Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

Abstract

Genome-wide association studies (GWAS) and candidate gene studies in ulcerative colitis (UC) have identified 18 susceptibility loci. We conducted a meta-analysis of 6 UC GWAS, comprising 6,687 cases and 19,718 controls, and followed-up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P<5×10^-8), increasing the number of UC associated loci to 47. After annotating associated regions using GRAIL, eQTL data and correlations with non-synonymous SNPs, we identified many candidate genes providing potentially important insights into disease pathogenesis, including IL1R2, IL8RA/B, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease (IBD) risk loci is now 99, including a minimum of 28 shared association signals between Crohn’s disease (CD) and UC.

UC and CD represent the two major forms of inflammatory bowel disease (IBD: OMIM #266600), which together affect approximately 1:250 people in Europe, North America and Australasia. Clinical features, epidemiological data and genetic evidence suggest that UC and CD are related polygenic diseases. In contrast to CD, bowel inflammation in UC is limited to the colonic mucosa. While disease-related mortality is low, morbidity remains high and 10-20% of affected individuals will undergo colectomy. Though the precise etiology is unknown, the current hypothesis is a dysregulated mucosal immune response to commensal gut flora in genetically susceptible individuals¹. Recent genome-wide and candidate-gene association studies have identified 18 UC susceptibility loci, including 7 that overlap with CD (e.g. IL23 pathway genes, NKX2-3 and IL10). Known UC specific loci (HNF4A, CDH1 and LAMB1) have highlighted the role of defective barrier function in disease pathogenesis².

The 18 confirmed UC loci explain approximately 11% of UC heritability (see Online Methods). To identify additional UC susceptibility loci and further elucidate disease pathogenesis, we combined data from six GWAS using genotype imputation and meta-analysis methodology (see Online Methods). The discovery panel consisted of 6,687 cases and 19,718 controls of European descent with data available for at least 1.1 million SNPs (Supplementary Table 1). A quantile-quantile plot of the meta-analysis test statistics showed a marked excess of significant associations in the tail of the distribution (Supplementary Figure 1). Although the majority (16/18) of previously confirmed UC loci are at a genome-wide significant level (P<5×10^-8), two just failed to meet this threshold in the meta-analysis – 4q27³, and 22q13⁴ (Table 1), though we still consider these to be true risk loci given the strength of association in the initial studies (P=1.35×10^-10 and P=4.21×10⁻⁸ respectively). Fifty loci with P< 1×10^-5 and not previously associated with UC were followed up by genotyping the most associated SNP from each locus in an independent panel of 9,628 UC cases and 12,917 population controls (see Online Methods and Supplementary Table 2). Of these, 28 loci had evidence of association (P<0.05) in the follow-up panel and attained genome-wide significance (P<5×10^-8) in the combined analysis of meta-analysis and follow-up cohorts (Table 2 and Supplementary Table 3). In addition, although the locus on 1q32 failed follow-up genotyping (rs7554511) it had been previously tested for association to UC in an independent cohort (rs11584383: P = 1.2×10^-5)⁵. This alternative tag SNP achieves genome-wide significancein our current meta-analysis (P=3.7×10^-11) and therefore we consider this a confirmed UC locus, bringing the total number of new UC loci to 29. It should be noted that 12 of the 29 loci had documented nominal evidence of association (5×10^-8<P<0.05) to UC in previous reports (1p36², 1q32⁶, 5q33⁶, 6p21⁵, 7q32⁷, 9p24^5,8, 9q34^5,9, 10p11⁶, 11q23⁵, 13q12⁸, 13q13² and 20q13¹⁰). We also tested the 28 loci with follow-up genotype data for association with two clinically relevant disease sub-phenotypes (maximum disease extent and need for colectomy for medically refractory disease) but no significant associations were seen following correction for multiple testing (P<5.2×10^-4) (Supplementary Table 4). In summary, there are 47 confirmed UC susceptibility loci, 18 from previous studies and 29 from the current study.

Table 1. Association results and in silico analyses for the 18 previously confirmed (P<5×10^-8) ulcerative colitis (UC) loci.

Left-right association boundaries are given for each index SNP (see Online Methods). RAF = risk allele frequency. OR is estimated using the meta-analysis cohort only. Known associations represent phenotypes previously associated with the locus at P<5×10^-8). AS = ankylosing spondylitis, Ast = Asthma, BD = Behçet’s disease, CD = Crohn’s disease, CeD = celiac disease, Graves’ disease = GD, HL = Hodgkin’s lymphoma, MS = multiple sclerosis, PBC = primary biliary sclerosis, Ps = psoriasis, RA = rheumatoid arthritis, SLE = systemic lupus erythematosus, T1D = type 1 diabetes and WBC = white blood cell count. Candidate genes of interest are listed. Those in bold were highlighted by in silico analyses (GRAIL connectivity and/or presence of an eQTL or nonsynonymous SNP. See Online Methods and Supplementary Table 7 for more details).

dbSNP ID	Chr.	Left-right(Mb)	Risk Allele	Allele frequency in controls	P-value (meta)	OR (95% CI)	Association reported with other phenotypes	Positional candidate genes of interest
rs6426833	1p36	19.93-20.18	A	0.541	3.93 × 10-35	1.30 (1.25-1.35)
rs11209026	1p31	67.30-67.54	G	0.935	5.12 × 10-28	1.74 (1.57-1.92)	CD, AS, BD, Ps	IL23R
rs1801274	1q23	159.54-159.91	A	0.505	2.16 × 10-20	1.21 (1.16-1.26)	SLE	FCGR2A, FCGR2B, HSPA6
rs3024505	1q32	204.85-205.11	A	0.159	5.76 × 10-17	1.25 (1.19-1.32)	CD, BD, SLE, T1D	IL10, IL19
rs7608910	2p16	60.76-61.87	G	0.390	1.70 × 10-14	1.19 (1.14-1.24)	CD, CeD, RA	PUS10
rs4676406	2q37	241.20-241.32	T	0.516	8.32 × 10-11	1.14 (1.09-1.18)		GPR35
rs9822268	3p21	48.14-51.77	A	0.302	1.60 × 10-17	1.21 (1.16-1.26)	CD	MST1, UBA7, APEH, AMIGO3, GMPPB, BSN
rs17388568	4q27	123.20-123.78	A	0.273	9.49 × 10-7	1.12 (1.07-1.17)	CeD, T1D	IL21, IL2, ADAD1
rs11739663	5p15	0.48-0.80	T	0.767	2.80 × 10-8	1.15 (1.09-1.21)		EXOC3
rs9268853	6p21	31.49-33.01	T	0.661	1.35 × 10-55	1.40 (1.34-1.47)	CD, CeD, GrD, MS, PBC, RA, T1D	HLA-DRB5, HLA-DQA1, HLA-DRB1, HLA-DRA, BTNL2
rs4510766	7q22	107.20-107.39	A	0.559	2.00 × 10-16	1.20 (1.15-1.26)
rs6584283	10q24	101.25-101.33	T	0.472	8.46 × 10-21	1.21 (1.16-1.26)	CD
rs7134599	12q14	66.72-66.92	A	0.385	1.06 × 10-16	1.19 (1.14-1.24)		IFNG, IL26
rs6499188	16q22	66.98-67.40	A	0.749	3.97 × 10-8	1.14 (1.09-1.20)		ZFP90
rs2872507	17q12	34.62-35.51	A	0.463	5.44 × 10-11	1.15 (1.10-1.19)	CD, Ast, PBC, T1D, WBC	IKZF3, ORMDL3, IKZF3, PNMT, ZPBP2, GSDML
rs6017342	20q13	42.49-42.70	C	0.538	1.09 × 10-20	1.20 (1.15-1.26)	HDL	SERINC3
rs2836878	21q22	39.34-39.41	G	0.738	1.86 × 10-22	1.25 (1.20-1.32)	AS
rs5771069	22q13	48.70-48.83	G	0.515	1.87 × 10-7	1.11 (1.07-1.16)		PIM3, IL17REL

Table 2. Association results and in silico analyses for the 29 newly confirmed ulcerative colitis (UC) loci.

UC loci that meet genome-wide significance P<5×10^-8 in the combined analysis and P<0.05 in the replication study. Left-right association boundaries are given for each index SNP (see Online Methods). RAF = risk allele frequency. OR is estimated using the replication cohort only. Known associations represent phenotypes previously associated with the locus at P<5×10^-8. AtD = atopic dermatitis, BMD = bone mineral density, CD = Crohn’s disease, CeD = celiac disease, Gli = glioma, Lep = leprosy, MS = multiple sclerosis, MyN = myeloproliferative neoplasms, PBC = primary biliary sclerosis, Ps = psoriasis, RA = rheumatoid arthritis and SLE = systemic lupus erythematosus. Candidate genes of interest are listed. Those in bold were highlighted by in silico analyses (GRAIL connectivity and/or presence of an eQTL or nonsynonymous SNP. See Online Methods and Supplementary Table 7 for more details).

dbSNP ID	Chr.	Left-right(Mb)	Risk Allele	Allele frequency in controls	P-value (meta)	P-value (follow-up)	P-value (comb)	OR (95% CI)	Association reported with other phenotypes	Positional candidate genes of interest
rs734999	1p36	2.39-2.80	C	0.524	1.21 × 10-9	1.51 × 10-2	3.34 × 10-9	1.05 (1.01-1.09)	CeD, PBC	TNFRSF14, MMEL1, PLCH2, C1orf93
rs35675666	1p36	7.83-8.13	G	0.829	1.09 × 10-8	1.13 × 10-2	4.84 × 10-9	1.08 (1.02-1.15)	CD	TNFRSF9, ERFFI1,UTS2,PARK7
rs7524102	1p36	22.54-22.61	A	0.828	1.04 × 10-11	2.06 × 10-4	1.65 × 10-13	1.10 (1.05-1.16)	BMD
rs7554511	1q32	199.06-199.33	C	0.721	2.04 × 10-13	NA	NA	1.19 (1.14-1.25)	CD, CeD	C1orf106
rs2310173	2q11	101.66-102.13	T	0.461	8.44 × 10-8	5.94 × 10-6	3.17 × 10-12	1.09 (1.05-1.14)		IL1R2
rs11676348	2q35	218.58-218.97	T	0.486	8.78 × 10-9	6.18 × 10-4	1.25 × 10-10	1.07 (1.03-1.11)		IL8RA, SLC11A1, IL8RB, AAMP, ARPC
rs267939	5p15	10.72-10.90	C	0.368	9.67 × 10-7	1.27 × 10-6	6.01 × 10-12	1.10 (1.06-1.15)		DAP
rs3194051	5p13	35.83-36.07	G	0.269	2.19 × 10-6	2.06 × 10-3	4.22 × 10-8	1.07 (1.02-1.12)	MS	IL7R
rs6451493*	5p13	40.32-40.85	T	0.610	1.78 × 10-6	2.09 × 10-4	2.80 × 10-9	1.08 (1.04-1.12)	CD, MS	PTGER4
rs254560	5q31	134.41-134.53	A	0.397	3.06 × 10-7	4.19 × 10-4	1.25 × 10-9	1.07 (1.03-1.12)
rs6871626	5q33	158.46-158.86	A	0.334	1.02 × 10-8	1.40 × 10-14	1.11 × 10-21	1.17 (1.12-1.22)	CD, Ps, SLE	IL12B
rs943072	6p21	43.88-43.92	G	0.092	1.05 × 10-6	3.71 × 10-5	2.37 × 10-10	1.15 (1.08-1.23)
rs6911490	6q21	106.51-106.67	T	0.210	3.51 × 10-7	1.70 × 10-3	1.01 × 10-8	1.08 (1.03-1.13)	CD, RA, SLE	PDRM1
rs6920220	6q23	137.88-138.17	A	0.207	6.38 × 10-10	1.94 × 10-8	8.05 × 10-17	1.14 (1.09-1.20)	CeD, Ps, RA, SLE
rs798502	7p22	2.70-2.90	A	0.711	1.21 × 10-8	3.82 × 10-8	2.61 × 10-15	1.13 (1.08-1.18)		GNA12
rs4728142	7q32	128.33-128.56	A	0.444	1.68 × 10-6	1.25 × 10-3	1.74 × 10-8	1.07 (1.03-1.11)	SLE, RA, PBC	IRF5, TNPO3
rs10758669	9p24	4.93-5.28	C	0.350	8.52 × 10-13	3.78 × 10-14	2.22 × 10-25	1.17 (1.12-1.21)	CD, MyN	JAK2
rs4246905	9q32	116.48-116.74	C	0.713	4.77 × 10-8	1.44 × 10-5	5.65 × 10-12	1.10 (1.05-1.15)	CD, Lep	TNFSF8, TNFSF15
rs10781499	9q34	138.27-138.55	A	0.411	6.95 × 10-13	2.50 × 10-8	2.62 × 10-19	1.12 (1.08-1.17)	CD	CARD9, INPP5E, SDCCAG3, SEC16A, SNAPC4
rs12261843	10p11	35.22-35.94	G	0.286	2.35 × 10-8	1.22 × 10-3	7.09 × 10-10	1.07 (1.03-1.12)	CD	CCNY
rs907611	11q15	1.82-1.93	A	0.317	2.49 × 10-8	3.58 × 10-4	1.38 × 10-10	1.08 (1.03-1.13)		LSP1
rs2155219	11q13	75.72-76.02	T	0.500	6.33 × 10-8	1.61 × 10-9	5.39 × 10-16	1.13 (1.08-1.17)	CD, AtD
rs678170	11q23	113.76-114.08	A	0.661	6.88 × 10-11	2.50 × 10-5	4.65 × 10-14	1.09 (1.05-1.14)
rs17085007	13q12	26.39-26.46	C	0.178	3.30 × 10-9	4.66 × 10-9	9.65 × 10-17	1.16 (1.10-1.21)
rs941823	13q13	39.90-39.95	C	0.756	3.93 × 10-7	1.93 × 10-6	3.82 × 10-12	1.12 (1.07-1.17)
rs16940202	16q24	84.53-84.58	C	0.180	1.27 × 10-12	1.42 × 10-8	5.96 × 10-19	1.15 (1.10-1.21)	MS
rs2297441	20q13	61.66-61.98	A	0.766	5.78 × 10-8	2.68 × 10-4	1.70 × 10-10	1.09 (1.04-1.15)	CD, Gli	SLC2A4RG, STMN3, ZBTB46, ZGPAT, RTEL1, TNFRSF6B
rs1297265	21q21	15.62-15.77	A	0.564	1.73 × 10-7	5.02 × 10-7	6.99 × 10-13	1.11 (1.06-1.15)	CD
rs2838519	21q22	44.41-44.52	G	0.390	2.26 × 10-8	7.10 × 10-4	6.41 × 10-11	1.14 (1.05-1.22)	CD	ICOSLG

As a first step towards obtaining biological insight from the identification of these 47 loci, we examined the gene content of the associated regions (Supplementary Figure 2). Although three regions contained a single gene (5p15:DAP, 6q21:PRDM1, 10q24:NKX2-3), most (35/47) contain multiple genes and nine are not believed to contain any gene (Table 1). We attempted to identify plausible candidate genes by (a) using a literature-mining tool (GRAIL) to identify non-random, evidence-based links between genes, (b) searching an existing eQTL database¹¹ for correlations with our most associated SNPs (Supplementary Table 5), (c) using 1000 genomes data to identify non-synonymous SNPs in linkage disequilibrium (LD) (r²>0.5) with the most associated SNP in the locus (Supplementary Table 6), and (d) determining the gene in closest physical proximity to the most associated SNP (see Online Methods). These approaches (results summarized in Table 1, Table 2 and Supplementary Table 7) consistently identified a single candidate gene in six of the associated regions (2q11:IL1R2, 5p15:IL7R, 7p22:GNA12, 10p11:CCNY, 1p31:IL23R, 16q22:ZFP90), potentially prioritizing which genes to follow up in future genetic and functional studies. Noteworthy candidate genes are described in Box 1. Follow-up genotyping in even larger independent panels of cases and controls from a range of ethnicities may be needed to identify the genes containing causal variants.

BOX 1 – Candidate genes within associated loci.

TNFRSF14 / MMEL1 (1p36). TNFRSF14 encodes a member of the TNF receptor superfamily. In a T cell transfer model of colitis, TNFRSF14 expression by innate immune cells has an important role in preventing intestinal inflammation²². MMEL1 encodes membrane metalloendopeptidase-like 1. This locus is associated with susceptibility to celiac disease and primary biliary cirrhosis; a nsSNP in MMEL1 was nominally associated with multiple sclerosis.

TNFRSF9 (1p36): Tumour necrosis factor receptor superfamily member 9 is involved as a co-stimulator in the regulation of peripheral T cell activation, with enhanced proliferation and IL2 secretion. It is expressed by dendritic cells, granulocytes and endothelial cells at sites of inflammation. SCID mice transferred with naive CD4+ T cells from TNFRFSF9-deficient mice develop colitis of equal intensity as SCID mice transferred with wild type naïve T cells, but with amodified cytokine response²³.

IL1R2 (2q11): Interleukin 1 receptor, type II binds IL1a, IL1b and IL1R1, inhibiting the activity of these ligands. Two alternative splice transcripts of IL1R2 have been reported. This protein serves to antagonise the action of IL1a and IL1b, pleiotropic cytokines with various roles in inflammatory processes. IL1b production by lamina propria macrophages is increased in patients with UC²⁴.

This locus is immediately adjacent to a CD-associated locus containing IL18RAP, ILR1 and other genes. It is unclear at present whether the CD-associated and UC-associated SNPs in these regions tag two separate loci or one locus. The lead CD SNP has a P=0.001 in our UC meta-analysis. There is a large recombination hotspot between IL1R2 (UC) and IL1R1 (CD).

IL8RA / IL8RB (2q35): IL8RA and IL8RB encode two receptors for interleukin-8, a powerful neutrophil chemotactic factor. IL8RA expression, limited to a subpopulation of lamina propria macrophages and germinal centre lymphocytes in the healthy colon, is increased in macrophages, lymphocytes and epithelium in UC²⁵. IL8RB expression is more limited and not upregulated in UC. IL8 expression is profoundly increased in colonic tissue from UC patients compared with controls; this increase is driven by inflammation²⁶.

DAP (5p15) encodes death-associated protein. The DAPs are a heterogenous group of polypeptides isolated in a screen for elements involved in the IFNγ – induced apoptosis of HeLa cells. DAP negatively regulates autophagy and is a substrate of mTOR¹³.

IL7R (5p13) encodes the receptor for interleukin-7. IL7 is a key regulator of naïve and memory T cell survival, specifically the transition from effector to memory T cells²⁷. T cells expressing high levels of IL7R are seen in human and murine colitis; selective depletion of these cells ameliorates established colitis ²⁸. IL7R is a confirmed multiple sclerosis susceptibility gene²⁹. The gene may have undergone extensive evolutionary selective pressure by intestinal helminths³⁰.

PRDM1 (6q21) encodes PR domain containing 1, with ZNF domain (synonym BLIMP1), the master transcriptional regulator of plasma cells and a transcriptional repressor of the IFN-β promoter. It plays important roles in the proliferation, survival and differentiation of B and T lymphocytes.

GNA12 (7p22) encodes guanine nucleotide binding protein (G protein) alpha 12, a membrane bound GTPase that plays an important role in tight junction assembly in epithelial cells, through interactions with ZO-1 and Src²⁰.

IRF5 (7q32) encoding interferon regulatory factor 5, is a confirmed susceptibility gene for rheumatoid arthritis, SLE and primary biliary cirrhosis. This transcription factor regulates activity of type I interferons and induces cytokines including IL-6, IL-12 and TNFα, via TLR signaling. In response to mycobacterium tuberculosis infection of macrophages, Type I interferon expression is dependent on a pathway including IRF5, NOD2 and RIP2³¹.

LSP1 (11q15): Lymphocyte-specific protein-1 is expressed by lymphocytes and macrophages, and also in endothelium wherein it is critical for normal neutrophil transmigration³².

Additional bioinformatic analyses were also performed on the entire set of genes in the associated regions to search for functional commonalities across this large number of loci (see Online Methods). Specifically, using a gene set enrichment approach the UC loci are seen to have more genes associated with cytokines and cytokine receptors (including IFNγ, several interleukins, five TNF and TNFR superfamily members), key regulators of cytokine-mediated signaling pathways, innate and adaptive immune response, macrophage activation and regulation of apoptosis than would be expected by chance (Supplementary Table 8 and Supplementary Figure 3). Enrichment analysis of the subset of candidate loci with no known association to other inflammatory diseases showed significant over-representation of gene sets associated with MAP kinase signaling, actin binding, calcium-dependent processes, fatty acid and lipid metabolism (Supplementary Table 8 and Supplementary Figure 3).

The 5p15 locus contains a single gene, DAP (death-associated protein), with the most associated SNP in this region having a strong eQTL effect on DAP expression (P=2.59×10^-12)¹¹. DAP kinase expression has been shown to increase with inflammation in UC¹², and DAP itself has recently been identified as a novel substrate of mTOR (mammalian target of rapamycin)¹³ and as a negative regulator of autophagy. While autophagic processes have previously been implicated in CD due to associations with ATG16L1 and IRGM¹⁴, this association with DAP suggests a possible link between autophagy and UC.

Association to loci containing PRDM1, IRF5 and NKX2-3 suggests an important role for transcriptional regulation in UC pathogenesis. A key example is BLIMP-1, encoded by the PRDM1 gene, whose most important function is in B cells, as the master transcriptional regulator of plasma cells¹⁵. It also functions in T cells to attenuate IL-2 production upon antigen stimulation¹⁶, and topromote the development of short-lived effector cells and regulate clonal exhaustion in both CD4 and CD8 cells¹⁷. It is noteworthy that the 11q24 celiac disease susceptibility locus containing ETS1, a transcription factor essential for T-bet induced production of IFNγ and the development of colitis in animal models, just fails to reach genome-wide significance in our study (P=1.22×10^-7, Supplementary Table 3b)^18,19.

Identification of GNA12 as the most likely candidate at the 7p22 locus suggests a role for intestinal barrier function as this gene is implicated in tight junction assembly in epithelial cells²⁰. Barrier integrity appears to be a key pathway in UC pathogenesis given previous associations to loci containing HNF4A, CDH1 and LAMB1^2,5.

Given the phenotypic overlap between UC and CD, we examined the evidence for association at all 47 UC loci in our recently completed CD GWAS meta-analysis comprising 6,333 cases and 15,056 controls¹⁴ and, conversely, for evidence of association at all confirmed CD loci in our UC meta-analysis (Table 3 and Supplementary Table 9). We find that, among the 99 confirmed IBD loci meeting genome-wide significance (P<5×10^-8) either in UC and/or CD, 28 independent index SNPs have P<1×10^-4 in both scans. Interestingly, all index SNPs meeting these criteria showed the same direction of effect in both diseases, thus pointing to a minimum of 28 shared association signals between UC and CD. Multiple genes involved in the IL23 signaling pathway are included in this overlapping SNP list, specifically IL23R, JAK2, STAT3, IL12B (p40), and PTPN2. The significance of these findings is underlined by the central role played by IL23 in the induction of IL17 by Th17 lymphocytes, its established role in other autoimmune disorders, and the intense interest in therapeutic manipulation of the IL23-IL23R interaction through blockade of the p40 or p19 IL23 subunits.

Table 3. Shared association signals between UC and CD.

A shared association is defined as a confirmed association (P_combined < 5×10^-8) in either UC or CD and P_meta < 1×10-4 in the other form of IBD. For more details and comparative results across all 99 reported IBD risk loci see Supplementary table 9.

LOCUS		GENE	INDEX SNP			CD-META (6333/15056)		UC-META (6687/19718)
Chr.	Left-Right (Mb)	Candidate	SNP	Risk Allele	Allele frequency in controls	p-value	OR (95% CI)	p-value	OR (95% CI)
1p31	67.30-67.54	IL23R	rs11209026	G	0.94	1.00×10-64	2.67 (2.37-3.01)	5.12×10-28	1.74 (1.57-1.92)
1q32	199.0 -199.33	KIF21B	rs7554511	C	0.72	1.58×10-7	1.14 (1.08-1.19)	2.04×10-13	1.19 (1.14-1.25)
1q32	204.85-205.11	IL10	rs3024505	A	0.16	8.32×10-9	1.18 (1.12-1.25)	5.76×10-17	1.25 (1.19-1.32)
2p16	60.76-61.87	REL	rs7608910	G	0.39	3.11×10-7	1.14 (1.09-1.21)	1.70×10-14	1.19 (1.14-1.24)
2q11	101.66-102.13	IL1R2	rs2310173	T	0.46	8.31×10-5	1.09 (1.04-1.14)	8.44×10-8	1.12 (1.07-1.16)
3p21	48.14-51.77	MST1	rs3197999	A	0.30	6.17×10-17	1.22 (1.16-1.27)	1.86×10-17	1.21 (1.16-1.26)
5p13	40.32-40.85	PTGER4	rs6451493	T	0.61	1.61×10-27	1.35 (1.28-1.43)	1.78×10-6	1.12 (1.07-1.17)
		IL12B	rs6871626	A	0.33	6.08×10-12	1.15 (1.10-1.20)	1.02×10-8	1.12 (1.08-1.17)
5q33	158.46-158.86	IL12B	rs6556412 (r2=0.03)	A	0.34	5.37×10-14	1.18 (1.13-1.23)	1.69×10-5	1.09 (1.05-1.14)
6p22	20.60-21.25	CDKAL1	rs6908425	C	0.78	1.41×10-8	1.17 (1.11-1.23)	7.75×10-5	1.11 (1.05-1.16)
6q21	106.51-106.67	PRDM1	rs6911490	T	0.21	4.28×10-7	1.12 (1.07-1.18)	3.51×10-7	1.13 (1.07-1.18)
9p24	4.93-5.29	JAK2	rs10758669	C	0.35	1.00×10-13	1.18 (1.13-1.23)	8.52×10-13	1.16 (1.11-1.21)
9q32	116.48-116.74	TNFSF15	rs4246905	C	0.71	1.33×10-15	1.21 (1.15-1.28)	4.77×10-8	1.13 (1.08-1.18)
9q34	138.27-138.55	CARD9	rs10781499	A	0.40	3.49×10-18	1.20 (1.15-1.26)	6.95×10-13	1.16 (1.11-1.21)
10p11	35.22-35.94	CREM/CCNY	rs12261843	G	0.29	1.87×10-9	1.15 (1.10-1.20)	2.35×10-8	1.13 (1.08-1.18)
10q21	63.97-64.43	ZNF365	rs10761659	G	0.54	4.37×10-22	1.23 (1.18-1.28)	7.39×10-6	1.10 (1.05-1.14)
10q24	101.25-101.33	NKX2.3	rs6584283	T	0.47	7.18×10-20	1.21 (1.16-1.27)	8.46×10-21	1.21 (1.16-1.26)
11q13	75.72-76.02	C11Orf30	rs2155219	T	0.50	1.58×10-12	1.16 (1.11-1.21)	6.33×10-8	1.12 (1.07-1.16)
15q22	65.2-65.27	SMAD3	rs17293632	T	0.24	1.41×10-13	1.19 (1.14-1.25)	9.52×10-6	1.11 (1.06-1.16)
17q12	34.62-35.51	ORMDL3	rs2872507	A	0.46	1.51×10-9	1.14 (1.09-1.19)	5.44×10-11	1.15 (1.10-1.19)
18p11	12.73-12.92	PTPN2	rs1893217	G	0.16	1.29×10-14	1.25 (1.18-1.32)	4.78×10-5	1.12 (1.06-1.18)
19p13	10.26-10.5	TYK2	rs12720356	C	0.08	9.20×10-10	1.22 (1.14-1.31)	3.90×10-6	1.17 (1.09-1.26)
19q13	38.42-38.47	-	rs736289	T	0.61	2.69×10-7	1.11 (1.06-1.16)	1.89×10-5	1.08 (1.03-1.12)
20q13	61.66-61.98	RTEL1/SLC2A4RG	rs2297441	A	0.76	1.83×10-11	1.19 (1.13-1.25)	5.78×10-8	1.14 (1.09-1.20)
21q21	15.62-15.77	-	rs1297265	A	0.57	1.41×10-8	1.16 (1.10-1.22)	1.73×10-7	1.11 (1.06-1.16)
21q22	39.34-39.41	-	rs2836878	G	0.74	3.22×10-6	1.12 (1.06-1.17)	1.86×10-22	1.25 (1.20-1.32)
21q22	44.41-44.52	ICOSLG	rs2838519	G	0.39	2.09×10-14	1.18 (1.13-1.23)	2.26×10-8	1.12 (1.08-1.17)
22q11	20.14-20.39	YDJC	rs181359	A	0.19	6.31×10-13	1.21 (1.15-1.28)	2.73×10-5	1.11 (1.06-1.17)

Loci not meeting these inclusion criteria cannot be formally discounted as shared loci, indeed many of the confirmed UC/CD loci with nominal association (1×10^-4<P<0.05) to the other disease may be shared. Among the confirmed UC loci with no evidence (P>0.05) of association to CD are the three containing candidate genes that play a role in intestinal barrier function (GNA12, HNF4A, and LAMB1).

In addition to loci shared with CD, 19 of the 47 UC risk loci are also associated with other immune-mediated diseases (Table 1 and Table 2). In particular, these “shared loci” are enriched for genes involved in T-cell differentiation, specifically in the differentiation of T_H1 and T_H17 cells (e.g. loci encoding IL23R, IL21, IL10, IL7R, IFNG). Dysregulated auto-antigen specific T_H1 responses are believed to be involved in organ-specific autoimmune diseases, and T_H17 cells are increasingly recognized to contribute to host defense and induction of autoimmunity and tissue inflammation²¹. Another shared pathway between UC and other immune mediated diseases involves TNF-signaling (TNFRSF9, TNFRSF14, TNFSF15) with widespread immunological effects including NF-κB activation, a known key component of the inflammatory response in IBD.

The current study has more than doubled the number of confirmed UC susceptibility loci and we estimate that 16% of UC heritability is explained by these loci (see Online Methods). We have identified potentially causal genes at several loci but confirmation of causality awaits detailed fine-mapping, expression and functional studies. Dense fine-mapping and large-scale re-sequencing studies are underway with the goal of identifying the causal variation within many of these loci.