Citations 1
Genomic and phenomic landscape of clonal hematopoiesis in over a million ancestrally diverse participants
Uddin, Md Mesbah , Weinstock, Joshua S. , Niroula, Abhishek , Vlasschaert, Caitlyn , Koyama, Satoshi , Nakao, Tetsushi , Urbut, Sarah , Paruchuri, Kaavya , Silver, Alexander J. , Mack, Taralynn , Wong, Megan , Bhattacharya, Romit , Jorshery, Saman Doroodgar , Raddatz, Michael A. , Hornsby, Whitney , Kresge, Hailey A. , Cho, Kelly , Sun, Yan V. , Pyarajan, Saiju , Chen, Yii‐Der Ida , Sheu, Wayne H-H , Hung, Yi‐Jen , Hidalgo, Bertha , Fornage, Myriam , Kaplan, Robert C., Williams, L. Keoki , Province, Mike , Kardia, Sharon, Peyser, Patricia A., Yanek, Lisa R. , Becker, Lewis C. , Meyers, Deborah A. , Naseri, Take, Barnes, Kathleen C. , Redline, S S, Schwartz, D A, Shoemaker, M. Benjamin , Palmer, Nicholette D., Bowden, Donald W., Kumar, Rajesh, Nj, Smith, Floyd, James, Tracy, Russell, Bis, Joshua C. , SS, Rich, Boerwinkle, Eric, Wang, Zhe, Silverman, Edwin K. , Auer, Paul L. , Reiner, Alexander P. , Ebert, Benjamin L. , Natarajan, Pradeep , Uddin, Md M , Niroula, Abhishek , Weinstock, Joshua S , Bhattacharya, Romit , Ebert, Benjamin L , Natarajan, Pradeep , Yu, Zhi , Zekavat, Seyedeh M , Truong, Buu Minh Thanh , Haidermota, Sara , Honigberg, Michael C. , Zhang, Martin Jinye , Dron, Jacqueline S. , Heimlich, Jonathan Brett , Sankaran, Vijay G. , Griffin, Gabriel K. , Gibson, Christopher James , Wilson, Peter W.F. , Genovese, Giulio , Xu, Yaomin , Savona, Michael R. , Raffield, Laura M. , Arnett, Donna K. , Konkle, Barbara A. , Peyser, Patricia A. , Smith, Jennifer A. , Mathias, Rasika A. , Andrade, Mariza de , Darbar, Dawood , He, Jiang , Blangero, John , Weiss, Scott T. , Custer, Brian , Minster, Ryan L , Viali, Satupaitea , Mitchell, Braxton D. , Palmer, Nicholette D , Freedman, Barry I. , Bowden, Donald W. , Albert, Christine M. , Smith, Nicholas, Tracy, Russell P. , Psaty, Bruce M. , Taylor, Kent D. , Rotter, Jerome I. , Boerwinkle, Eric , Vasan, Ramachandran S. , Lubitz, Steven A. , Ellinor, Patrick T. , Loos, Ruth J. F. , Yun, Jeong H. , Cho, Michael H. , Abecasis, Gonçalo R. , Kooperberg, Charles , Reiner, Alex P. , Jaiswal, Siddhartha , Bick, Alexander G.
No container title available | July 31, 2022 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract With aging, somatic mutations in hematopoietic stem and progenitor cells (HSPC) can give rise to clonal hematopoiesis of indeterminate potential (CHIP), a premalignant state associated with diverse age-related diseases. Here we report the largest multi-ancestry genome-wide analysis of CHIP to date (N = 1,018,305), including individuals of African (N = 85,978), Admixed American (N = 191,371), East Asian (N = 13,532), European (N = 694,015), and South Asian (N = 13,193) ancestry. Multi-ancestry meta-analyses identified 72 genome-wide significant loci, including 44 novel associations implicating genes such as AFF1 , ATF7IP , ATP8B4 , BCL2 , CEBPA , CYRIA , DNM2 , ELF1 , NKX2-3 , PIK3CB , PRDM16 , RPN1 , TERC , and TRIM4 . Notably, variants at MECOM and PHF20L1 showed opposite allelic effects between DNMT3A - and non- DNMT3A -driven CHIP, highlighting driver-specific germline influences. Implicated loci converge on pathways regulating telomere maintenance, cell-cycle control, hematopoietic transcription, DNA damage response and immune signaling. These findings support a model in which germline variation both expands the HSPC pool and biases clonal selection in a driver-dependent manner, providing a mechanistic basis for inter-individual heterogeneity in CHIP. Phenome-wide association analyses further linked CHIP to hematologic, neoplastic, and circulatory traits, with enrichment across hematopoietic and non-hematopoietic cell types. Together, this work expands the genomic and phenomic landscape of CHIP and reveals germline–somatic interactions that shape clonal evolution during aging.