From genetics of inflammatory bowel disease towards mechanistic insights

• One hundred and sixty-three loci have been identified that associate with IBD.
• Genetic variation within IBD loci may dysregulate immune homeostasis in the gut.
• Innovations in genomics pave the way to decipher genotype–phenotype relationships.

Advancements in human genetics now poise the field to illuminate the pathophysiology of complex genetic disease. In particular, genome-wide association studies (GWAS) have generated insights into the mechanisms driving inflammatory bowel disease (IBD) and implicated genes shared by multiple autoimmune and autoinflammatory diseases. Thus, emerging evidence suggests a central role for the mucosal immune system in mediating immune homeostasis and highlights the complexity of genetic and environmental interactions that collectively modulate the risk of disease. Nevertheless, the challenge remains to determine how genetic variation can precipitate and sustain the inappropriate inflammatory response to commensals that is observed in IBD. Here, we highlight recent advancements in immunogenetics and provide a forward-looking view of the innovations that will deliver mechanistic insights from human genetics.