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Refined mapping of autoimmune disease associated genetic variants with gene expression suggests an important role for non-coding RNAs

By Isis Ricaño-Ponce, Daria V. Zhernakova, Patrick Deelen, Oscar Luo, Xingwang Li, Aaron Isaacs, Juha Karjalainen, Jennifer Di Tommaso, Zuzanna Agnieszka Borek, Maria M. Zorro, Javier Gutierrez-Achury, Andre G. Uitterlinden, Albert Hofman, Joyce van Meurs, Mihai G. Netea, Iris H. Jonkers, Sebo Withoff, Cornelia M. van Duijn, Yang Li, Yijun Ruan, Lude Franke, Cisca Wijmenga, Vinod Kumar, Bastiaan T. Heijmans, Peter A.C. 't Hoen, Joyce van Meurs, Aaron Isaacs, Rick Jansen, Lude Franke, Dorret I. Boomsma, René Pool, Jenny van Dongen, Jouke J. Hottenga, Marleen M.J. van Greevenbroek, Coen D.A. Stehouwer, Carla J.H. van der Kallen, Casper G. Schalkwijk, Cisca Wijmenga, Alexandra Zhernakova, Ettje F. Tigchelaar, P. Eline Slagboom, Marian Beekman, Joris Deelen, Diana van Heemst, Jan H. Veldink, Leonard H. van den Berg, Cornelia M. van Duijn, Bert A. Hofman, André G. Uitterlinden, P. Mila Jhamai, Michael Verbiest, H. Eka D. Suchiman, Marijn Verkerk, Ruud van der Breggen, Jeroen van Rooij, Nico Lakenberg, Hailiang Mei, Maarten van Iterson, Michiel van Galen, Jan Bot, Peter van 't Hof, Patrick Deelen, Irene Nooren, Matthijs Moed, Martijn Vermaat, Daria V. Zhernakova, René Luijk, Marc Jan Bonder, Freerk van Dijk, Wibowo Arindrarto, Szymon M. Kielbasa, Morris A. Swertz and Erik W. van Zwet

Abstract

AbstractGenome-wide association and fine-mapping studies in 14 autoimmune diseases (AID) have implicated more than 250 loci in one or more of these diseases. As more than 90% of AID-associated SNPs are intergenic or intronic, pinpointing the causal genes is challenging. We performed a systematic analysis to link 460 SNPs that are associated with 14 AID to causal genes using transcriptomic data from 629 blood samples. We were able to link 71 (39%) of the AID-SNPs to two or more nearby genes, providing evidence that for part of the AID loci multiple causal genes exist. While 54 of the AID loci are shared by one or more AID, 17% of them do not share candidate causal genes. In addition to finding novel genes such as ULK3, we also implicate novel disease mechanisms and pathways like autophagy in celiac disease pathogenesis. Furthermore, 42 of the AID SNPs specifically affected the expression of 53 non-coding RNA genes. To further understand how the non-coding genome contributes to AID, the SNPs were linked to functional regulatory elements, which suggest a model where AID genes are regulated by network of chromatin looping/non-coding RNAs interactions. The looping model also explains how a causal candidate gene is not necessarily the gene closest to the AID SNP, which was the case in nearly 50% of cases

Publisher: The Authors. Published by Elsevier Ltd.
Year: 2016
DOI identifier: 10.1016/j.jaut.2016.01.002
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