Most psoriasis susceptibility genes were identified in cohorts of mixed clinical phenotypes and exploration of genes in clinical subtypes is scarce. IL-22 has an established role in host defense and in psoriasis skin pathology, reflecting the delicate balance between control of infection and immunopathology. In a case-control study, we compared the genetic association to IL22 in psoriasis onset between 0-9 (n=207), 10-20 (n=394) and 21-40 (n=468) years to healthy controls (n=1529). Logistic regression analysis revealed association to regulatory elements in the IL22 promoter confined to onset of psoriasis before puberty (OR=1.45, P<0.0007). The associated variants contain putative binding sites for AhR, a potent inducer of IL-22 expression. In a luciferase assay, transcriptional activity of a high-risk gene variant resulted in eighty percent higher promoter activity (P=0.012) compared to a low-risk variant. Ex vivo stimulated T cells from peripheral blood were analyzed with flow cytometry. Children with psoriasis carrying a high-risk variant, produced 1.7 times more IL-22 compared to low-risk variants (P=0.042). Our combined genetic and functional data support the notion that a genetic IL22 variant that promotes epithelial barrier defense is preferentially enriched in and may precipitate onset of psorasis at an early age.Journal of Investigative Dermatology accepted article preview online, 3 January 2014. doi:10.1038/jid.2014.5.