Inflammatory bowel disease is a complex multifactorial disease with a strong genetic component. Recent studies have identified innate immunity (NOD2), autophagy (ATG16L1) and Th17 pathway (IL23R) genes in the pathogenesis of Crohn's disease. The pathogenesis of ulcerative colitis (UC) is less clear; however, there is growing evidence that proteins involved in the apical junction complex are involved in UC. Here we review the up-to-date studies on the genetic basis for IBD and explore the newly described UC-associated apical junction complex pointing to a primary defect in barrier defense. We will focus on the PTPRS (encoding PTPsigma) gene and discuss its and other apical junction complex proteins' role in the pathogenesis of UC.