Genetic associations with disease in populations with Indigenous American ancestries

The genetic architecture of complex diseases affecting populations with Indigenous American ancestries is poorly understood due to their underrepresentation in genomics studies. While most of the genetic diversity associated with disease trait variation is shared among worldwide populations, a fraction of this component is expected to be unique to each continental group, including Indigenous Americans. Here, I describe the current state of knowledge from genome-wide association studies on Indigenous populations, as well as non-Indigenous populations with partial Indigenous ancestries from the American continent, focusing on disease susceptibility and anthropometric traits. While some studies identified risk alleles unique to Indigenous populations, their effects on trait variation are mostly small. I suggest that the associations rendered by many inter-population studies are probably inflated due to the absence of socio-cultural-economic covariates in the association models. I encourage the inclusion of admixed individuals in future GWAS studies to control for inter-ancestry differences in environmental factors. I suggest that some complex diseases might have arisen as trade-off costs of adaptations to past evolutionary selective pressures. Finally, I discuss how expanding panels with Indigenous ancestries in GWAS studies is key to accurately assess genetic risk in populations from the American continent, thus decreasing global health disparities.