RNAseq Transcriptome Study Implicates Immune-Related Genes in Schizophrenia. A. R. Sanders1,2, E. I. Drigalenko3, J. Duan1,2, W. Moy1, J. Freda1, M. G. S.4, H. H. H. Göring3, P. V. Gejman1,2 1) Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, IL; 2) Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL; 3) Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX; 4) Molecular Genetics of Schizophrenia (MGS) Collaboration.
GWAS have implicated over 100 loci as being associated at genome-wide significant (GWS) levels with risk for schizophrenia (SZ), a common and severe psychotic disorder. Regulation of mRNA expression may be involved in the etiology for some of these loci. In a previous transcriptomic profiling study (Sanders et al., 2013), using arrays on lymphoblastoid cell lines from 268 SZ cases and 446 controls, we found 89 genes to be differentially expressed by affection status (FDR<0.05) and enriched for immune-related genes, consistent with hypothesized immune contributions to SZ risk. For the current study, we assayed expression by RNAseq on another set of 490 SZ cases and 662 controls, also of European ancestry from the Molecular Genetics of SZ dataset. After inverse normalization of expression data, we used regression analysis to identify genes differentially expressed by affection status, while simultaneously controlling for confounding effects (sex, age, ancestry, viral load, growth rate, energy status, RNAseq batch) as before, focusing here on the 8,466 genes detected well with both array and RNAseq. We found 807 genes to be differentially expressed by affection status (Bonferroni p<0.05) in this RNAseq dataset. These differentially expressed genes were somewhat enriched for genes involved in autoimmunity (Fisher p=0.01), and their pathway analyses showed gene ontology term enrichment (FDR<0.05) for categories such as response (immune, to virus), endoplasmic reticulum categories, activation (cell, leukocyte, lymphocyte), regulation of cell proliferation, and membrane (integral, intrinsic). Of the 89 genes differentially expressed in our previous array study, 80 had appreciable expression in the RNAseq data, and 18 of those were differentially expressed by affection status (Bonferroni p<0.05, all with the same direction of effect). Notable examples thereof included DBNDD2 (dysbindin domain containing 2, which mediates neural differentiation and apoptosis), B3GNT2 (UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 2, GWS association with rheumatoid arthritis), and SYT11 (synaptotagmin XI, GWS association with Parkinsons Disease). In future work, we will identify the expression quantitative trait nucleotides (eQTNs) for these differentially expressed genes and examine the relationship of these eQTNs to GWAS findings. This work was supported NIH grants RC2MH090030, R01MH094091, and R01MH094116.
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