01874nas a2200277   4500000000100000000000100001008004100002260001500043653002200058653003600080653002600116100001700142700001800159700001200177700001600189700001800205700001200223700002000235700001400255700002100269245009500290856005500385300000800440520113400448022001401582       2026                            d  c2026-09-1410aGenetics research10aGenome-wide association studies10aPersonalized medicine1 aKristin Tsuo1 aZhuozheng Shi1 aTian Ge1 aRavi Mandla1 aKangcheng Hou1 aYi Ding1 aBogdan Pasaniuc1 aYing Wang1 aAlicia R. Martin00aAll of Us diversity and scale yield context-dependent improvements in polygenic prediction  uhttps://www.nature.com/articles/s41588-026-02734-4  a1-93 aPolygenic 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.  a1546-1718