Multi-ancestry genome-wide association studies of biliary tract cancer

PROJECT SUMMARY/ABSTRACT Biliary tract cancers (BTC) include cancers of the bile ducts and gallbladder and they claim approximately 170,000 lives each year globally. BTC has a median overall survival of 4.5 months, increasing incidence, and is estimated to be the sixth leading cause of cancer death in 2024. Due to its aggressive nature and lack of efficacious treatments, prevention is of the utmost importance in preventing lives lost to this disease. Currently, BTC etiology is poorly understood. Major lifestyle risk factors include obesity, diabetes, gallstones, smoking tobacco, and alcohol intake, but it remains unclear if their associations with BTC risk are causal. Previous genome-wide association studies (GWAS) suggested markedly high heritability, but these studies were small, with <2,500 cases. We propose to significantly expand an ongoing GWAS of BTC by leveraging data and biologic samples from 21 studies and biobanks throughout the world including, conservatively,12,000 BTC cases and >700,000 controls. In Aim 1, we will assemble and harmonize data from 21 studies. In Aim 2, we will perform GWAS for BTC and its subtypes within studies and ancestral groups and combine the results with meta-analysis as appropriate to identify genetic variants associated with BTC risk. In Aim 3 we will delineate potential causal associations of BTC risk with the aforementioned BTC risk factors using two-sample Mendelian randomization methods. Study instruments will be derived from existing GWAS conducted for these risk factors. These analyses will allow us to identify genetic risk factors for BTC and provide the most robust evaluation of potential causal associations of lifestyle risk factors with BTC risk to date, directly supporting BTC primary and secondary prevention. 1