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

Isis Ricano-Ponce, Dania 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 RuanLude Franke, Cisca Wijmenga, Vinod Kumar*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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. The Authors.
Original languageEnglish
Pages (from-to)62-74
JournalJournal of Autoimmunity
Volume68
DOIs
Publication statusPublished - Apr 2016

Keywords

  • Long non-coding RNAs
  • eQTLs
  • RNA-sequencing
  • Genome-wide association
  • Causal genes

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