Inherited determinants of Crohn's disease and XXXX phenotypes: a genetic association study.

@entity1 @entity39915 @entity3998 @entity31 @entity3544 @entity29 @entity6820 @entity30
BACKGROUND: @entity30 and @entity31 are the two major forms of @entity29 ; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for @entity29 , mostly shared between @entity30 and @entity31 . We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of @entity29 with the goal of further understanding the biological relations between diseases. METHODS: This study included @entity1 from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of @entity29 subphenotypes to 34   819 @entity1 (19   713 with @entity30 , 14   683 with @entity31 ) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156   154 genetic variants. We generated genetic risk scores by combining information from all known @entity29 associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that @entity30 , @entity30 , and @entity31 are all genetically distinct from each other, and to attempt to identify @entity1 with a mismatch between clinical diagnosis and genetic risk profile. FINDINGS: After quality control, the primary analysis included 29   838 @entity1 (16   902 with @entity30 , 12   597 with @entity31 ). Three loci ( @entity6820 , @entity3998 , and @entity39915 3 @entity3544 ) were associated with subphenotypes of @entity29 , mainly disease location (essentially fixed over time; median follow-up of 10  5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for @entity29 showed strong association with disease subphenotype (p=1  65   *   10(-78)), even after exclusion of @entity6820 , @entity3998 , and 3p21 (p=9  23   *   10(-18)). Predictive models based on the genetic risk score strongly distinguished colonic from @entity30 . Our genetic risk score could also identify a small number of @entity1 with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6  8   *   10(-4)). INTERPRETATION: Our data support a continuum of @entity29 , much better explained by three groups ( @entity30 , @entity30 , and @entity31 ) than by @entity30 and @entity31 as currently defined. Disease location is an intrinsic aspect of a @entity1 's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. FUNDING: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).
