14The genome-wide association studies (GWAS) have identified hundreds of 15 susceptibility loci associated with autoimmune diseases. However, over 90% of risk 16 variants are located in the noncoding regions, leading to great challenges in 17 deciphering the underlying causal functional variants/genes and biological 18 mechanisms. Previous studies focused on developing new scoring method to 19 prioritize functional/disease-relevant variants. However, they principally 20 incorporated annotation data across all cells/tissues while omitted the cell-specific or 21 context-specific regulation. Moreover, limited analyses were performed to dissect the 22 detailed molecular regulatory circuits linking functional GWAS variants to disease 23 etiology. Here we devised a new analysis frame that incorporate hundreds of immune 24 cell-specific multi-omics data to prioritize functional noncoding susceptibility SNPs 25 with gene targets and further dissect their downstream molecular mechanisms and 26 clinical applications for 19 autoimmune diseases. Most prioritized SNPs have genetic 27 associations with transcription factors (TFs) binding, histone modification or 28 chromatin accessibility, indicating their allelic regulatory roles on target genes. Their 29 target genes were significantly enriched in immunologically related pathways and 30other immunologically related functions. We also detected long-range regulation on 31 90.7% of target genes including 132 ones exclusively regulated by distal SNPs (eg, 32 CD28, IL2RA), which involves several potential key TFs (eg, CTCF), suggesting the 33 important roles of long-range chromatin interaction in autoimmune diseases.
34Moreover, we identified hundreds of known or predicted druggable genes, and 35 predicted some new potential drug targets for several autoimmune diseases, including 36 two genes (NFKB1, SH2B3) with known drug indications on other diseases, 37 highlighting their potential drug repurposing opportunities. In summary, our analyses 38 may provide unique resource for future functional follow-up and drug application on 39 autoimmune diseases, which are freely available at http://fngwas.online/. 40 41 42 3 Author Summary 43Autoimmune diseases are groups of complex immune system disorders with high 44 prevalence rates and high heritabilities. Previous studies have unraveled thousands 45 of SNPs associated with different autoimmune diseases. However, it remains largely 46 unknown on the molecular mechanisms underlying these genetic associations.
47Striking, over 90% of risk SNPs are located in the noncoding region. By leveraging 48 multiple immune cell-specific multi-omics data across genomic, epigenetic, 49 transcriptomic and 3D chromatin interaction information, we systematically analyzed 50 the functional variants/genes and biological mechanisms underlying genetic 51 association on 19 autoimmune diseases. We found that most functional SNPs may 52 affect target gene expression through altering transcription factors (TFs) binding, 53 histone modification or chromatin acce...
