Polygenic prediction of actinic keratosis identifies transplant recipients at risk of extreme lesion burden.

Transplant recipients have an elevated risk of actinic keratosis (AK), a precursor for squamous cell carcinoma (SCC). We assessed whether an AK polygenic risk score (PRS) can identify transplant-naive individuals and transplant recipients at risk of multiple AKs who may benefit from early prevention. Using genome-wide association data (140,339 cases; 1,430,776 controls), we developed an AK PRS and evaluated it in cohort studies of European descent individuals in QSkin (N=12,843), STAR (N=357), UK Biobank (N=963), and All of Us (N=1,859). The PRS was strongly associated with high AK burden in transplant-naive individuals, conferring a five-fold increased risk of developing ≥20 AKs (OR per standard deviation (SD) increase in the PRS =5.06, 95%CI=4.69-5.46). In transplant recipients, it was associated with up to a 2.5-fold increased risk of developing ≥1 AK (UKB OR per SD =2.49, 95%CI=1.91-3.23; STAR OR per SD=1.79, 95%CI=1.10-2.91; All of Us OR per SD=1.52, 95%CI=1.35-1.70). The PRS improved prediction of ≥20 AKs by 13% beyond age and sex (AUC 0.90 vs 0.77) and identified the highest-risk 20% with a 9-fold increased risk in transplant-naive individuals (OR=8.61, 95%CI=7.26-10.22) and a 2-fold increased risk in transplant recipients (OR=2.23, 95%CI=1.26-4.20), compared to the middle-risk 60%. Incorporating PRS into pre- and post-transplant care could enable earlier, personalised prevention.