During the last cycle of this Program Project (PPG), genome-wide association study (GWAS) technology has created a revolution in complex genetics. We have contributed to many of the collaborations that have identified lists of susceptibility genes for common genetic traits, including specifically Crohn's disease (CD) and ulcerative colitis (UC). As is now well-known, Identification of a susceptibility gene provides clues, not only to variation within the identified gene, but also to additional genes and gene-gene Interactions that are pathway-related. Thus, as the GWAS revolution moved forward during the last cycle, we expanded our study of the genetics of IBD-related Immuno-phenotypes into two directions using haplotype-based analyses: (1) testing the role of GWAS-identlfied genes, and (2) testing genes In the same pathway as GWAS-identified loci. Furthermore, we have laid a foundation for this present cycle by completing a GWAS on over 1000 CD and over 900 UC subjects, with well-characterized clinical phenotypes and antibody expression data for ANCA, ASCA, anti-CBir1, anti-I2, and anti-OmpC (i.e. IBD Immuno-phenotypes) (with Project 2, 3 and Core B). As this PPG has demonstrated, these immuno-phenotypes are heritable and associated with IBD severity. We therefore propose a GWAS-identified pathway approach for unraveling the genetic contribution to the immuno-phenotypes and thus for clinical course and response to therapies. Given our preliminary data, we hypothesize that combinations of genetic variation in multiple genes in the Tcell receptor activation pathway are related to differences in both immuno-phenotypes and in disease course (i.e. IBD severity), and that this can be established in a pathway-directed two-stage study design. With the goal of identifying genes that contribute to immuno-phenotypes and thus IBD severity, we propose 3 Specific Aims: Aim 1- genotyping 4608 haplotype tagged and functional SNPs in a 2600 member discovery cohort; Aim 2 - genotyping 2304 SNPs in a 3400 member confirmation cohort along with trans-ethnic mapping; and Aim 3 - testing association with clinical features. This project will interact with the other projects (Projects 2 - 5) of the PPG by collaborating in the genetic aspects of their Aims.