期刊
JOURNAL OF AUTOIMMUNITY
卷 68, 期 -, 页码 62-74出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jaut.2016.01.002
关键词
Long non-coding RNAs; eQTLs; RNA-sequencing; Genome-wide association; Causal genes
类别
资金
- European Research Council Advanced Grant/ERC [2012-322698]
- Dutch Digestive Diseases Foundation [MLDS WO11-30]
- European Union's Seventh Framework Programme (EU FP7) TANDEM project [HEALTH-F3-2012-305279]
- Netherlands Organization for Scientific Research (NWO VENI grant) [916-10135, 863.13.011]
- Netherlands Organization for Scientific Research (NWO VIDI grant) [917-14374]
- Dutch Multiple Sclerosis Foundation [11-752]
- BBMRI-NL - Dutch government [NWO 184.021.007]
- Samenwerkingsverband Noord Nederland
- European Fund for Regional Development
- Dutch Ministry of Economic Affairs
- Pieken in de Delta
- province of Groningen
- province of Drenthe
Genome-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. (C) 2016 The Authors. Published by Elsevier Ltd.
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