Common and rare variant associations with clonal haematopoiesis phenotypes
Open accessAbstract
Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes 1-5. Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75, which are associated with reduced incidence of CHIP. We also identify novel rare variant associations with clonal haematopoiesis and telomere length. Analysis of 5,041 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID-19 outcomes, cardiovascular disease, haematologic traits, malignancy, smoking, obesity, infection and all-cause mortality. Longitudinal and Mendelian randomization analyses revealed that CHIP is associated with solid cancers, including non-melanoma skin cancer and lung cancer, and that CHIP linked to DNMT3A is associated with the subsequent development of myeloid but not lymphoid leukaemias. Additionally, contrary to previous findings from the initial 50,000 UKB exomes 6, our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogeneous phenotypes with shared and unique germline genetic causes and varied clinical implications.
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Two recent studies investigating CHIP variants primarily using whole-exome sequencing data from blood cells found no effect or a protective effect on Alzheimer's disease risk.
“Two recent studies investigating CHIP variants primarily using whole-exome sequencing (WES) data from blood cells found no effect24 or a protective effect25 on AD risk.”
From Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states (2026) · cites this paper as [24]
The paper describes identifying CHIP carriers using exome sequencing data, but the passages from its Phenotypic associations and Longitudinal disease risk sections do not report an Alzheimer’s disease result. Searches for Alzheimer’s disease, AD risk, and dementia found no passage establishing the attributed finding of no effect on Alzheimer’s risk. (LLM, conf=0.72)
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- Authors
- Kessler, M. D., Damask, A., O’Keeffe, S., Banerjee, N., Li, D., Watanabe, K., Marketta, A., Van Meter, M., Semrau, S., Horowitz, J., Tang, J., Kosmicki, J. A., Rajagopal, V. M., Zou, Y., Houvras, Y., Ghosh, A., Gillies, C., Mbatchou, J., White, R. R., Verweij, N., Bovijn, J., Parikshak, N. N., LeBlanc, M. G., Jones, M., Regeneron Genetics Center, GHS-RGC DiscovEHR Collaboration, Glass, D. J., Lotta, L. A., Cantor, M. N., Atwal, G. S., Locke, A. E., Ferreira, M. A. R., Deering, R., Paulding, C., Shuldiner, A. R., Thurston, G., Ferrando, A. A., Salerno, W., Reid, J. G., Overton, J. D., Marchini, J., Kang, H. M., Baras, A., Abecasis, G. R., & Jorgenson, E.
- Affiliations
- Regeneron (United States) (US)
- Corresponding author
- Jorgenson, Eric
- ORCID
- Kessler, Michael D.
- Damask, Amy
- O’Keeffe, Sean
- Banerjee, Nilanjana
- Li, Dadong
- Watanabe, Kyoko
- Horowitz, Julie
- Tang, Jing
- Kosmicki, Jack A.
- Rajagopal, Veera M.
- Zou, Yuxin
- Houvras, Yariv
- Ghosh, Arkopravo
- Gillies, Christopher
- Mbatchou, Joelle
- White, Ryan R.
- Verweij, Niek
- Bovijn, Jonas
- Parikshak, Neelroop N.
- LeBlanc, Michelle G.
- Jones, Marcus
- Glass, David J.
- Lotta, Luca A.
- Cantor, Michael N.
- Atwal, Gurinder S.
- Locke, Adam E.
- Ferreira, Manuel A. R.
- Deering, Raquel
- Paulding, Charles
- Shuldiner, Alan R.
- Thurston, Gavin
- Ferrando, Adolfo A.
- Reid, Jeffrey G.
- Overton, John D.
- Marchini, Jonathan
- Kang, Hyun M.
- Baras, Aris
- Abecasis, Gonçalo R.
- Jorgenson, Eric
- Venue
- Nature
- Published
- 2022-11-30
- Volume
- 612
- Issue
- 7939
- Pages
- 301-309
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9713173
- OpenAlex
- W4310439055
- Cited by
- 313
- References
- 10
- Citations by year
- 2026: 61 · 2025: 95 · 2024: 97 · 2023: 57 · 2022: 3
- FWCI
- 46.24
- Type
- journal article
- Language
- en
- Update notices
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Medical Research Council (MC_PC_17228)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- clonal hematopoiesis of indeterminate potential, germline genetic variants, rare variant association, genetic susceptibility loci, telomere length, COVID-19 severity, cardiovascular disease, non-melanoma skin cancer, lung cancer, myeloid leukemia, DNMT3A, IL-6 inhibition, cancer susceptibility
- MeSH terms
- Clonal Hematopoiesis, COVID-19, Cardiovascular Diseases, Humans
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