Intergenic disease-associated regions are abundant in novel transcripts.

Area of Science:

• Genomics
• Molecular Biology
• Transcriptomics

Background:

• Genome-wide association studies (GWAS) identify genomic variants linked to traits and diseases.
• Many GWAS single nucleotide polymorphisms (SNPs) and haplotype blocks reside in intronic and intergenic regions, posing challenges for functional evaluation.
• The transcriptional potential of these cis-regulatory regions has not been systematically investigated.

Purpose of the Study:

• To systematically explore the transcriptional potential of intronic and intergenic regions identified by GWAS.
• To identify novel, rare, and tissue-specific transcripts associated with human traits and diseases.

Main Methods:

• Employed the transcript-enrichment method CaptureSeq across 21 human tissues.
• Analyzed 561 intronic and intergenic haploblocks associated with 392 traits and diseases.
• Sequenced transcriptomes from 13 melanomas, targeting nine melanoma-associated haploblocks.

Main Results:

• Identified 1775 multi-exonic transcripts from intronic and intergenic haploblocks, covering 73.9 Mb of the human genome.
• Found that 85% of disease-associated haploblocks express novel, tissue-specific, non-coding transcripts enriched for GWAS SNPs and epigenetic markers.
• Characterized 31 novel melanoma-specific transcripts, including fusion proteins and non-coding RNAs, with one-third showing allelic imbalance.

Conclusions:

• A significant resource of previously unreported transcripts in disease-associated regions has been generated.
• This resource provides a starting point for the translational research community.
• Facilitates the search for novel biomarkers, disease mechanisms, and drug targets.