Abstract
BackgroundThe observation that the genetic variants identified in genome-wide association studies (GWAS) frequently lie in non-coding regions of the genome that contain cis-regulatory elements suggests that altered gene expression underlies the development of many complex traits. In order to efficiently make a comprehensive assessment of the impact of non-coding genetic variation in immune related diseases we emulated the whole-exome sequencing paradigm and developed a custom capture panel for the known DNase I hypersensitive site (DHS) in immune cells – “Immunoseq”.ResultsWe performed Immunoseq in 30 healthy individuals where we had existing transcriptome data from T cells. We identified a large number of novel non-coding variants in these samples. Relying on allele specific expression measurements, we also showed that our selected capture regions are enriched for functional variants that have an impact on differential allelic gene expression. The results from a replication set with 180 samples confirmed our observations.ConclusionsWe show that Immunoseq is a powerful approach to detect novel rare variants in regulatory regions. We also demonstrate that these novel variants have a potential functional role in immune cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-016-0220-7) contains supplementary material, which is available to authorized users.
Highlights
The observation that the genetic variants identified in genome-wide association studies (GWAS) frequently lie in non-coding regions of the genome that contain cis-regulatory elements suggests that altered gene expression underlies the development of many complex traits
It is notable that the majority of the associated variants identified through immune disease GWAS are located in non-coding regions of the genome that are enriched for regulatory elements that are active in immune cell types [9,10,11], suggesting that a resequencing effort focused in these regulatory regions would provide a highly efficient means to identify both common and rare variation of relevance in such diseases
It has been noted that the enrichment of Single nucleotide polymorphism (SNP) altering expression (eSNP) is most pronounced in those functional elements that are located closest to their respective Expression quantitative trait loci (eQTL) [17] and that there might be an inverse relationship between the effect size of cis-eQTLs and the minor allele frequency (MAF) of the relevant eSNP; suggesting that rare variants might have a higher impact on gene expression than common variants [20,21,22,23]
Summary
The observation that the genetic variants identified in genome-wide association studies (GWAS) frequently lie in non-coding regions of the genome that contain cis-regulatory elements suggests that altered gene expression underlies the development of many complex traits. In order to efficiently make a comprehensive assessment of the impact of non-coding genetic variation in immune related diseases we emulated the whole-exome sequencing paradigm and developed a custom capture panel for the known DNase I hypersensitive site (DHS) in immune cells – “Immunoseq”. It is notable that the majority of the associated variants identified through immune disease GWAS are located in non-coding regions of the genome that are enriched for regulatory elements that are active in immune cell types [9,10,11], suggesting that a resequencing effort focused in these regulatory regions would provide a highly efficient means to identify both common and rare variation of relevance in such diseases. It has been noted that the enrichment of eSNPs is most pronounced in those functional elements that are located closest to their respective eQTL [17] and that there might be an inverse relationship between the effect size of cis-eQTLs and the minor allele frequency (MAF) of the relevant eSNP; suggesting that rare variants might have a higher impact on gene expression than common variants [20,21,22,23]
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