Gallbladder Cancer Risk and Indigenous South American Mapuche Ancestry: Instrumental Variable Analysis Using Ancestry-Informative Markers

SIMPLE SUMMARY: An association between individual levels of indigenous Chilean Mapuche ancestry and the risk of gallbladder cancer has been reported in observational studies, and the current program for gallbladder prevention in Chile takes the number of Mapuche surnames into account for prophylactic cholecystectomy. However, the association between Mapuche ancestry and gallbladder cancer could be due to known and unknown confounders (e.g., overweight and obesity) and non-random measurement errors (e.g., socio-economic level and access to health care). To investigate whether Mapuche ancestry and gallbladder cancer risk are statistically correlated or causally related, we used ancestry-informative markers for instrumental variable analysis. We aim to provide robust evidence on the potential of accounting for ethnic differences (in this study, Mapuche ancestry) for disease interception (in this study, gallbladder cancer prevention through prophylactic cholecystectomy). The methodology used and the results obtained may also guide future admixture mapping studies. ABSTRACT: A strong association between the proportion of indigenous South American Mapuche ancestry and the risk of gallbladder cancer (GBC) has been reported in observational studies. Chileans show the highest incidence of GBC worldwide, and the Mapuche are the largest indigenous people in Chile. We set out to assess the confounding-free effect of the individual proportion of Mapuche ancestry on GBC risk and to investigate the mediating effects of gallstone disease and body mass index (BMI) on this association. Genetic markers of Mapuche ancestry were selected based on the informativeness for assignment measure, and then used as instrumental variables in two-sample Mendelian randomization analyses and complementary sensitivity analyses. Results suggested a putatively causal effect of Mapuche ancestry on GBC risk (inverse variance-weighted (IVW) risk increase of 0.8% per 1% increase in Mapuche ancestry proportion, 95% CI 0.4% to 1.2%, p = 6.7 × 10(−5)) and also on gallstone disease (3.6% IVW risk increase, 95% CI 3.1% to 4.0%), pointing to a mediating effect of gallstones on the association between Mapuche ancestry and GBC. In contrast, the proportion of Mapuche ancestry showed a negative effect on BMI (IVW estimate −0.006 kg/m(2), 95% CI −0.009 to −0.003). The results presented here may have significant implications for GBC prevention and are important for future admixture mapping studies. Given that the association between the individual proportion of Mapuche ancestry and GBC risk previously noted in observational studies appears to be free of confounding, primary and secondary prevention strategies that consider genetic ancestry could be particularly efficient.