<i>ESR1</i> Variants and Subcontinental Genomic Ancestry: Insights from the 1000 Genomes Project and Native American Populations

The ESR1 gene is relevant in breast cancer treatments in the pharmacogenetics context. However, Native, African, and mixed populations are known to be underrepresented in genomic studies. This is particularly important given that the difference in variants' frequencies among different populations can lead to population-specific clinical implications. Therefore, this study aims to infer the genomic subcontinental ancestry and allele frequencies of the ESR1 gene variants in 2,427 individuals from 26 populations worldwide from the 1000 Genomes Project and 125 Natives from Peru, whose genomes have not yet been analyzed in the literature regarding this gene. Linear regression with Bonferroni correction analyses was conducted based on ancestry inference and frequencies. Our findings demonstrate subcontinental differentiation of African, Asian, European, and Native populations. Overall, 102 associations (P < 0.01) were found for 68 clinically relevant variants. Particularly, subcontinental associations were observed for variants associated with the Native, Asian, European, and African components. We highlight the findings for the rs9349799 and rs2234693 variants, previously associated with altered responses to breast cancer treatments. rs9349799 was positively associated with the South-Asian component, while rs2234693 was negatively associated with the Coast/Amazonian Native and positively associated with the East-African component. Nearly half of the variants are intronic, highlighting the importance of studying whole genomes rather than just exomes. These results emphasize subcontinental differences' relevance for designing pharmacogenetic panels. Including neglected populations in genomic and pharmacogenomic studies is essential for democratic access to scientific advances and for more egalitarian and effective pharmacogenetic implementation, tailored to each population's specificities.