Genome-wide association study of actinic keratosis identifies new susceptibility loci implicated in pigmentation and immune regulation pathways
Yuhree Kim, Jie Yin, Hailiang Huang, Eric Jorgenson, Hélène Choquet, Maryam M. Asgari
Abstract
Abstract 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.