Genetic substructure in Latin American individuals reveals novel associations, mechanistic insights, and variable polygenic risk score transferability for alcohol traits

Genome-wide association studies (GWAS) have substantially advanced our understanding of the genetic architecture underlying alcohol consumption. However, Latin American populations represent only ~ 1.8% of participants in current GWAS. Here, we present the largest GWAS meta-analysis of alcohol consumption in Latin American populations to date, analyzing 465,516 individuals through the Latin American Genomics Consortium (LAGC). We identified 14 independent loci, including 13 previously known associations and one novel locus in WRN . Multi-omic integrative network analysis revealed two functional modules: synaptic signaling pathways and inflammatory response mechanisms, extending beyond alcohol metabolism genes. Polygenic risk score (PRS) transferability varied substantially across Latin American subgroups. This study-derived PRS outperformed European-derived scores in South Americans and Puerto Ricans, while European PRS performed better in Mexicans and Cubans. Unsupervised genetic clustering confirmed that PRS performance depends on ancestral composition rather than geographic labels. These findings expand our understanding of the genetics of alcohol consumption in Latin Americans by identifying novel associations and demonstrating significant genetic heterogeneity within Latin American populations. Results underscore that population-specific approaches are essential to ensure broadly applicable genomic medicine.