Multiomics dissection of molecular regulatory mechanisms underlying autoimmune-associated noncoding SNPs

More than 90% of autoimmune-associated variants are located in noncoding regions, leading to challenges in deciphering the underlying causal roles of functional variants and genes and biological mechanisms. Therefore, to reduce the gap between traditional genetic findings and mechanistic understandi...

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Bibliographic Details
Published in:	JCI insight 2020-09, Vol.5 (17)
Main Authors:	Chen, Xiao-Feng, Guo, Ming-Rui, Duan, Yuan-Yuan, Jiang, Feng, Wu, Hao, Dong, Shan-Shan, Zhou, Xiao-Rong, Thynn, Hlaing Nwe, Liu, Cong-Cong, Zhang, Lin, Guo, Yan, Yang, Tie-Lin
Format:	Article
Language:	eng
Subjects:	Adaptor Proteins, Signal Transducing - genetics Autoimmune Diseases - genetics Autoimmunity CCCTC-Binding Factor - genetics Genetics Genome-Wide Association Study - methods Genomics - methods Humans NF-kappa B p50 Subunit - genetics Pharmacogenomic Variants Polymorphism, Single Nucleotide Regulatory Sequences, Nucleic Acid Software
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Summary:	More than 90% of autoimmune-associated variants are located in noncoding regions, leading to challenges in deciphering the underlying causal roles of functional variants and genes and biological mechanisms. Therefore, to reduce the gap between traditional genetic findings and mechanistic understanding of disease etiologies and clinical drug development, it is important to translate systematically the regulatory mechanisms underlying noncoding variants. Here, we prioritized functional noncoding SNPs with regulatory gene targets associated with 19 autoimmune diseases by incorporating hundreds of immune cell-specific multiomics data. The prioritized SNPs are associated with transcription factor (TF) binding, histone modification, or chromatin accessibility, indicating their allele-specific regulatory roles. Their target genes are significantly enriched in immunologically related pathways and other known immunologically related functions. We found that 90.1% of target genes are regulated by distal SNPs involving several TFs (e.g., the DNA-binding protein CCCTC-binding factor [CTCF]), suggesting the importance of long-range chromatin interaction in autoimmune diseases. Moreover, we predicted potential drug targets for autoimmune diseases, including 2 genes (NFKB1 and SH2B3) with known drug indications on other diseases, highlighting their potential drug repurposing opportunities. Taken together, these findings may provide useful information for future experimental follow-up and drug applications on autoimmune diseases.
ISSN:	2379-3708 2379-3708