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

The paper addresses how genetic ancestry and biological sex contribute to variability in health outcomes, disease susceptibility, drug efficacy, and toxicity. It highlights persistent underrepresentation of non-European populations in genetic studies, which limits discovery and accurate risk prediction (e.g., PRS). The review motivates the need for inclusive, human-relevant preclinical models to better understand genotype–phenotype relationships across ancestries and sexes and to reduce health disparities. It frames organoids derived from hPSCs and adult stem cells as platforms to capture human diversity for pharmacogenomics and disease modeling.

The review synthesizes evidence that health and drug-response disparities are linked to ancestry and sex. It notes that although nearly half of GWAS include non-European participants, about 79% of samples are still European, limiting locus fine-mapping and PRS transferability. Examples include ancestry-specific disease mutations (e.g., CFTR ΔF508 ~70% in Caucasians vs <30% in Africans; transthyretin V122I in African ancestry) and pharmacogenomic variants (HLA-B*57:01—abacavir; HLA-B*15:02—carbamazepine; CYP2C19—clopidogrel; CYP2D6, SLCO1B1). It discusses PRS miscalibration (schizophrenia PRS overestimates risk ~10× in Africans) and sex differences in immunity, disease prevalence, and pharmacokinetics (e.g., higher autoimmune disease in women; more ADR reports in women; female-specific risks revealed post hoc in WHI and drug withdrawals). Table 1 summarizes disease prevalence patterns across ancestry and sex, while Table 2 compiles ancestry- and sex-associated ADR susceptibilities across drugs (e.g., warfarin, statins, tacrolimus, tamoxifen, trastuzumab, docetaxel, platinum agents, SRIs). The review emphasizes nuances within broad descriptors such as "African" or "Asian," highlighting within-continent genetic diversity (e.g., G6PD variants differences among South African groups).

As a narrative review, no primary experimental methods were performed. The paper outlines methodological frameworks for modeling human diversity using organoids: (1) Individual organoid lines cultured in parallel, including micro-engineered hydrogel substrates and microcavity arrays to standardize growth and create high-throughput organoid arrays, reducing technical variability and enabling reproducible phenotypic assays. (2) Pooled "village-in-a-dish" approaches that mix cells from multiple donors into single cultures to scale diversity representation. Two pooled strategies are highlighted: Chimeroids (multi-donor brain organoids assembled from independently formed early organoids, enabling single-cell RNA-seq to trace donor contributions and assess interindividual responses to perturbagens) and Population Organoid Panels (PoP), in which mixed clonal progenitors generate mosaic organoids; >90% of each organoid originates from a unique donor, verifiable by donor-specific genomic PCR, allowing organoid-level phenotyping via imaging and immunostaining. The paper also details practical considerations for sex modeling in hPSC organoids, including the need to select lines with stable X chromosome inactivation (XCI), monitor XIST expression, and employ allele-specific expression analyses; alternatively, adult stem cell organoids retain stable XCI and are suitable for sex-specific studies across multiple tissues. It describes integration with automation, standardized assays and readouts, and gene-editing to model specific variants across ancestries. Finally, it discusses building diverse organoid biobanks and leveraging regulatory pathways (e.g., FDA ISTAND) to qualify models for drug discovery.

- Underrepresentation persists: Although nearly half of GWAS include non-European participants, ~79% of samples are still European, limiting PRS transferability and fine-mapping. Schizophrenia PRS can overestimate risk ~10-fold in African populations. - Ancestry-specific variants impact disease and drug response: Examples include CFTR ΔF508 (~70% Caucasians vs <30% Africans), TTR V122I in African ancestry, population-specific HLA risk alleles (HLA-B*57:01—abacavir hypersensitivity; HLA-B*15:02—carbamazepine SJS/TEN), and CYP2C19 variants affecting clopidogrel activation. CYP3A5*1 carriers (more common in African ancestry) require higher tacrolimus doses. - Sex-specific biology affects outcomes: Women show stronger immune responses, higher autoimmune disease prevalence, and approximately twice the ADR reports vs men; several drugs historically withdrawn had higher adverse events in women. Sex hormones modulate pharmacokinetics; sex-stratified analyses are needed. - Organoids capture diversity and reveal novel insights: African ancestry patient-derived breast cancer organoids identified essential kinases via CRISPR-Cas9 screening; African American prostate cancer organoids recapitulated aggressive molecular alterations. Brain organoid Chimeroids revealed interindividual susceptibility to neurotoxins (ethanol, valproic acid). Adult stem cell colonoids linked male-biased KDM5D upregulation to invasiveness and immune evasion in CRC, matching worse outcomes in men. - Practical modeling strategies: Microcavity/hydrogel organoid arrays increase reproducibility; pooled systems (Chimeroids, PoP) enable scaled diversity assays, with PoP producing mosaic organoids where >90% of each organoid often derives from a unique donor. - Policy and infrastructure: DEPICT and FDORA mandate diversity planning in clinical trials; FDA Modernization Act 2.0 encourages human-based models. HLA-homozygous iPSC haplobanks (e.g., CiRA) and initiatives like FinnGen and emerging African iPSC resources can support globally relevant organoid models. - Clinical implications summarized in tables: Table 1 details ancestry/sex disease prevalence differences; Table 2 compiles ADR risks and genetic/sex modifiers across major drugs (e.g., elevated warfarin bleeding risk in African ancestry; higher docetaxel neutropenia in East Asians; statin myopathy linked to SLCO1B1 c.521T>C; sex-linked differences in levodopa-induced dyskinesia).

The review argues that organoids derived from genetically diverse and sex-balanced donors can address biases inherent in current genomic and clinical datasets by enabling mechanistic, scalable, and human-relevant studies. By modeling ancestry- and sex-specific biology, organoids can improve pharmacogenomic prediction, refine dosing (e.g., CYP- and HLA-associated risks), and better anticipate ADRs in underrepresented populations. Standardized and automated organoid platforms can reduce experimental variability, while pooled approaches increase throughput and statistical power to detect genetic effects. Integration with regulatory initiatives (DEPICT, FDORA, FDA Modernization Act 2.0) and validation pathways (ISTAND) can accelerate adoption in drug development. The paper emphasizes building regionally representative biobanks and ethical, culturally sensitive engagement to improve global equity. Overall, the findings support organoids as pivotal tools to connect genotype to phenotype across ancestries and sexes, thereby enhancing precision medicine and reducing health disparities.

This review highlights organoids as versatile, physiologically relevant platforms to model ancestry- and sex-linked differences in health, disease, and drug response. It synthesizes evidence of substantial disparities in GWAS representation, PRS performance, disease prevalence, and pharmacogenomics—then outlines technical strategies (organoid arrays, Chimeroids, PoP, automation, standardized assays, gene editing) to incorporate diversity early in preclinical pipelines. The authors call for expanding diverse donor biobanks, improving standardization and high-throughput phenotyping, integrating detailed clinical metadata and computational modeling, and leveraging regulatory pathways for qualification. Future work should prioritize regional capacity building, North–South collaborations, ethical governance of biospecimens, and large-scale pooled organoid studies to capture rare and population-specific variants. These efforts can enhance translatability, safety, and efficacy of therapies across global populations.

- As a narrative review, it does not present new primary data; conclusions rely on published literature and illustrative case studies. - Access to diverse donor samples remains limited; existing stem cell and organoid biobanks are skewed toward Northern European ancestry, constraining generalizability. - hPSC-derived organoids face challenges modeling sex differences due to unstable X chromosome inactivation; careful line selection and monitoring are required. Adult stem cell organoids mitigate this but are tissue-limited. - Large sample sizes are needed to capture within-population diversity and rare variants, especially in highly diverse groups (e.g., African and Latin American populations). - Experimental variability across donor lines and differentiation batches persists despite advances; broad standardization and automation are still being adopted. - Ethical, legal, and cultural considerations around consent, sample sharing, and data governance may limit global representativeness of biobanks.