Abstract
BackgroundGenetic variants identified through genome-wide association studies (GWAS) are predominantly non-coding and typically attributed to altered regulatory elements such as enhancers and promoters. However, the contribution of non-coding RNAs to complex traits is not clear.ResultsUsing targeted RNA sequencing, we systematically annotated multi-exonic non-coding RNA (mencRNA) genes transcribed from 1.5-Mb intervals surrounding 139 breast cancer GWAS signals and assessed their contribution to breast cancer risk. We identify more than 4000 mencRNA genes and show their expression distinguishes normal breast tissue from tumors and different breast cancer subtypes. Importantly, breast cancer risk variants, identified through genetic fine-mapping, are significantly enriched in mencRNA exons, but not the promoters or introns. eQTL analyses identify mencRNAs whose expression is associated with risk variants. Furthermore, chromatin interaction data identify hundreds of mencRNA promoters that loop to regions that contain breast cancer risk variants.ConclusionsWe have compiled the largest catalog of breast cancer-associated mencRNAs to date and provide evidence that modulation of mencRNAs by GWAS variants may provide an alternative mechanism underlying complex traits.
Highlights
Based on the ERCC controls, the lower limit of detection (LLD), defined as the lowest molar amount of ERCC transcript detected in each library, was ~ 300 times lower across the four captured libraries compared to non-captured controls (Additional file 1: Figure S1)
We identified 800 multi-exonic non-coding RNA (mencRNA) which were expression quantitative trait loci (eQTL) (FDR < 0.05), nine of these eQTLs overlapped with breast cancer signals, based on the p value for the top eQTL SNP being within two orders of magnitude of the eQTL p value for a credible causal variants (CCVs)
We show that CCVs are enriched in the exons but not the introns or promoters of mencRNAs, suggesting that genetic variants may alter mencRNA structure and/or function. long non-coding RNAs (lncRNAs) can act as protein scaffolds; it is possible that a genetic variant could alter the binding of proteins to mencRNAs
Summary
The majority of transcripts are long non-coding RNAs (lncRNAs), defined as > 200 base pairs in length and transcribed antisense, intronic or intergenic to proteincoding genes. RNA sequencing studies conducted on different tissues and cell types are continually identifying new lncRNAs, which indicates that comprehensive annotation of lncRNA genes is far from complete [1,2,3,4,5,6]. Genome-wide association studies (GWAS) in combination with fine-mapping have identified 196 independent signals associated with breast cancer risk (conditional p values < 1 × 10−6) [9]. Due to complex linkage disequilibrium (LD), genetic variants within a signal are frequently co-. Genetic variants identified through genome-wide association studies (GWAS) are predominantly noncoding and typically attributed to altered regulatory elements such as enhancers and promoters. The contribution of non-coding RNAs to complex traits is not clear
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