppublish SO - Brain Behav Immun. 2021 Oct;97:176-185. doi: 10.1016/j.bbi.2021.07.009. Epub 2021 Jul 16.