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Crohn’s disease (CD) and ulcerative colitis (UC), two major subtypes of inflammatory bowel disease, show substantial differences in their clinical course and treatment response. To identify the genetic factors underlying the distinct characteristics of these two diseases, we performed a genome-wide association study (GWAS) between CD (n = 2359) and UC (n = 2175) in a Korean population, followed by replication in an independent sample of 772 CD and 619 UC cases. Two novel loci were identified with divergent effects on CD and UC: rs9842650 in CD200 and rs885026 in NCOR2. In addition, the seven established susceptibility loci [major histocompatibility complex (MHC), TNFSF15, OTUD3, USP12, IL23R, FCHSD2 and RIPK2] reached genome-wide significance. Of the nine loci, six (MHC, TNFSF15, OTUD3, USP12, IL23R and CD200) were replicated in the case–case GWAS of European populations. The proportion of variance explained in CD–UC status by polygenic risk score analysis was up to 22.6%. The area under the receiver-operating characteristic curve value was 0.74, suggesting acceptable discrimination between CD and UC. This CD–UC GWAS provides new insights into genetic differences between the two diseases with similar symptoms and might be useful in improving their diagnosis and treatment.

Background: Recent studies report an important—and previously underestimated—role of rare variation in risk of obsessive-compulsive disorder (OCD) and chronic tic disorders (CTD). Using data from a large epidemiological study, we evaluate the distribution of potentially damaging copy number variation (pdCNV) in OCD and CTD, examining associations between pdCNV and the phenotypes of probands, including a consideration of early- vs. late-diagnoses. Method: The Obsessive-Compulsive Inventory-Revised (OCI-R) questionnaire was used to ascertain psychometric profiles of OCD probands. CNV were identified genome-wide using chromosomal microarray data. Results: For 993 OCD cases, 86 (9%) were identified as pdCNV carriers. The most frequent pdCNV found was at the 16p13.11 region. There was no significant association between pdCNV and the OCI-R total score. However, pdCNV was associated with Obsessing and Checking subscores. There was no significant difference in pdCNV frequency between early- vs. late-diagnosed OCD probands. Of the 217 CTD cases, 18 (8%) were identified as pdCNV carriers. CTD probands with pdCNV were significantly more likely to have co-occurring autism spectrum disorder (ASD). Conclusions: pdCNV represents part of the risk architecture for OCD and CTD. If replicated, our findings suggest pdCNV impact some OCD symptoms. Genes within the 16p13.11 region are potential OCD risk genes.

Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional signals. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. We conducted a multi-population GWAS meta-analysis in 38,463 participants (2,440 cases) and population specific GWAS, discovering twelve significant associations (eight novel). Fine-mapping implicated specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk signal. Non-HLA loci colocalized with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs was lacking, but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associated with earlier disease onset in two independent cohorts. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cellspecific insights into its molecular drivers.

Background and Aims Genome-wide association studies [GWAS] of inflammatory bowel disease [IBD] in multiple populations have identified over 240 susceptibility loci. We previously performed a largest-to-date Asian-specific IBD GWAS to identify two new IBD risk loci and confirm associations with 28 established loci. To identify additional susceptibility loci in Asians, we expanded our previous study design by doubling the case size with an additional dataset of 1726 cases and 378 controls. Methods An inverse-variance fixed-effects meta-analysis was performed between the previous and the new GWAS dataset, comprising a total of 3195 cases and 4419 controls, followed by replication in an additional 1088 cases and 845 controls. Results The meta-analysis of Korean GWAS identified one novel locus for ulcerative colitis at rs76227733 on 10q24 [pcombined = 6.56 × 10–9] and two novel loci for Crohn’s disease [CD] at rs2240751 on 19p13 [pcombined = 3.03 × 10–8] and rs6936629 on 6q22 [pcombined = 3.63 × 10–8]. Pathway-based analysis of GWAS data using MAGMA showed that the MHC and antigenic stimulus-related pathways were more significant in Korean CD, whereas cytokine and transcription factor-related pathways were more significant in European CD. Phenotype variance explained by the polygenic risk scores derived from Korean data explained up to 14% of the variance of CD whereas those derived from European data explained 10%, emphasizing the need for large-scale genetic studies in this population. Conclusions The identification of novel loci not previously associated with IBD suggests the importance of studying IBD genetics in diverse populations.

Genome-wide association studies (GWAS) of Crohn’s disease (CD) in European and leprosy in Chinese population have shown that CD and leprosy share genetic risk loci. As these shared loci were identified through cross-comparisons across different ethnic populations, we hypothesized that meta-analysis of GWAS on CD and leprosy in East Asian populations would increase power to identify additional shared loci. We performed a cross-disease meta-analysis of GWAS data from CD (1621 cases and 4419 controls) and leprosy (2901 cases 3801 controls) followed by replication in additional datasets comprising 738 CD cases and 488 controls and 842 leprosy cases and 925 controls. We identified one novel locus at 7p22.3, rs77992257 in intron 2 of ADAP1, shared between CD and leprosy with genome-wide significance (P = 3.80 × 10−11) and confirmed 10 previously established loci in both diseases: IL23R, IL18RAP, IL12B, RIPK2, TNFSF15, ZNF365-EGR2, CCDC88B, LACC1, IL27, NOD2. Phenotype variance explained by the polygenic risk scores derived from Chinese leprosy data explained up to 5.28% of variance of Korean CD, supporting similar genetic structures between the two diseases. Although CD and leprosy shared a substantial number of genetic susceptibility loci in East Asians, the majority of shared susceptibility loci showed allelic effects in the opposite direction. Investigation of the genetic correlation using cross-trait linkage disequilibrium score regression also showed a negative genetic correlation between CD and leprosy (rg [SE] = −0.40[0.13], P = 2.6 × 10−3). These observations implicate the possibility that CD might be caused by hyper-sensitive reactions toward pathogenic stimuli.

Crohn's disease (CD) and ulcerative colitis (UC) are the major types of chronic inflammatory bowel disease (IBD) characterized by recurring episodes of inflammation of the gastrointestinal tract. Although it is well established that human leukocyte antigen (HLA) is a major risk factor for IBD, it is yet to be determined which HLA alleles or amino acids drive the risks of CD and UC in Asians. To define the roles of HLA for IBD in Asians, we fine-mapped HLA in 12 568 individuals from Korea and Japan (3294 patients with CD, 1522 patients with UC and 7752 controls). We identified that the amino acid position 37 of HLA-DRβ1 plays a key role in the susceptibility to CD (presence of serine being protective, P = 3.6 × 10-67, OR = 0.48 [0.45-0.52]). For UC, we confirmed the known association of the haplotype spanning HLA-C*12:02, HLA-B*52:01 and HLA-DRB1*1502 (P = 1.2 × 10-28, OR = 4.01 [3.14-5.12]).

Background and aim CDKN2A/CDKN2B locus on 9p21 is reported to be associated with various diseases, including cancer and cardiovascular and inflammatory diseases. Significant downregulation of CDKN2B-AS1 in inflamed colon tissue of inflammatory bowel disease (IBD) cases was reported in Europeans. This study aimed to confirm the suggestive association of CDKN2A/CDKN2B with IBD identified in our recent genome-wide association study (GWAS). Methods We examined the association of CDKN2A/CDKN2B locus with IBD in an additional sample of 574 IBD cases and 542 controls, totaling 4068 cases and 8074 controls. In silico study was performed at various levels for functional annotation of the causal variant. Co-localization of the GWAS association signals and the corresponding expression quantitative trait loci in IBD-related tissues was evaluated using eCAVIAR. Results An expanded GWAS showed genome-wide significant association of rs3731257 at 9p21 with IBD (odds ratio = 1.17, 95% confidence interval = 1.12-1.22, Pcombined = 5.68 × 10-9 ) and Crohn's disease (odds ratio = 1.22, 95% confidence interval = 1.15-1.28, Pcombined = 8.85 × 10-9 ) in the Korean population. Co-localization study suggested that both CDKN2B-AS1 and CDKN2A might be functionally associated with the locus in the small intestine. Conclusions rs3731257 in CDKN2A/CDKN2B is an IBD-susceptible locus in Koreans, with a suggestive role for small intestine-specific gene regulation. Our findings suggested that alterations of the CDKN2A/CDKN2B locus could affect the pathophysiology of IBD.

BACKGROUND AND AIMS: Recent meta-analysis of genome-wide association studies have identified over 241 inflammatory bowel disease susceptibility loci. However, the known variants only account for a fraction of inflammatory bowel disease heritability. To identify additional susceptibility loci, we performed a trans-ethnic meta-analysis as well as an Asian-specific meta-analysis, using all published Immunochip association results of inflammatory bowel disease. METHODS: An inverse-variance fixed-effects meta-analysis was carried out across Korean and East Asian Immunochip datasets of 4156 cases and 4904 controls [Asian ancestry]. A trans-ethnic meta-analysis of inflammatory bowel disease was performed together with the European datasets of 38 155 cases and 48 485 controls genotyped on the immunochip using a Bayesian approach, Meta-Analysis of Trans-ethnic Association studies [MANTRA]. RESULTS: We identified seven novel associations, including three novel susceptibility loci at MYO10-BASP1, PPP2R3C/KIAA0391/PSMA6/NFKB1A and LRRK1 as well as four novel secondary associations within previously known loci at NCF4, TSPAN32, CIITA and VANGL2. The new loci further implicate alterations in B cell biology in Crohn’s disease pathogenesis. The effects of five loci were universal across European and Asian ancestries, whereas the NCF4 and CIITA loci showed significant heterogeneity between European and East Asian populations. In addition, 103 previously known IBD loci showed supporting evidence of association with nominal significance [p < 0.05] in Asians. CONCLUSIONS: Our findings of new loci not previously associated with IBD support the importance of studying inflammatory bowel disease genetics in diverse populations.

BACKGROUND AND AIMS The genetic contribution to the prognosis of ulcerative colitis [UC] is poorly understood, and most currently known susceptibility loci are not associated with prognosis. To identify genetic variants influencing the prognosis of UC, we performed an Immunochip-based study using an extreme phenotype approach. METHODS Based on the finding that the only association, Pdiscovery-meta

CDKN2A/CDKN2B locus on 9p21 is reported to be associated with various diseases, including cancer and cardiovascular and inflammatory diseases. Significant downregulation of CDKN2B-AS1 in inflamed colon tissue of inflammatory bowel disease (IBD) cases was reported in Europeans. This study aimed to confirm the suggestive association of CDKN2A/CDKN2B with IBD identified in our recent genome-wide association study (GWAS).We examined the association of CDKN2A/CDKN2B locus with IBD in an additional sample of 574 IBD cases and 542 controls, totaling 4068 cases and 8074 controls. In silico study was performed at various levels for functional annotation of the causal variant. Co-localization of the GWAS association signals and the corresponding expression quantitative trait loci in IBD-related tissues was evaluated using eCAVIAR.An expanded GWAS showed genome-wide significant association of rs3731257 at 9p21 with IBD (odds ratio = 1.17, 95% confidence interval = 1.12-1.22, Prs3731257 in CDKN2A/CDKN2B is an IBD-susceptible locus in Koreans, with a suggestive role for small intestine-specific gene regulation. Our findings suggested that alterations of the CDKN2A/CDKN2B locus could affect the pathophysiology of IBD.

Background and Aims Genome-wide association studies of inflammatory bowel disease identified > 200 susceptibility loci only in autosomes. This study aimed to identify inflammatory bowel disease susceptibility loci on the X chromosome. Methods We performed an X chromosome-wide association study in Korean patients with inflammatory bowel disease. We analysed X chromosome data from our recent genome-wide association studies, including 1505 cases [922 Crohn's disease and 583 ulcerative colitis] and 4041 controls during the discovery phase, followed by replication in additional 1989 cases [993 Crohn's disease, 996 ulcerative colitis] and 3491 controls. Sex-related differential effects of single nucleotide polymorphisms on disease were also evaluated. Results We confirmed a significant association of a previously reported inflammatory bowel disease susceptibility locus at chromosome Xq26.3 [CD40LG-ARHGEF6; odds ratio, 1.22; 95% confidence interval, 1.16-1.28; combined p = 3.79 × 10-15]. This locus accounted for 0.18% and 0.12% of genetic variance in Crohn's disease and ulcerative colitis, respectively, and increased the total autosomal chromosome genetic variance from 6.65% to 6.83% and from 5.47% to 5.59% for Crohn's disease and ulcerative colitis risk, respectively, in the Korean population. Sex-stratified analyses did not reveal sex-related differences in effect sizes. Conclusions We confirmed the association of rs2427870 at the CD40LG-ARHGEF6 locus with an inflammatory bowel disease through an X chromosome-wide association study in a Korean population. Our data suggest that the CD40LG-ARHGEF6 locus on the X chromosome might play a role in inflammatory bowel disease pathogenesis in the Korean population.

Recent genome-wide association studies have identified more than 200 regions that affect susceptibility to inflammatory bowel disease (IBD). However, identified common variants account for only a fraction of IBD heritability and largely have been identified in populations of European ancestry. We performed a genome-wide association study of susceptibility loci in Korean individuals, comprising a total of 1505 IBD patients and 4041 controls. We identified 2 new susceptibility loci for IBD at genome-wide significance: rs3766920 near PYGO2-SHC1 at 1q21 and rs16953946 in CDYL2 at 16q23. In addition, we confirmed associations, in Koreans, with 28 established IBD loci ( P -4 ). Our findings support the complementary value of genetic studies in different populations.