Investigating the neuroimmunogenic architecture of schizophrenia

R. Birnbaum; A. E. Jaffe; Q. Chen; J. H. Shin; J. E. Kleinman; T. M. Hyde; D. R. Weinberger

doi:10.1038/mp.2017.89

Investigating the neuroimmunogenic architecture of schizophrenia

R. Birnbaum, A. E. Jaffe, Q. Chen, J. H. Shin, J. E. Kleinman, T. M. Hyde, D. R. Weinberger

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31 Scopus citations

Abstract

The role of the immune system in schizophrenia remains controversial despite numerous studies to date. Most studies have profiled expression of select genes or proteins in peripheral blood, but none have focused on the expression of canonical pathways that mediate overall immune response. The current study used a systematic genetic approach to investigate the role of the immune system in a large sample of post-mortem brain of patients with schizophrenia: RNA sequencing was performed to assess the differential expression of 561 immune genes and 20 immune pathways in dorsolateral prefrontal cortex (DLPFC) (144 schizophrenia and 196 control subjects) and hippocampus (83 schizophrenia and 187 control subjects). The effect of RNA quality on gene expression was found to be highly correlated with the effect of diagnosis even after adjustment for observable RNA quality parameters (i.e. RNA integrity), thus this confounding relationship was statistically controlled using principal components derived from the gene expression matrix. In DLPFC, 23 immune genes were found to be differentially expressed (false discovery rate <0.05), of which seven genes replicated in both directionality and at nominal significance (P<0.05) in an independent post-mortem DLPFC data set (182 schizophrenia and 212 control subjects), although notably at least five of these genes have prominent roles in pathways other than immune function and overall the effect sizes were minimal (fold change <1.1). In the hippocampus, no individual immune genes were identified to be differentially expressed, and in both DLPFC and hippocampus none of the individual immune pathways were relatively differentially expressed. Further, genomic schizophrenia risk profiles scores were not correlated with the expression of individual immune pathways or differentially expressed genes. Overall, past reports claiming a primary pathogenic role of the immune system intrinsic to the brain in schizophrenia could not be confirmed.

Original language	English (US)
Pages (from-to)	1251-1260
Number of pages	10
Journal	Molecular psychiatry
Volume	23
Issue number	5
DOIs	https://doi.org/10.1038/mp.2017.89
State	Published - May 1 2018

ASJC Scopus subject areas

Molecular Biology
Psychiatry and Mental health
Cellular and Molecular Neuroscience

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10.1038/mp.2017.89

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title = "Investigating the neuroimmunogenic architecture of schizophrenia",

abstract = "The role of the immune system in schizophrenia remains controversial despite numerous studies to date. Most studies have profiled expression of select genes or proteins in peripheral blood, but none have focused on the expression of canonical pathways that mediate overall immune response. The current study used a systematic genetic approach to investigate the role of the immune system in a large sample of post-mortem brain of patients with schizophrenia: RNA sequencing was performed to assess the differential expression of 561 immune genes and 20 immune pathways in dorsolateral prefrontal cortex (DLPFC) (144 schizophrenia and 196 control subjects) and hippocampus (83 schizophrenia and 187 control subjects). The effect of RNA quality on gene expression was found to be highly correlated with the effect of diagnosis even after adjustment for observable RNA quality parameters (i.e. RNA integrity), thus this confounding relationship was statistically controlled using principal components derived from the gene expression matrix. In DLPFC, 23 immune genes were found to be differentially expressed (false discovery rate <0.05), of which seven genes replicated in both directionality and at nominal significance (P<0.05) in an independent post-mortem DLPFC data set (182 schizophrenia and 212 control subjects), although notably at least five of these genes have prominent roles in pathways other than immune function and overall the effect sizes were minimal (fold change <1.1). In the hippocampus, no individual immune genes were identified to be differentially expressed, and in both DLPFC and hippocampus none of the individual immune pathways were relatively differentially expressed. Further, genomic schizophrenia risk profiles scores were not correlated with the expression of individual immune pathways or differentially expressed genes. Overall, past reports claiming a primary pathogenic role of the immune system intrinsic to the brain in schizophrenia could not be confirmed.",

author = "R. Birnbaum and Jaffe, {A. E.} and Q. Chen and Shin, {J. H.} and Kleinman, {J. E.} and Hyde, {T. M.} and Weinberger, {D. R.}",

note = "Funding Information: The replication data set used for the analyses in the manuscript were generated as part of the CommonMind Consortium supported by funding from Takeda Pharmaceuticals Company Limited, F Hoffman-La Roche and NIH Grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881 and R37MH057881S1, HHSN271201300031C, AG02219, AG05138 and MH06692. Brain tissue for the study was obtained from the following brain-bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer{\textquoteright}s Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories and the NIMH Human Brain Collection Core. CMC Leadership: P Sklar, J Buxbaum (Icahn School of Medicine at Mount Sinai), B Devlin, D Lewis (University of Pittsburgh), R Gur, C-G Hahn (University of Pennsylvania), K Hirai, H Toyoshiba (Takeda Pharmaceuticals Company), E Domenici, L Essioux (F Hoffman-La Roche), L Mangravite, M Peters (Sage Bionetworks), T Lehner, B Lipska (NIMH). Funding Information: CRS, PO, JQ, JRW, HSX and ARW are employees and stockholders of Pfizer. ED, LE and TK-T are employees and stockholders of F Hoffmann-La Roche, AG. DCA, JNC, DAC, HW, BE, PE, YL, LN, CR, JES, RMS and H-RQ are employees and stockholders of Eli Lilly and Company. KM is an employee of TransThera Consulting and an ex-employee of Eli Lilly and Company. MD is an employee and stockholder of H Lundbeck A/S. MM and TS are employees of Astellas Pharma. NJB, AJC and QW are employees and stockholders of AstraZeneca LP. HM, HK, MF and WCD are employees of Janssen Research and Development, LLC, and of Johnson and Johnson, and stockholders of Johnson and Johnson. JHS, AEJ, YJ, RES, AD-S, TMH, JEK and DRW are employees of the Lieber Institute for Brain Development, a non-profit organization. The authors declare no conflict of interest. Funding for the research currently reported is from the Lieber Institute for Brain Development, the BrainSeq Consortium and the Division of Intramural Research Programs, National Institute of Mental Health. Publisher Copyright: {\textcopyright} The Author(s) 2018.",

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AU - Shin, J. H.

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AU - Hyde, T. M.

AU - Weinberger, D. R.

N1 - Funding Information: The replication data set used for the analyses in the manuscript were generated as part of the CommonMind Consortium supported by funding from Takeda Pharmaceuticals Company Limited, F Hoffman-La Roche and NIH Grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881 and R37MH057881S1, HHSN271201300031C, AG02219, AG05138 and MH06692. Brain tissue for the study was obtained from the following brain-bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer’s Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories and the NIMH Human Brain Collection Core. CMC Leadership: P Sklar, J Buxbaum (Icahn School of Medicine at Mount Sinai), B Devlin, D Lewis (University of Pittsburgh), R Gur, C-G Hahn (University of Pennsylvania), K Hirai, H Toyoshiba (Takeda Pharmaceuticals Company), E Domenici, L Essioux (F Hoffman-La Roche), L Mangravite, M Peters (Sage Bionetworks), T Lehner, B Lipska (NIMH). Funding Information: CRS, PO, JQ, JRW, HSX and ARW are employees and stockholders of Pfizer. ED, LE and TK-T are employees and stockholders of F Hoffmann-La Roche, AG. DCA, JNC, DAC, HW, BE, PE, YL, LN, CR, JES, RMS and H-RQ are employees and stockholders of Eli Lilly and Company. KM is an employee of TransThera Consulting and an ex-employee of Eli Lilly and Company. MD is an employee and stockholder of H Lundbeck A/S. MM and TS are employees of Astellas Pharma. NJB, AJC and QW are employees and stockholders of AstraZeneca LP. HM, HK, MF and WCD are employees of Janssen Research and Development, LLC, and of Johnson and Johnson, and stockholders of Johnson and Johnson. JHS, AEJ, YJ, RES, AD-S, TMH, JEK and DRW are employees of the Lieber Institute for Brain Development, a non-profit organization. The authors declare no conflict of interest. Funding for the research currently reported is from the Lieber Institute for Brain Development, the BrainSeq Consortium and the Division of Intramural Research Programs, National Institute of Mental Health. Publisher Copyright: © The Author(s) 2018.

PY - 2018/5/1

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N2 - The role of the immune system in schizophrenia remains controversial despite numerous studies to date. Most studies have profiled expression of select genes or proteins in peripheral blood, but none have focused on the expression of canonical pathways that mediate overall immune response. The current study used a systematic genetic approach to investigate the role of the immune system in a large sample of post-mortem brain of patients with schizophrenia: RNA sequencing was performed to assess the differential expression of 561 immune genes and 20 immune pathways in dorsolateral prefrontal cortex (DLPFC) (144 schizophrenia and 196 control subjects) and hippocampus (83 schizophrenia and 187 control subjects). The effect of RNA quality on gene expression was found to be highly correlated with the effect of diagnosis even after adjustment for observable RNA quality parameters (i.e. RNA integrity), thus this confounding relationship was statistically controlled using principal components derived from the gene expression matrix. In DLPFC, 23 immune genes were found to be differentially expressed (false discovery rate <0.05), of which seven genes replicated in both directionality and at nominal significance (P<0.05) in an independent post-mortem DLPFC data set (182 schizophrenia and 212 control subjects), although notably at least five of these genes have prominent roles in pathways other than immune function and overall the effect sizes were minimal (fold change <1.1). In the hippocampus, no individual immune genes were identified to be differentially expressed, and in both DLPFC and hippocampus none of the individual immune pathways were relatively differentially expressed. Further, genomic schizophrenia risk profiles scores were not correlated with the expression of individual immune pathways or differentially expressed genes. Overall, past reports claiming a primary pathogenic role of the immune system intrinsic to the brain in schizophrenia could not be confirmed.

AB - The role of the immune system in schizophrenia remains controversial despite numerous studies to date. Most studies have profiled expression of select genes or proteins in peripheral blood, but none have focused on the expression of canonical pathways that mediate overall immune response. The current study used a systematic genetic approach to investigate the role of the immune system in a large sample of post-mortem brain of patients with schizophrenia: RNA sequencing was performed to assess the differential expression of 561 immune genes and 20 immune pathways in dorsolateral prefrontal cortex (DLPFC) (144 schizophrenia and 196 control subjects) and hippocampus (83 schizophrenia and 187 control subjects). The effect of RNA quality on gene expression was found to be highly correlated with the effect of diagnosis even after adjustment for observable RNA quality parameters (i.e. RNA integrity), thus this confounding relationship was statistically controlled using principal components derived from the gene expression matrix. In DLPFC, 23 immune genes were found to be differentially expressed (false discovery rate <0.05), of which seven genes replicated in both directionality and at nominal significance (P<0.05) in an independent post-mortem DLPFC data set (182 schizophrenia and 212 control subjects), although notably at least five of these genes have prominent roles in pathways other than immune function and overall the effect sizes were minimal (fold change <1.1). In the hippocampus, no individual immune genes were identified to be differentially expressed, and in both DLPFC and hippocampus none of the individual immune pathways were relatively differentially expressed. Further, genomic schizophrenia risk profiles scores were not correlated with the expression of individual immune pathways or differentially expressed genes. Overall, past reports claiming a primary pathogenic role of the immune system intrinsic to the brain in schizophrenia could not be confirmed.

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Investigating the neuroimmunogenic architecture of schizophrenia

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