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.

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Nature Communications
Published
2026-11-02
DOI
https://doi.org/10.1038/s41467-026-79107-2
Primary Topic
Hemoglobinopathies and Related Disorders
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article
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article

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

Shunmin He, Jiaofeng Qin, Mingyan Fang, Xinjiang Tan et al.
2 links
Nature Communications
Hemoglobinopathies and Related Disorders
article

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

Shunmin He, Jiaofeng Qin, Mingyan Fang, Xinjiang Tan, Tianyu Zhong, Jingyu Zeng, 林宛瑩, Shuhua Xu, 刘日阳, Narla Mohandas, Qiujun Liu, Ling Ling, Songyang Li, Honggui Qin, Qinlong Zeng, Xuemei Song, Shuquan Rao, Liuhua Liao, Yushan Huang, Lihong Zeng, Xin Jin, Deguo Tang, Jinquan Lao, Peng Zhang, Jin Li, Chao Shi Niu, Yang Gao, Xing‐Jiang Long, Yuhua Ye, Linxuan Li, Xiangmin Xu, Jinfu Cai, Xiaoyun Hua, Xianming Chen, Lian Deng, Lang Qin, Xinyue Liu, Huanhuan Zhu, Yumeng Sun, Xiaoman Zhou, Xiang Qu, Weijian Zhu, Yong Long, Xiaoqin Feng, Juanjuan Chen, Yanyan Li, Duonan Yu, Ziyi Yang, Kui Li, Weijie Chen, Xiang Guo, Bin Lin, Qianqian Zhang, Lian Yu, Jufang Tan, Yirong Shi, Lixiang Yan, Zhanping Lu, Yaoyun Li, Xinhua Zhang, Yueyan Huang, Yongzhong Zhao, Yidan Liang, Dan Xie, Xiaoyu Yan, Xia Tang, Binbin Huang, Zhijing Huang, Yan Chen, Chengwu Fan
article en

Abstract

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.

Nature Communications
BGI Group (China) (CN), Fujian Medical University (CN), New York Blood Center (US), University of Electronic Science and Technology of China (CN), Chongqing University (CN), Jinan University (CN), Shenzhen University (CN), Chinese Academy of Sciences (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Fudan University (CN), Shanghai Institute of Nutrition and Health (CN), Youjiang Medical College for Nationalities (CN), Nanfang Hospital (CN), Zhuhai People's Hospital (CN), Institute of Biophysics (CN), Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (CN), Affiliated Hospital of Youjiang Medical University for Nationalities (CN), First Affiliated Hospital of Gannan Medical University (CN), Fourth Affiliated Hospital of Guangxi Medical University (CN), Huizhou Central People's Hospital (CN), Institute of Hematology & Blood Diseases Hospital (CN), Chenzhou First People's Hospital (CN), Chinese People's Liberation Army (CN), Shenzhen Second People's Hospital (CN), University of Chinese Academy of Sciences (CN), BGI Research (CN), State Key Laboratory of Experimental Hematology (CN), Southern Medical University (CN), Yangzhou University (CN), Northwest A&F University (CN), South China University of Technology (CN)
National Natural Science Foundation of China
Good health and well-being
Openalex Percentile: Top 14%
Hemoglobinopathies and Related Disorders
DOIOpen Access PDFOpenAlex
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