Expression profiles of long non-coding RNAs located in autoimmune disease-associated regions reveal immune cell-type specificity

Harri Lähdesmäki,Vinod Kumar,Riitta Lahesmaa,Yang Li,Ubaid Ullah,Subhash Tripathi,Cisca Wijmenga,Rutger Modderman,Riikka J Lund,Lude Franke,Wayel Abdulahad,Kartiek Kanduri,Juha Karjalainen,Daria V Zhernakova,Barbara Hrdlickova,Sebo Withoff

doi:10.1186/preaccept-4701398771324073

Abstract

BackgroundAlthough genome-wide association studies (GWAS) have identified hundreds of variants associated with a risk for autoimmune and immune-related disorders (AID), our understanding of the disease mechanisms is still limited. In particular, more than 90% of the risk variants lie in non-coding regions, and almost 10% of these map to long non-coding RNA transcripts (lncRNAs). lncRNAs are known to show more cell-type specificity than protein-coding genes.MethodsWe aimed to characterize lncRNAs and protein-coding genes located in loci associated with nine AIDs which have been well-defined by Immunochip analysis and by transcriptome analysis across seven populations of peripheral blood leukocytes (granulocytes, monocytes, natural killer (NK) cells, B cells, memory T cells, naive CD4+ and naive CD8+ T cells) and four populations of cord blood-derived T-helper cells (precursor, primary, and polarized (Th1, Th2) T-helper cells).ResultsWe show that lncRNAs mapping to loci shared between AID are significantly enriched in immune cell types compared to lncRNAs from the whole genome (α <0.005). We were not able to prioritize single cell types relevant for specific diseases, but we observed five different cell types enriched (α <0.005) in five AID (NK cells for inflammatory bowel disease, juvenile idiopathic arthritis, primary biliary cirrhosis, and psoriasis; memory T and CD8+ T cells in juvenile idiopathic arthritis, primary biliary cirrhosis, psoriasis, and rheumatoid arthritis; Th0 and Th2 cells for inflammatory bowel disease, juvenile idiopathic arthritis, primary biliary cirrhosis, psoriasis, and rheumatoid arthritis). Furthermore, we show that co-expression analyses of lncRNAs and protein-coding genes can predict the signaling pathways in which these AID-associated lncRNAs are involved.ConclusionsThe observed enrichment of lncRNA transcripts in AID loci implies lncRNAs play an important role in AID etiology and suggests that lncRNA genes should be studied in more detail to interpret GWAS findings correctly. The co-expression results strongly support a model in which the lncRNA and protein-coding genes function together in the same pathways.

Highlights

Genome-wide association studies (GWAS) have identified hundreds of variants associated with a risk for autoimmune and immune-related disorders (AID), our understanding of the disease mechanisms is still limited
Using expression quantitative trait loci analysis, we recently demonstrated that single-nucleotide polymorphism (SNP) associated with complex diseases can affect the expression of long non-coding RNAs, suggesting that lncRNA genes are disease-susceptibility candidate genes [12]
We have recently shown that approximately 10% of autoimmune diseases (AIDs)-associated SNPs localize to lncRNA genes present in AID-associated loci [10], suggesting that the lncRNAs they encode play a role in disease etiology

Summary

Introduction

Genome-wide association studies (GWAS) have identified hundreds of variants associated with a risk for autoimmune and immune-related disorders (AID), our understanding of the disease mechanisms is still limited. Autoimmune and immune-related disorders (AID) are a heterogeneous group of disorders that occur in 7 to 9% of people worldwide [1]. These diseases are caused by an inappropriate response of the human immune system against self-antigens. By integrating GWAS and Immunochip data with Gencode data from the Encyclopedia of DNA Elements (ENCODE) project, it has become clear that more than 90% of the AID-associated SNPs map to non-coding, regulatory regions [9,10] that may encompass noncoding RNA genes [11]. Using expression quantitative trait loci (eQTLs) analysis, we recently demonstrated that SNPs associated with complex diseases can affect the expression of long non-coding RNAs (lncRNAs), suggesting that lncRNA genes are disease-susceptibility candidate genes [12]

Objectives

Methods

Results

Discussion

Conclusion