A multi-phenotype analysis reveals 19 novel susceptibility loci for basal cell carcinoma and 15 for squamous cell carcinoma

ABSTRACT Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common forms of skin cancer. There is genetic overlap between skin cancers, pigmentation traits, and autoimmune diseases. We use linkage disequilibrium score regression to identify 20 traits (melanoma, pigmentation traits, autoimmune diseases, and blood biochemistry biomarkers) with a high genetic correlation ( r g > 10%, P < 0.05) with BCC (20,791 cases and 286,893 controls in the UK Biobank) and SCC (7,402 cases and 286,892 controls in the UK Biobank), and use a multi-trait genetic analysis to identify 78 and 69 independent genome-wide significant (P < 5 × 10 -8 ) susceptibility loci for BCC and SCC respectively; 19 BCC and 15 SCC loci are both novel and replicated (P < 0.05) in a large independent cohort; 23andMe, Inc (BCC: 251,963 cases and 2,271,667 controls, and SCC: 134,700 cases and 2,394,699 controls. Novel loci are implicated in BCC/SCC development and progression (e.g. CDKL1 ), pigmentation (e.g. DSTYK ), cardiometabolic pathways (e.g. FADS2 ), and immune-regulatory pathways including; innate immunity against coronaviruses (e.g. IFIH1 ), and HIV-1 viral load modulation and disease progression (e.g. CCR5 ). We also report a powerful and optimised BCC polygenic risk score that enables effective risk stratification for keratinocyte cancer in a large prospective Canadian Longitudinal Study of Aging (794 cases and 18139 controls); e.g. percentage of participants reclassified; MTAG PRS = 36.57%, 95% CI = 35.89-37.26% versus UKB PRS = 33.23%, 95% CI=32.56-33.91%).