A lifelong inflammatory bowel disease that can affect any part of the digestive tract. Its genetics are unusually well mapped — NOD2 was the first susceptibility gene ever found for a common complex disease, and IL23R showed a drug class where to aim.
Solid lines are connections this site curates. Dashed lines mean the two ends share a research paper — worth knowing, and not a claim that one explains the other.
Crohn's disease is a long-term condition in which the immune system attacks the lining of the digestive tract. Anywhere from the mouth to the anus can be involved, though the end of the small intestine and the start of the colon are the most common sites. It comes in flares and remissions rather than steadily, and it is a disease people live with for decades rather than one they recover from.
The everyday reality of it is diarrhoea, abdominal pain that often settles in the lower right, weight loss and a fatigue that is out of proportion to everything else. Because the inflammation goes through the whole thickness of the bowel wall rather than staying on the surface, it can also tunnel — forming narrowings that block the bowel, or channels between the bowel and other organs or the skin. That depth is the main thing that distinguishes it from ulcerative colitis, which stays on the inner lining and stays in the colon.
Crohn's disease occupies an unusual place in the history of human genetics. In 2001, NOD2 became the first susceptibility gene identified for any common complex disease — before that, genetics had been good at rare single-gene conditions and had almost nothing to say about the ordinary ones. NOD2 is a sensor inside cells that recognises a fragment of bacterial cell wall. That a bacterial sensor turned out to be the first Crohn's gene reframed the disease: not the immune system misfiring at random, but a misjudged conversation between the gut and the bacteria living in it.
The second landmark was IL23R, found in 2006. One coding change in it, rs11209026, swaps arginine for glutamine at position 381 of the receptor, and the glutamine version substantially protects against Crohn's disease. Protective findings are rare and valuable: they say that turning this pathway down is safe and beneficial in people who are born that way. Drugs that block interleukin-23 were developed and are now in use for Crohn's disease. This is one of the clearest examples anywhere of a genetic finding leading to a treatment.
Less than that history might suggest. A 2012 meta-analysis of more than 75,000 people brought the count of inflammatory bowel disease loci to 163, and most of them affect both Crohn's disease and ulcerative colitis rather than one alone. Together they explain only a modest share of who develops the disease. Incidence has risen sharply over decades in which the gene pool cannot have changed, which by itself shows how much of the risk is environmental.
The two variants on this site are among the strongest of the 163, and they are still probabilistic:
Neither is a test. Most people carrying either will never develop Crohn's disease, and plenty of people who have it carry neither.
Nothing diagnostic. Crohn's disease is diagnosed by endoscopy, biopsy and imaging, and genotype plays no part in that. If you have symptoms that fit — persistent diarrhoea, unexplained weight loss, blood in the stool, abdominal pain that does not settle — those are worth a doctor's attention regardless of what any variant says, and the same symptoms with a normal genotype deserve exactly the same attention.
Positions joined since this page was written
What this is The text above discusses the variants this page was written around. Since then the catalogue has joined 22 more positions to it, by shared trait or shared paper. They are listed here by the paper each came from; the text does not describe them, and each variant page carries that study's own record.
Verma A et al. 2024, Science (New York, N.Y.) rs146528649 (NKD1), rs576910164 (RBMS2), rs1992660 (near TTC33), rs111978729 (CEACAM20), rs76872831 (SMIM3), rs550831531 (VWF), rs946573151 (near SUB1), rs185658725 (near MGMT), rs369013158 (NMT1), rs540193863 (near MTHFD2P1), rs191293575 (near LINC01734) — PMID:39024449
Kim K et al. 2024, Journal of Crohn's & colitis rs56211063 (near TNFSF15), rs10786560 (near NKX2-3), rs73243351 (LINC02513), rs224135 (near ALDH7A1P4), rs12033764 (near RNU4ATAC4P) — PMID:37523193
Khrom M et al. 2023, Inflammatory bowel diseases rs361525 (near TNF), rs7171171 (LINC02694) — PMID:37262302
Wang BR et al. 2024, Journal of affective disorders rs28653100 (MSRA), rs380571 (near TSBP1-AS1) — PMID:38154582
Jung S et al. 2022, Human molecular genetics rs10817678 (near TNFSF15) — PMID:35512355
Franke A et al. 2010, Nature genetics rs6651252 (LINC00824) — PMID:21102463
2026-06-26 · Exploring the genetic correlation between inflammatory bowel disease and psychiatric disorders: insights from genome-wide association studies. European Archives of Psychiatry and Clinical Neuroscience. 2026. DOI:10.1007/s00406-026-02302-1
IBD's genetic overlap with anxiety, PTSD and ADHD runs partly through NOD2 and the gut-brain axis
Anxiety and depression are known to be more common in people with inflammatory bowel disease (IBD) than in the general population, and this study tested whether that comorbidity has a shared genetic basis. Combining GWAS summary statistics for IBD (486,601 people) with data for eight psychiatric disorders, it found significant genome-wide genetic correlation between IBD and ADHD, anxiety disorder, autism spectrum disorder, OCD and PTSD -- strongest for PTSD (p=1.16x10^-19) and anxiety (p=8.02x10^-11). Local genetic correlation analysis found 274 significant shared regions, and multi-trait/SMR analysis prioritized 21 pleiotropic genes including NOD2 and IL10 -- both already on this site's own Crohn's disease and ulcerative colitis pages as classic IBD genes -- plus AURKB, implicating JAK-STAT signaling, oxidative stress response, and GABAergic synapse pathways as shared mechanisms across the gut-brain axis. This adds real context to this site's existing NOD2 and IL10 variants: the same genes long known for IBD itself also carry a documented genetic link to psychiatric comorbidity, not just a clinical association observed after the fact. This study reports genetic correlation and pleiotropy statistics rather than new IBD-specific lead SNPs, so this entry adds context to the existing variants rather than introducing new ones.
2026-01-17 · Polygenic risk scores for Crohn's disease risk prediction in a Chinese population: insights from multi-ethnic genome-wide association studies. European Journal of Medical Research. 2026. DOI:10.1186/s40001-026-03838-7
A Crohn's risk score built from Western data still works surprisingly well in a Chinese cohort
Polygenic risk scores (PRS) built from mostly European GWAS data often transfer poorly to other populations -- a well-documented, general problem in the field. This study tested a Crohn's disease (CD) PRS, built from causal effect sizes derived from a public large-scale multi-ethnic GWAS, against a Chinese cohort (76 CD patients, 552 controls, using whole-exome sequencing data). It found the PRS model distinguished CD patients from controls effectively, achieving an AUC of 0.75 and an odds ratio of 13 for individuals scoring above a 2.3 threshold -- a genuinely strong result for cross-population PRS transfer, and better performance than typically seen for many other conditions tested this way. This doesn't add new risk variants to this site's Crohn's disease page (85 variants), but adds useful context on how well the field's existing genetic risk tools generalize to Chinese populations specifically -- a practical question distinct from variant discovery.
Disease definition. Crohn's disease is a chronic, relapsing transmural inflammatory bowel disease that may affect any segment of the gastrointestinal tract, most often the terminal ileum and proximal colon, with discontinuous ("skip") involvement. Transmural inflammation underlies the stricturing and penetrating (fistulising) behaviours that distinguish it from ulcerative colitis, which is mucosal and continuous and confined to the colon and rectum. Diagnosis is clinical, endoscopic, histological and radiological; there is no genetic diagnostic test.
NOD2 rs2076756. An intron variant in NOD2 (16q12.1; the gene was originally reported as CARD15). In the GWAS Catalog the G allele is reported as the risk allele with an odds ratio of 1.53 (95% CI 1.46-1.60, p = 4 x 10-69) at a risk allele frequency of about 0.26, with independent reports of 1.66 (95% CI 1.48-1.88, p = 1 x 10-37) and 1.71 (95% CI 1.42-2.05, p = 1 x 10-21). NOD2 encodes an intracellular pattern-recognition receptor for muramyl dipeptide, a bacterial peptidoglycan fragment. The classical coding risk alleles in this gene (R702W, G908R and the 1007fs frameshift) are separate variants that are not covered on this site; rs2076756 is a common intronic marker at the same locus and is not a substitute for them.
IL23R rs11209026. A missense variant in IL23R (1p31.3), NM_144701 / ENST00000347310, p.Arg381Gln, alleles G/A. The A allele encodes Gln381 and is the protective allele; the GWAS Catalog reports rs11209026-G as the risk allele for Crohn disease with an odds ratio of 2.66 (95% CI 2.36-3.00, p = 1 x 10-64) and for inflammatory bowel disease at 2.56 (95% CI 1.92-3.45, p = 7 x 10-11). The association is directionally consistent with the clinical efficacy of IL-12/IL-23 and selective IL-23 pathway inhibitors in Crohn's disease, and is a standard example of human genetics validating a drug target prospectively.
Genetic architecture. Jostins et al. (Nature 2012; PMID 23128233) reported 71 new associations for a total of 163 IBD loci in a meta-analysis of more than 75,000 cases and controls; most loci contribute to both Crohn's disease and ulcerative colitis, and the authors reported significant overlap between IBD susceptibility loci and loci for mycobacterial infection. Heritability is substantial but the identified common variants account for a minority of it, and the marked secular rise in incidence establishes a large environmental component. Familial aggregation is real but risk to relatives is far below Mendelian expectation.
Clinical status of genotype. None of these variants is used diagnostically, prognostically or for treatment selection in routine practice. NOD2 genotype has been studied in relation to ileal, stricturing and early-onset disease, and IL23R in relation to treatment response, but neither is established as a clinical decision aid. Genotype should not influence when a person seeks assessment for symptoms.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Crohn's Disease comes down to these specific, well-studied positions — not a diagnosis. 107 positions are linked to this page; the ones this page's own text discusses are shown first.
The studies behind these variants recruited participants from different ancestries — a result found in one population doesn't always transfer to another. Based on 86 of 107 linked studies with a resolved discovery ancestry.
Research-derived gene–drug associations only — not a prescription, dosing guide, or medical advice. Always follow your prescriber's guidance.
| Gene | Drug | What the research shows |
|---|---|---|
| TPMT | Thiopurines (azathioprine, mercaptopurine, thioguanine) | Worth knowing before the first dose rather than after a blood count collapses. TPMT breaks thiopurines down, and its activity is inherited codominantly: one low-activity copy means the drug accumulates more than expected, two mean it accumulates a great deal. CPIC recommends a reduced starting dose for intermediate metabolisers and drastically reduced dosing — or a different drug — for those with no working enzyme, because standard doses in that situation cause severe, life-threatening myelosuppression. Testing before starting is routine in many hospitals. The point of it is to choose the right dose, not to withhold a drug that works. (CPIC Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update, Clinical Pharmacology & Therapeutics (PMID 30447069)) |
| NUDT15 | Thiopurines (azathioprine, mercaptopurine, thioguanine) | The second gene, and the reason the guideline was rewritten. NUDT15 does a different job from TPMT — it removes the active thiopurine metabolites once they have acted — and losing it lets them accumulate in dividing cells, causing the same myelosuppression by another route. CPIC states plainly that NUDT15 loss-of-function alleles are common in Asians and Hispanics. That matters here: testing TPMT alone, which was standard practice for years, misses a large share of the risk in east Asian patients, and this site is read in Korean. Dose recommendations follow the same shape as TPMT — reduced start for one no-function copy, drastic reduction or an alternative for two. (CPIC Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update, Clinical Pharmacology & Therapeutics (PMID 30447069)) |
| OTUD7A (nearest gene by distance — not gene-reported by the study itself) | Mesalamine (5-ASA) / sulfasalazine | A rare, large-effect finding rather than a dosing rule. A 2022 Japanese GWAS of 2,311 people with IBD (Suzuki et al., PMID:33501934) found the mesalamine allergy reaction — fever and worsening diarrhea after starting the drug — significantly more frequent in ulcerative colitis than in Crohn's disease. Carriers of the rs77344822-T allele (frequency about 2.3%) had roughly 4.8 times the odds of this reaction. There is no dosing guideline built on this finding — it identifies who is more likely to react, not a dose to adjust, and a single study of one population is not the same as a validated clinical marker. (Suzuki K, et al. Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease. Inflammatory Bowel Diseases 2022;28(6):865-873. PMID:33501934) |
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Crohn's Disease. MyGeneLog™. https://www.mygenelog.com/conditions/crohns-disease
Crohn's disease can affect any part of the digestive tract, goes through the full thickness of the bowel wall, and typically appears in patches with normal bowel in between. Ulcerative colitis is confined to the colon and rectum, involves only the inner lining, and spreads continuously upward from the rectum. They share many of the same genetic risk loci, which is why both sit under the umbrella term inflammatory bowel disease.
No. These are common variants with modest effects. Most people who carry them never develop the disease, and many people who have it carry neither of the two on this site. Incidence has risen steeply over decades in which the gene pool cannot have changed, which shows how much of the risk is environmental.
Because it is protective rather than harmful. People born with the glutamine version of the receptor at position 381 get Crohn's disease substantially less often, which is evidence that turning this pathway down is both safe and useful. Drugs blocking interleukin-23 were developed and are now used in Crohn's disease — one of the clearest cases anywhere of a genetic finding leading to a treatment.
It was the first susceptibility gene found for any common complex disease, in 2001. Until then genetics could explain rare single-gene conditions and had almost nothing to say about ordinary ones. NOD2 senses a fragment of bacterial cell wall, which reframed Crohn's disease as a misjudged conversation between the gut and its bacteria rather than an immune system misfiring at random.
There is no clinical reason to. Crohn's disease is diagnosed by endoscopy, biopsy and imaging, and no guideline uses genotype to diagnose it, predict its course or choose treatment. Symptoms that fit the disease deserve medical assessment whatever your genotype says.
Free to reuse. This page's text is original writing from freely-available research, licensed CC BY 4.0 — reuse it, including commercially, with attribution to MyGeneLog™. It's general research-derived information, not medical advice or a diagnosis — see Terms of Use.