55. DISSECTING THE ANCESTRY-SPECIFIC GENETIC ARCHITECTURE OF ALCOHOL CONSUMPTION IN LATIN AMERICANS

Genome-wide association studies (GWAS) have made substantial contributions to our understanding of the genetic factors that influence alcohol consumption. However, most efforts have been made in populations of European ancestry, resulting in less representation of other populations, with Latin American (LA) populations among the least represented, comprising less than 2% of the total GWAS participants. LA populations are characterized by varying degrees of genetic admixture from Indigenous American, European, and African ancestries, which creates challenges when modeling the genetic architecture of complex traits. However, recently developed GWAS approaches, such as Tractor, that leverage local ancestry information (defined as the genetic ancestry of an individual at a particular genomic location) could help overcome this challenge. This study, led by members of the Latin American Genomics Consortium (LAGC), is a meta-analysis of GWAS studies of self-reported alcohol consumption in 465,516 individuals from cohorts based in Latin American countries and the United States (US). We also conducted a local ancestry-aware GWAS on 11,655 LA individuals using Tractor. We replicated well-known genetic associations for alcohol consumption in genes that include the ADH locus (lead variant rs1229984, p-value = 1.12e-203) and others associated with psychiatric and behavioral traits, such as CADM2. We also identified a signal in the ALDH2 locus, previously associated only in East Asian populations. Using the local ancestry-aware GWAS, we identified associations in genes previously associated with the number of drinks consumed per week (Drkwk) by the GWAS and Sequencing Consortium of Alcohol and Nicotine use consortium (GSCAN), rs1874323 (p-value = 2.5860e-08) in the MAGI1 gene, and rs6833926 (p-value = 3.00e-08) in the ARAP2 gene. We also identified potential novel associations in the SLIT3 gene (rs73805262, p-value = 9.95e-09 and rs115143510, p-value = 1.23e-08), as well as one intergenic variant (rs3929849, p-value = 2.3930e-09) among segments of African-like ancestry. We also identified associations in intergenic regions of American-like descent (rs4130378, p-value = 9.673e-09; rs536315876, p-value = 4.3640e-09; rs115675116, p-value = 4.3190e-09). Nevertheless, given the small sample size in the local ancestry-aware GWAS, these results required further replication. We also compared the association of the polygenic risk score (PRS) derived from the European population using GSCAN (PRS-EUR) data with the PRS from our large-scale meta-analysis (PRS-LA), examining the relationship with drinks consumed per week in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort, identifying a heterogeneity in the transferability of the PRS across geographical LA subgroups. We identified that both the PRS-EUR and PRS-La were associated with Drkwk in individuals from Puerto Rico (PRS-EUR, p-value = 7.40e-03; PRS-LA, p-value = 1.40e-02); meanwhile, only the PRS-EUR was associated in individuals from Mexico (p-value = 7.41e-3) and Cuba (p-value = 1.31e-02), and only the PRS-LA was associated in individuals from South America (p-value = 3.23e-02) Our study contributes to current efforts to elucidate the genetic architecture of alcohol consumption in Latin American populations, implicating novel genes (such as WRN) and revealing varying performance of PRS across different geographical subgroups.