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Background Genome-wide association studies (GWAS) have identified more than 240 susceptibility loci associated with IBD mainly in Caucasians, however, there are limited studies in other populations. Methods To identify additional susceptibility loci in Asians, we expanded our previous study design (comprising a total of 1,621 patients with Crohn’s disease [CD] and 4,419 controls), followed by replication in an additional 582 patients with CD and 845 controls. To determine biological processes associated with candidate genes for CD, we conducted pathway analyses by MAGMA using the results obtained through the current meta-analyses and the summary statistics of the largest meta-analysis in the European population as input. Results The meta-analysis of Korean GWAS identified two novel susceptibility loci for CD at rs2240751 in the MFSD12-C19orf71-FZR1-DOHH region on 19p13 (pcombined = 3.03 × 10–8) and rs6936629 in the RFX6-GPRC6A-FAM162B region on 6q22 (pcombined = 3.63 × 10–8), of which rs6936629 showed significant association in European population (p = 1.88 × 10–4). Comparisons of the top 10 pathways for CD between the Korean and European data showed that MHC class Ⅱ protein complex, antigen binding, and response to antigenic stimulus-related pathways were more significant in the Korean population (Figure 1A), whereas cytokine and transcription factor-related pathways were more significant in the European population (Figure 1B). Conclusion Our findings provide additional biological insight into CD pathogenesis and support the importance of studying IBD genetics in diverse populations.

Background Familial IBD may have its own signatures with respect to host genetic variants and/or gut microbiome. However, available data focussing on this topic is still limited, particularly for Asian patients with familial IBD. We aimed to investigate the possible host genetic and gut microbial signatures in familial IBD through a combined analysis of genomic and metagenomic profiles. Methods All patients were affiliated with a prospectively recruited cohort of patients with IBD (NCT03589183) and met the diagnostic criteria of Crohn’s disease (CD) or ulcerative colitis (UC). We constructed a unique family cohort comprising ≥2 affected individuals with familial IBD and ≥1 their unaffected, healthy first-degree relative (FDR) in each family. Whole-exome sequencing for rare variants followed by a genome-wide single-nucleotide polymorphism analysis for common variants was performed. A polygenic risk score (PRS) was calculated separately in Crohn’s disease (CD), ulcerative colitis (UC) or IBD. Gut microbial community was analysed by 16s rRNA sequencing of stool samples. Results Eight Korean families comprising 16 with familial IBD (12 concordant IBD, 4 discordant IBD) and 9 FDRs were included for analysis. Whole-exome sequencing identified four family-specific candidate genes (LAMA5, MYO15B, TTN, and WDR66) with rare missense variants that were transmitted preferentially to the affected FDRs in at least ≥3 families (Figure 1). An in silico analysis identified the deleterious effect of the identified variants on the gene products including LAMA5 (SIFT = 0, PolyPhen-2 = 0.72). The patients with CD, but not those with UC, had a significantly higher mean PRS than controls (PRS = 2.137 vs. 0.742, p-value = 0.030). Metagenomic sequencing revealed significant differences in α- and β-diversity of gut microbiota among the patients with CD, those with UC, and unaffected FDRs (all p < 0.05), showing lower microbial richness in the patients with familial IBD (p = 0.02). In various taxonomic levels, compared with unaffected FDRs, the patients with familial IBD showed the significantly differential abundance of several gut bacteria (all corrected p < 0.05; Figure 2). Conclusion Family-specific host genetic and gut microbial signatures have a beneficial role in early-identification of familial IBD (NCT03515070).

Background Genome-wide association studies have deciphered the single nucleotide polymorphisms (SNPs) which are responsible for ulcerative colitis (UC) susceptibility. However, to understand how these SNPs are involved in UC, additional methods are necessary. One such approach is in silico network propagation modelling, which can discover how the effects of SNPs in UC can affect the whole cell. A complementary approach is weighted gene co-expression network analysis (WGCNA), where co-regulated genes are identified using transcriptomic data. Integrating these two methods can shed light on how SNPs are affecting the transcriptome of UC patients. Methods We used immunochip profiles of 941 UC patients and focussed on UC-associated SNPs altering regulatory regions. Based on these regions, we identified affected genes. To understand how their corresponding proteins rewire transcriptional regulation, we predicted the path between these proteins and relevant transcription factors (TF) using the OmniPath signalling network (http://omnipathdb.org). From the TFs, we propagated the signal further to target genes using TFlink (https://tflink.net) and GTRD (http://gtrd.biouml.org). To evaluate the predicted network propagation signal, we conducted WGCNA with transcriptomics data from 46 matching patients’ (GEO ID: GSE48959). To interpret the results, we used Gene Ontology Biological Process annotations of the target genes, and we compared the function and regulation of affected genes and the determined WGCNA modules. Results We found 9 predominant signalling pathways, some already known from other studies to be involved in UC pathogenesis, including NFkB signalling, chemokine signalling, Notch pathway, JAK/STAT signalling. Downstream of these pathways we identified potential key TFs regulate the UC phenotype, for example NFKB1, GATA3, GTF2I. The targets of these TFs were enriched in the WGCNA modules of the patients. The WGCNA modules and the transcriptionally affected genes had enriched processes including cell migration, TGF-β signalling, exocytosis, adaptive T- and B-cell-specific immune responses and tight junctions. We also found myogenetic development specific TFs affected transcriptionally such as MyoD, MEF2A, MEF2D. We are currently validating these results through patient-specific biopsies. Conclusion In silico methods bring us closer to understanding UC pathogenesis. Our results suggest that in a well-defined set of patients, weakened tight junctions and insufficient immune response can lead to dysfunctional epithelial barrier, resulting in poor wound healing in UC. We hope the developed workflow will provide novel diagnostic and therapeutic options in UC.

Background: Both genetic & environmental risk factors contribute to Crohn's disease (CD) susceptibility, & genetic biomarkers may allow for the characterization of disease activity & severity as well as response to therapeutic agents. Here, we evaluated the association of genetic polymorphisms with