Abstract
Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. However, no studies have investigated pan-cancer pleiotropy within single, well-defined populations. We undertook novel genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (413,870 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detected 29 novel genome-wide significant risk variants. In addition, numerous cancer sites exhibited clear heritability. Investigations of pleiotropy identified 12 cancer pairs exhibiting genetic correlations and 43 pleiotropic loci. We also detected 158 variants associated with multiple cancers, including 21 with positive associations for some cancers and negative associations for others. Our findings demonstrate widespread pleiotropy and offer insight into the complex genetic architecture of cross-cancer susceptibility.