Genome-wide association study of actinic keratosis identifies new susceptibility loci implicated in pigmentation and immune regulation pathways

Actinic keratosis (AK) is a common precancerous cutaneous neoplasm that arises on chronically sun-exposed skin. AK susceptibility has a moderate genetic component, and although a few susceptibility loci have been identified, including IRF4, TYR , and MC1R , additional loci have yet to be discovered. We conducted a genome-wide association study of AK in non-Hispanic white participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort ( n = 63,110, discovery cohort), with validation in the Mass-General Brigham (MGB) Biobank cohort ( n = 29,130). We identified eleven loci ( P < 5 × 10 −8 ), including seven novel loci, of which four novel loci were validated. In a meta-analysis (GERA + MGB), one additional novel locus, TRPS1 , was identified. Genes within the identified loci are implicated in pigmentation ( SLC45A2, IRF4, BNC2 , TYR, DEF8, RALY, HERC2 , and TRPS1 ), immune regulation ( FOXP1 and HLA-DQA1 ), and cell signaling and tissue remodeling ( MMP24 ) pathways. Our findings provide novel insight into the genetics and pathogenesis of AK susceptibility.