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Intergenic disease-associated regions are abundant in novel transcripts

Abstract

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.

Type Journal
ISBN 1474-760X (Electronic) 1474-7596 (Linking)
Authors Bartonicek, N.; Clark, M. B.; Quek, X. C.; Torpy, J. R.; Pritchard, A. L.; Maag, J. L. V.; Gloss, B. S.; Crawford, J.; Taft, R. J.; Hayward, N. K.; Montgomery, G. W.; Mattick, J. S.; Mercer, T. R.; Dinger, M. E.
Responsible Garvan Author Dr Timothy Mercer
Publisher Name GENOME BIOLOGY
Published Date 2017-12-28
Published Volume 18
Published Issue 1
Published Pages 241
Status Published in-print
DOI 10.1186/s13059-017-1363-3
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/29284497