Intergenic disease-associated regions are abundant in novel transcripts

Journal article

Background

Genotyping of large populations through genome-wide association studies (GWAS) has successfully identified many genomic variants associated with traits or disease risk. Unexpectedly, a large proportion of GWAS single nucleotide polymorphisms (SNPs) and associated haplotype blocks are in intronic and intergenic regions, hindering their functional evaluation. While some of these risk-susceptibility regions encompass cis-regulatory sites, their transcriptional potential has never been systematically explored.

Results

To detect rare tissue-specific expression, we employed the transcript-enrichment method CaptureSeq on 21 human tissues to identify 1775 multi-exonic transcripts from 561 intronic and intergenic haploblocks associated with 392 traits and diseases, covering 73.9 Mb (2.2%) of the human genome. We show that a large proportion (85%) of disease-associated haploblocks express novel multi-exonic non-coding transcripts that are tissue-specific and enriched for GWAS SNPs as well as epigenetic markers of active transcription and enhancer activity. Similarly, we captured transcriptomes from 13 melanomas, targeting nine melanoma-associated haploblocks, and characterized 31 novel melanoma-specific transcripts that include fusion proteins, novel exons and non-coding RNAs, one-third of which showed allelically imbalanced expression.

Conclusions

This resource of previously unreported transcripts in disease-associated regions (http://gwas-captureseq.dingerlab.org) should provide an important starting point for the translational community in search of novel biomarkers, disease mechanisms, and drug targets.

Authors: Bartonicek, N; Clark, MB; Quek, XC; Torpy, JR; Pritchard, AL

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BioMed Central
• Journal: Genome Biology
• Volume: 18
• Article number: 241
• Publication date: 2017-12-28
• Acceptance date: 2017-11-21
• DOI: 10.1186/s13059-017-1363-3
• EISSN: 1474-7596
• ISSN: 1474-760X
• Pmid: 29284497
• Language: English
• Keywords: research-article; Journal Article