The Genome Atlas of 1,020 Probands and 409 Unaffected Parents Decodes the Clinical Heterogeneity in β-thalassemia

β-thalassemia is an extensively studied monogenic disorder, yet the basis of its striking phenotypic diversity remains unresolved. Here we present the 1000 β-Thalassemia Genomes Project (KbTGP), providing the first comprehensive atlas of 1,429 Chinese genomes (1,020 probands and 409 unaffected parents, 61.63× coverage) linked to 77 clinical traits. We identify 11 independent phenotype-associated loci in probands, and 15 additional loci by integrating 2,746 ethnically matched controls from the NyuWa Project and the 1000 Genomes Project. Functional experiments further highlight non-coding regions at 17p13.3 and the autophagy-related gene PIK3C3 as modulators of thalassemic phenotypes. Loss-of-function structural variants are enriched in hemoglobinopathy-related genes, and structural variants in TF and SLC25A37 are significantly associated with iron metabolism and fetal hemoglobin, respectively. Notably, de novo structural variants and clonal hematopoiesis mutations are enriched in severe cases. These findings collectively establish a phenome-genome resource that delineates the genetic architecture of β-thalassemia, offering candidate targets for precision therapies and laying the groundwork for future research into dissecting the Mendelian disease variability. The authors sequence 1020 Chinese patients with beta thalassemia and 409 unaffected parents to identify genes that modulate the phenotypes. Functional validation in mice and cultured cells confirm the role of autophagy-associated gene PIK3C3.