Gallbladder Cancer Risk and Indigenous South American Mapuche Ancestry: Instrumental Variable Analysis Using...

Area of Science:

• Population genetics
• Cancer epidemiology
• Genetic epidemiology

Background:

• Observational studies report a strong association between Mapuche ancestry and gallbladder cancer (GBC) risk.
• Chile has the world's highest GBC incidence, with the Mapuche being the largest indigenous group.
• Previous associations may be confounded by other factors.

Purpose of the Study:

• To assess the confounding-free effect of Mapuche ancestry proportion on GBC risk.
• To investigate the mediating roles of gallstone disease and body mass index (BMI) in this association.

Main Methods:

• Two-sample Mendelian randomization (MR) analyses using genetic markers for Mapuche ancestry as instrumental variables.
• Selection of informative genetic markers for ancestry assignment.
• Complementary sensitivity analyses were performed.

Main Results:

• A putatively causal effect of Mapuche ancestry on GBC risk was identified (0.8% risk increase per 1% increase in ancestry, P = 6.7 × 10^-5).
• Mapuche ancestry also causally increases gallstone disease risk (3.6% risk increase), suggesting mediation.
• Mapuche ancestry showed a negative effect on BMI (-0.006 kg/m²).

Conclusions:

• The association between Mapuche ancestry and GBC risk is likely causal and not due to confounding.
• Gallstone disease mediates the relationship between Mapuche ancestry and GBC risk.
• Ancestry-informed prevention strategies could enhance GBC prevention efficiency in relevant populations.