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.

The association of rs1051730 genotype on adherence to and consumption of prescribed nicotine replacement therapy dose during a smoking cessation attempt.

INTRODUCTION: While nicotine replacement therapy (NRT) is an effective pharmacological smoking cessation treatment, its efficacy is influenced by adherence to and consumption of the prescribed dose. The genetic variant rs1051730 in the nicotinic receptor gene cluster CHRNA5-A3-B4 influences smoking quantity. The aim of this study was to explore the impact of rs1051730 genotype on adherence to and consumption of NRT prescription following a smoking cessation attempt. METHODS: Secondary analysis of data from a pharmacogenetic smoking cessation trial. Participants (n = 448) were prescribed a daily dose of NRT for four weeks post quit attempt, and monitored during weekly clinic visits. Outcome measures were NRT prescription adherence rate (%) and average daily NRT consumption (mg) at 7- and 28-days after the quit attempt. RESULTS: An association between rs1051730 genotype and both outcome measures was observed at 7-days after the quit date. Each copy of the minor allele corresponded to a 2.9% decrease in adherence to prescribed NRT dose (P = 0.044), and a 1.0mg decrease in daily NRT consumption (P = 0.026). Adjusting for number of cigarettes smoked during this period only slightly attenuated these associations. There was no clear statistical evidence of an association between genotype and adherence or consumption at 28-days. CONCLUSIONS: This is the first study to evaluate the impact of rs1051730 genotype on consumption of and adherence to NRT prescription during a smoking cessation attempt. We observed an association between this variant and both outcome measures at 7-days; however, this was only moderate. These findings require replication in an independent sample.

Comprehensive assessment of variation at the transforming growth factor beta type 1 receptor locus and colorectal cancer predisposition.

The role of transforming growth factor beta receptor type 1 (TGFBR1) polymorphisms, particularly a coding CGC insertion (rs11466445, TGFBR1*6A/9A) in exon 1, has been extensively investigated in regard to colorectal cancer (CRC) risk. These investigations have generated conflicting results. More recently, allele-specific expression (ASE) of TGFBR1 mRNA has been suggested as predisposing to CRC, with a relative risk of nearly 10-fold and a population attributable risk of approximately 10%. Owing to the potential importance of TGFBR1 variants in CRC, we performed a comprehensive examination of tagging SNPs at and around the gene in 3,101 CRC cases and 3,334 controls of northern European ancestry. To test whether rare or subpolymorphic TGFBR1 variants were associated with CRC risk, we sequenced the gene's exons in a subset of patients. We also evaluated TGFBR1 ASE in a panel of CRC cases and controls. Overall, we found no association between TGFBR1 polymorphisms and CRC risk. The rare variant screen did not identify any changes of potentially pathogenic effects. No evidence of greater ASE in cases than controls was detected, and no haplotype around TGFBR1 could account for the ASE reported in other studies. We conclude that neither genetic variation nor ASE at TGFBR1 is likely to be a major CRC risk factor.