Diversity in a dish: Leveraging organoids to reflect genetic ancestry and sex differences in health and disease

The interplay between genetic ancestry and biological sex is increasingly recognized as a critical factor influencing health outcomes, treatment efficacy, and drug toxicity. Current research highlights significant disparities in disease susceptibility and therapeutic responses across different ancestral groups and sexes, with underrepresentation of diverse populations in genomic studies impeding progress. Most Genome-Wide Association Studies (GWAS) remain predominantly European, hindering the development of accurate polygenic risk scores (PRS). Additionally, sex-related differences in drug metabolism, immune response, and disease prevalence necessitate sex-stratified analyses. This review underscores the potential of advanced in vitro models, particularly human pluripotent stem cells (hPSCs) and adult stem cell-derived organoids, to bridge these gaps by providing platforms that reflect human genetic diversity and facilitate high-throughput screening. By integrating diverse genetic data and leveraging donor/population-specific organoid models, researchers can uncover critical genotype-phenotype associations that enhance understanding of health disparities and improve pharmacogenomic applications. To increase reproducibility and throughput, standardized protocols, automation, organoid arrays, and well-controlled pooled populations can streamline workflows and enhance repeatability across studies and geographies. This approach fosters personalized medicine aimed at optimizing treatment efficacy and reducing adverse reactions across diverse populations, promoting equitable healthcare outcomes.