Abstract
Whilst susceptibility variants for many complex diseases, such as rheumatoid arthritis (RA), have been well characterised, the mechanism by which risk is mediated is still unclear for many loci. This is especially true for the majority of variants that do not affect protein-coding regions. lncRNA represent a group of molecules that have been shown to be enriched amongst variants associated with RA and other complex diseases, compared to random variants. In order to establish to what degree direct disruption of lncRNA may represent a potential mechanism for mediating RA susceptibility, we chose to further explore this overlap. By testing the ability of annotated features to improve a model of disease susceptibility, we were able to demonstrate a local enrichment of enhancers from immune-relevant cell types amongst RA susceptibility variants (log2 enrichment 3.40). This was not possible for lncRNA annotations in general, however a small, but significant enrichment was observed for immune-enriched lncRNA (log2 enrichment 0.867002). This enrichment was no longer apparent when the model was conditioned on immune-relevant enhancers (log2 enrichment -0.372734), suggesting that direct disruption of lncRNA sequence, independent of enhancer disruption, does not represent a major mechanism by which susceptibility to complex diseases is mediated. Furthermore, we demonstrated that, in keeping with general lncRNA characteristics, immune-enriched lncRNA are expressed at low levels that may not be amenable to functional characterisation.
Highlights
In keeping with other complex diseases, rheumatoid arthritis (RA) susceptibility loci are mainly non-coding, with relatively few variants having a potential impact upon the coding sequence for a protein [1,2]
By incorporating both cell-type specific enhancer and long non-coding RNA (lncRNA) annotations into a probabilistic model of RA susceptibility it is possible to demonstrate their respective levels of enrichment amongst RA susceptibility variants
Whilst previous studies have demonstrated an enrichment of lncRNA compared with randomly shuffled annotations these analyses fail to take into consideration the complex organisation of the genome and are confounded by alternative features
Summary
In keeping with other complex diseases, rheumatoid arthritis (RA) susceptibility loci are mainly non-coding, with relatively few variants having a potential impact upon the coding sequence for a protein [1,2]. Enhancers have been identified as likely to mediate disease susceptibility at many loci. Evidence to support this generalization includes demonstrated effects of genome wide association study (GWAS) variants on enhancers at individual loci [3], as well as an enrichment of RA GWAS variants amongst enhancers from relevant cell types [4]. Rheumatoid arthritis risk loci and long non-coding RNA http://fantom.gsc.riken.jp/5/suppl/Hon_et_al_2016/ data/, ftp://ftp.ebi.ac.uk/pub/databases/gwas/ summary_statistics/OkadaY_24390342_ GCST002318, https://lncipedia.org/download, http://mitranscriptome.org/download/, https:// egg2.wustl.edu/roadmap/data/byFileType/ chromhmmSegmentations/ChmmModels/core_ K27ac/jointModel/final/, and https://www.ncbi.nlm. Rheumatoid arthritis risk loci and long non-coding RNA http://fantom.gsc.riken.jp/5/suppl/Hon_et_al_2016/ data/, ftp://ftp.ebi.ac.uk/pub/databases/gwas/ summary_statistics/OkadaY_24390342_ GCST002318, https://lncipedia.org/download, http://mitranscriptome.org/download/, https:// egg2.wustl.edu/roadmap/data/byFileType/ chromhmmSegmentations/ChmmModels/core_ K27ac/jointModel/final/, and https://www.ncbi.nlm. nih.gov/sra, respectively
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
