Table 2.
Overview of significant GRS–phenotype associations
| Discovery cohort A | Replication cohort B | Meta-analyses | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Genetic risk score | Phenotype | pT | Variants [n] | Empirical p-value | FDR | R 2 | p-value | Z-score | p-value | Direction |
| Crohn’s disease | Ileocaecal resection | 8.0E-04 | 5379 | 1.0E-04 | 1.6E-03 | 4.1% | 2.0E-05 | 5.8 | 8.2E-09 | ++ |
| excluding NOD2, MST, MHC | 3836 | 1.0E-04 | 1.6E-03 | 4.3% | ||||||
| Crohn’s disease | Fibrostenotic Crohn’s | 1.0E-08 | 219 | 1.0E-03 | 0.02 | 6.9% | 2.2E-03 | 4.3 | 1.6E-05 | ++ |
| excluding NOD2, MST, MHC | 170 | 1.0E-04 | 1.6E-03 | 11.0% | ||||||
| Ulcerative colitis | Colonic Crohn’s | 1.0E-04 | 1334 | 1.0E-03 | 0.02 | 9.1% | 6.0E-03 | -4.1 | 3.8E-05 | -- |
| excluding NOD2, MST, MHC | 939 | 0.01 | 0.22 | |||||||
| Primary sclerosing cholangitis | Colonic Crohn’s | 0.01 | 12487 | 2.0E-03 | 0.03 | 3.6% | 0.04 | -3.5 | 5.5E-04 | -- |
| excluding NOD2, MST, MHC | 10913 | 0.09 | ||||||||
| Primary sclerosing cholangitis | IBD-PSC | 1.6E-03 | 2365 | 1.0E-04 | 1.6E-03 | 7.5% | 2.0E-06 | 6.1 | 8.9E-10 | ++ |
| Primary sclerosing cholangitis | Smoking history | 9.6E-03 | 9735 | 2.5E-03 | 0.04 | 1.7% | 7.6E-03 | -3.9 | 8.5E-05 | -- |
| Crohn’s disease prognosis | IBD-PSC | 1.5E-06 | 8 | 4.0E-04 | 6.4E-03 | 5.5% | 2.1E-05 | -5.5 | 3.4E-08 | -- |
| excluding MHC | 3 | 0.71 |
Associations between genetic risk scores and clinical IBD phenotypes that remained significant after Bonferroni correction in the discovery cohort and showed positive replication with consistent direction of effect in the independent replication cohort. For IBD phenotypes with previously known genetic predictors [NOD2, MHC, and MST1], analyses were repeated after excluding these genes from the genetic data. ‘Variants’ refers to the number of genetic variants included in the optimal GRS for that phenotype [most explained variance]. Empirical p-value refers to the p-value after 10 000 rounds of permutation. Meta-analyses p-value refers to meta-analyses of results from both discovery [FDR] and replication [p-value] cohorts.
IBD, inflammatory bowel disease; CD, Crohn’s disease; FDR, false-discovery rate; GRS, genetic risk score; PSC, primary sclerosing cholangitis; pT, p-value threshold for optimal GRS.