Human disease-associated genetic variation impacts large intergenic non-coding RNA expression

Abstract

Recently it has become clear that only a small percentage (7%) of disease-associated single nucleotide polymorphisms (SNPs) are located in protein-coding regions, while the remaining 93% are located in gene regulatory regions or in intergenic regions. Thus, the understanding of how genetic variations control the expression of non-coding RNAs (in a tissue-dependent manner) has far-reaching implications. We tested the association of SNPs with expression levels (eQTLs) of large intergenic non-coding RNAs (lincRNAs), using genome-wide gene expression and genotype data from five different tissues. We identified 112 cis-regulated lincRNAs, of which 45% could be replicated in an independent dataset. We observed that 75% of the SNPs affecting lincRNA expression (lincRNA cis-eQTLs) were specific to lincRNA alone and did not affect the expression of neighboring protein-coding genes. We show that this specific genotype-lincRNA expression correlation is tissue-dependent and that many of these lincRNA cis-eQTL SNPs are also associated with complex traits and diseases.

Figure 1. The number of detected cis-eQTLs is dependent on the expression levels of the transcripts.

(A) Quantile-normalized average expression intensity and (B) number of cis-eQTL affected probes in percentage, for 2,140 lincRNA probes, 2,140 non-lincRNA (matched for 2,140 lincRNA probes' median expression and standard deviation) and 2,140 most abundantly expressed non-lincRNA probes.

Figure 2. Distribution of lincRNA cis-eQTLs with respect to different transcripts.

(A) The majority of the lincRNA cis-eQTLs are located within the non-coding part of the genome and less than 6% of lincRNA cis-eQTLs are located within mRNA. (B) Distribution of lincRNA cis-eQTLs with respect to distance to the lincRNA transcripts. The x-axis displays the 250 kb window used for cis-eQTL mapping and the y-axis displays the fraction of lincRNA cis-eQTLs located within this window.

Figure 3. Localization of lincRNA cis-eQTLs in regulatory regions.

(A) A plot to indicate the location of lincRNA cis-eQTLs in cell-specific enhancers. The x-axis shows the different cell lines analyzed and the y-axis shows the fold enrichment of enhancers. (B) A plot to show the difference in fold enrichment of enhancers for real lincRNA cis-eQTLs compared to permuted lincRNA cis-eQTLs. The significance of the difference in fold enrichment was tested by T-test. The HaploReg database was used to analyze the fold enrichment of enhancers.