Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study

Bilirubin, an endogenous antioxidant, may play a protective role in cancer development. We applied two-sample Mendelian randomization to investigate whether genetically raised bilirubin levels are causally associated with the risk of ten cancers (pancreas, kidney, endometrium, ovary, breast, prostate, lung, Hodgkin's lymphoma, melanoma, and neuroblastoma). The number of cases and their matched controls of European descent ranged from 122,977 and 105,974 for breast cancer to 1200 and 6417 for Hodgkin's lymphoma, respectively. A total of 115 single-nucleotide polymorphisms (SNPs) associated (p < 5 × 10-8) with circulating total bilirubin, extracted from a genome-wide association study in the UK Biobank, were used as instrumental variables. One SNP (rs6431625) in the promoter region of the uridine-diphosphoglucuronate glucuronosyltransferase1A1 (UGT1A1) gene explained 16.9% and the remaining 114 SNPs (non-UGT1A1 SNPs) explained 3.1% of phenotypic variance in circulating bilirubin levels. A one-standarddeviation increment in circulating bilirubin (≈ 4.4 µmol/L), predicted by non-UGT1A1 SNPs, was inversely associated with risk of squamous cell lung cancer and Hodgkin's lymphoma (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.73-0.99, P 0.04 and OR 0.64, 95% CI 0.42-0.99, p 0.04, respectively), which was confirmed after removing potential pleiotropic SNPs. In contrast, a positive association was observed with the risk of breast cancer after removing potential pleiotropic SNPs (OR 1.12, 95% CI 1.04-1.20, p 0.002). There was little evidence for robust associations with the other seven cancers investigated. Genetically raised bilirubin levels were inversely associated with risk of squamous cell lung cancer as well as Hodgkin's lymphoma and positively associated with risk of breast cancer. Further studies are required to investigate the utility of bilirubin as a low-cost clinical marker to improve risk prediction for certain cancers

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Abstract: Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence