Inflammatory bowel disease associated genetic variants preferentially alter gene expression in neutrophil granulocytes. H. Westra1, D. Arends2, T. Esko3, M. J. Peters4,5, R. Weersma1, A. Metspalu3, A. G. Uitterlinden4,5,6, J. van Meurs4,5, R. Jansen2, L. Franke1 1) Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands; 2) Groningen Bioinformatics Centre, University of Groningen, Groningen, the Netherlands; 3) Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia; 4) Department of Internal Medicine, Erasmus Medical Centre Rotterdam, the Netherlands; 5) The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, the Netherlands; 6) Department of Epidemiology, Erasmus Medical Center Rotterdam, the Netherlands.

   Crohn's disease (CD) and ulcerative colitis (UC) are the two main forms of inflammatory bowel disease (IBD). IBD are immune-mediated chronic, relapsing intestinal inflammatory diseases. The most recent genome-wide association study in IBD has identified 163 genomic variants (SNPs) associated with the disease. We recently conducted cis-eQTL mapping in in whole blood of over 5,000 samples (Westra et al, Nature Genetics in press) and observed that 39% of these variants affect gene expression levels. However, it is still unclear what the primary cell type is in which these genes are expressed, because blood is a compound tissue that consists of many different cell-types. As eQTLs are often cell-type specific, identification of the cell-types where these eQTLs operate might help to identify the cell-type that is driving IBD. Although for some blood cell-types (e.g. monocytes, B-cells and CD4+ and CD8+ T-cells) eQTL studies in sample sizes of approximately 250 samples have now been presented, eQTL datasets for many other blood cell-types remain to be generated. However, generation of such data for e.g. neutrophil granulocytes is challenging: although they reflect a substantial proportion of circulating blood cells, they are difficult to purify and have a short lifespan after purification. In order to overcome these issues, we developed a new statistical method that uses whole peripheral blood eQTL data and individual blood cell count data to determine the cell-type specificity of cis-eQTLs. We applied this method to three independent peripheral blood datasets (n = 2,200) and observed that at least 5% of the cis-eQTLs that are detectable in whole peripheral blood are neutrophil specific. We then performed an enrichment analysis comparing unlinked (r2 0.2) IBD associated cis-eQTL SNPs to all other unlinked cis-eQTL SNPs that have been associated with complex traits and diseases, and observed that IBD cis-eQTL SNPs are strongly enriched for neutrophil specific cis-eQTLs (Fishers Exact test p-value 1 x 10-3). These findings reinforce the importance of neutrophils in the pathogenesis of IBD, which may provide clues for future treatment regiments. For the current study we have focused on neutrophils for this study, although our method is applicable to other cell types present in peripheral blood and other compound tissues as well. This enables cell-type specific eQTL mapping to prioritize cell types that are important in complex diseases or traits.

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