Abstract
Long non-coding RNAs are a new class of non-coding RNAs that are at the crosshairs in many human diseases such as cancers, cardiovascular disorders, inflammatory and autoimmune disease like Inflammatory Bowel Disease (IBD) and Type 1 Diabetes (T1D). Nearly 90% of the phenotype-associated single-nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) lie outside of the protein coding regions, and map to the non-coding intervals. However, the relationship between phenotype-associated loci and the non-coding regions including the long non-coding RNAs (lncRNAs) is poorly understood. Here, we systemically identified all annotated IBD and T1D loci-associated lncRNAs, and mapped nominally significant GWAS/ImmunoChip SNPs for IBD and T1D within these lncRNAs. Additionally, we identified tissue-specific cis-eQTLs, and strong linkage disequilibrium (LD) signals associated with these SNPs. We explored sequence and structure based attributes of these lncRNAs, and also predicted the structural effects of mapped SNPs within them. We also identified lncRNAs in IBD and T1D that are under recent positive selection. Our analysis identified putative lncRNA secondary structure-disruptive SNPs within and in close proximity (+/−5 kb flanking regions) of IBD and T1D loci-associated candidate genes, suggesting that these RNA conformation-altering polymorphisms might be associated with diseased-phenotype. Disruption of lncRNA secondary structure due to presence of GWAS SNPs provides valuable information that could be potentially useful for future structure-function studies on lncRNAs.
Highlights
Long non-coding RNAs are recently discovered class of non-coding RNAs that are 200 nucleotides or longer in transcript length, are similar to protein-coding genes and are sometimes transcribed as whole or partial antisense transcripts to coding genes [1,2]
We identified structure-disruptive single-nucleotide polymorphisms (SNPs) within the linkage disequilibrium (LD) blocks defined for the genomewide association studies (GWAS)/ImmunoChip loci and predicted their effect on the long non-coding RNAs (lncRNAs) secondary structure
We focused on the impact of GWAS/ImmunoChip SNPs within Inflammatory bowel disease (IBD) and Type 1 Diabetes (T1D) loci-associated lncRNAs, and identified number of SNPs with significant propensity to disrupt secondary structure of the loci-associated lncRNAs
Summary
Long non-coding RNAs (lncRNAs) are recently discovered class of non-coding RNAs that are 200 nucleotides or longer in transcript length, are similar to protein-coding genes and are sometimes transcribed as whole or partial antisense transcripts to coding genes [1,2]. LncRNA genes are poorly conserved in sequence across different species and do not contain any conserved motifs [3,4,5]. LncRNAs have emerged as important regulatory players of gene expression. LncRNAs are known to modulate gene expression by both cis and trans acting manner, and broadly wield their effect by direct interaction with the chromatin-modifying proteins and transcription factors, promoter inactivation by binding to basal transcription factors and activation of an accessory protein, [1,14,15,16,17,18]. Antisense lncRNA transcripts have been shown to control the transcription of protein-coding genes in cis [20,21]
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