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Multiomics dissection of molecular regulatory mechanisms underlying autoimmune-associated noncoding SNPs
Xiao-Feng Chen, … , Yan Guo, Tie-Lin Yang
Xiao-Feng Chen, … , Yan Guo, Tie-Lin Yang
Published September 3, 2020
Citation Information: JCI Insight. 2020;5(17):e136477. https://doi.org/10.1172/jci.insight.136477.
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Research Article Genetics

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

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Abstract

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.

Authors

Xiao-Feng Chen, Ming-Rui Guo, Yuan-Yuan Duan, Feng Jiang, Hao Wu, Shan-Shan Dong, Xiao-Rong Zhou, Hlaing Nwe Thynn, Cong-Cong Liu, Lin Zhang, Yan Guo, Tie-Lin Yang

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Figure 1

Prioritizing potential functional autoimmune noncoding SNPs.

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Prioritizing potential functional autoimmune noncoding SNPs.
(A) Flowcha...
(A) Flowchart showing integrative analysis method for prioritizing potential functional autoimmune SNPs with allele-specific regulatory activities. See brief description for epigenetic scoring process in Supplemental Figure 1. See Methods for more detailed information. (B) Ranking plot for scores of all autoimmune negative SNPs within 4 epigenetic categories. Red dashed line represents top 5% ranked value. (C) Schematic showing several potential allelic molecular-level regulatory mechanisms underlying functional autoimmune SNPs. Multiple intermediate molecular quantitative trait loci (QTL) data in blood immune cell types were collected, including bQTL (transcription factor binding quantitative trait loci) (28), hQTL (histone modification quantitative trait loci), caQTL (chromatin accessibility quantitative trait loci) (31, 89, 90), and dsQTL (DNase-I hypersensitivity quantitative trait loci) (30, 87). See more description for each QTL data in Supplemental Table 3. (D) Venn diagram showing overlapping of autoimmune SNPs with predicted allele-specific regulatory activity and autoimmune SNPs with at least one functionality support by the epigenetic functional scoring. The overlapped SNPs were prioritized to be potential functional.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

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