Biomedical subjects

Kristin Tsuo

Publications and source records attributed to Kristin Tsuo.

3 recordsLinked to original sources

PubMed2026

All of Us diversity and scale yield context-dependent improvements in polygenic prediction.

Polygenic risk scores (PRSs) trained on multiancestry data can improve prediction in under-represented groups, but large linked genetic and health datasets capturing broad human diversity remain limited. Using 245,388 whole-genome sequences from the All of Us research program (AoU) together with UK Biobank data, we developed multiancestry PRSs for 32 traits and diseases. We evaluated how ancestry, methodology and genetic architecture influenced PRS performance across ancestrally diverse AoU participants. Increased diversity in the AoU improved PRS accuracy for several traits, especially in under-represented populations. However, maximizing sample size by meta-analyzing AoU and UK Biobank was not universally optimal: for less polygenic traits, AoU-only training performed best in African ancestry participants, consistent with ancestry-enriched effects. Individual PRS accuracy declined linearly with increasing ancestry divergence from the discovery GWAS, but this decay was attenuated using multiancestry training data. These findings underscore the value of more representative biobanks for equitable PRS performance.

Journal Article↗

PubMed2025

Multipopulation GWAS for venous thromboembolism identifies novel loci followed by experimental validation in zebrafish.

Venous thromboembolisms (VTEs) are a leading cause of morbidity and mortality. Although many genetic risk factors have been identified, a substantial portion of the heritability remains unexplained. In this study, we employed a genome-wide association study (GWAS) for VTE across 9 international cohorts of the Global Biobank Meta-Analysis Initiative to address this question, along with in vivo functional validation. In this multipopulation GWAS (VTE cases, 27 987; controls, 1 035 290), 38 genome-wide significant loci were identified, 4 of which were potentially novel. For each autosomal locus, we performed gene prioritization using 7 independent, yet converging, lines of evidence. Through prioritization, we identified genes associated with VTE through GWAS and/or functional studies (eg, F5, F11, VWF, STAB2, PLCG2, TC2N), functionally validated those that did not have evidence other than GWAS (TC2N, TSPAN15), and discovered 1 not previously associated with coagulation (RASIP1). We evaluated the function of 6 prioritized genes with strong genetic evidence, including F7 as a positive control, using laser-mediated endothelial injury to induce thrombosis in zebrafish after CRISPR/Cas9 knockdown. From this assay, we have supportive evidence for the role of RASIP1 and TC2N in the modification of human VTE and suggestive evidence for STAB2 and TSPAN15. This study expands on the currently identified genomic architecture of VTE through biobank-based, multipopulation GWASs, in silico candidate gene predictions, and in vivo functional follow-up of candidate genes.

Zebrafish↗

PubMed2023

Low and differential polygenic score generalizability among African populations due largely to genetic diversity.

African populations are vastly underrepresented in genetic studies but have the most genetic variation and face wide-ranging environmental exposures globally. Because systematic evaluations of genetic prediction had not yet been conducted in ancestries that span African diversity, we calculated polygenic risk scores (PRSs) in simulations across Africa and in empirical data from South Africa, Uganda, and the United Kingdom to better understand the generalizability of genetic studies. PRS accuracy improves with ancestry-matched discovery cohorts more than from ancestry-mismatched studies. Within ancestrally and ethnically diverse South African individuals, we find that PRS accuracy is low for all traits but varies across groups. Differences in African ancestries contribute more to variability in PRS accuracy than other large cohort differences considered between individuals in the United Kingdom versus Uganda. We computed PRS in African ancestry populations using existing European-only versus ancestrally diverse genetic studies; the increased diversity produced the largest accuracy gains for hemoglobin concentration and white blood cell count, reflecting large-effect ancestry-enriched variants in genes known to influence sickle cell anemia and the allergic response, respectively. Differences in PRS accuracy across African ancestries originating from diverse regions are as large as across out-of-Africa continental ancestries, requiring commensurate nuance.

Humans↗