Common and rare variant associations with clonal haematopoiesis phenotypes

Michael D. Kessler, Amy Damask, Sean O’Keeffe, Nilanjana Banerjee, Dadong Li, Kyoko Watanabe, Anthony Marketta, Michael Meter, Stefan Semrau, Julie Horowitz, Jing Tang, Jack A. Kosmicki, Veera M. Rajagopal, Yuxin Zou, Yariv Houvras, Arkopravo Ghosh, Christopher Gillies, Joelle Mbatchou, Ryan R. White, Niek Verweij, Jonas Bovijn, Neelroop N. Parikshak, Michelle G. LeBlanc, Marcus Jones, David J. Glass, Luca A. Lotta, Michael N. Cantor, Gurinder S. Atwal, Adam E. Locke, Manuel A. R. Ferreira, Raquel Deering, Charles Paulding, Alan R. Shuldiner, Gavin Thurston, Adolfo A. Ferrando, Will Salerno, Jeffrey G. Reid, John D. Overton, Jonathan Marchini, Hyun M. Kang, Aris Baras, Gonçalo R. Abecasis and Eric Jorgenson ()
Additional contact information
Michael D. Kessler: Regeneron Genetics Center
Amy Damask: Regeneron Genetics Center
Sean O’Keeffe: Regeneron Genetics Center
Nilanjana Banerjee: Regeneron Genetics Center
Dadong Li: Regeneron Genetics Center
Kyoko Watanabe: Regeneron Genetics Center
Anthony Marketta: Regeneron Genetics Center
Michael Meter: Regeneron Pharmaceuticals
Stefan Semrau: Regeneron Pharmaceuticals
Julie Horowitz: Regeneron Genetics Center
Jing Tang: Regeneron Genetics Center
Jack A. Kosmicki: Regeneron Genetics Center
Veera M. Rajagopal: Regeneron Genetics Center
Yuxin Zou: Regeneron Genetics Center
Yariv Houvras: Regeneron Pharmaceuticals
Arkopravo Ghosh: Regeneron Genetics Center
Christopher Gillies: Regeneron Genetics Center
Joelle Mbatchou: Regeneron Genetics Center
Ryan R. White: Regeneron Pharmaceuticals
Niek Verweij: Regeneron Genetics Center
Jonas Bovijn: Regeneron Genetics Center
Neelroop N. Parikshak: Regeneron Genetics Center
Michelle G. LeBlanc: Regeneron Genetics Center
Marcus Jones: Regeneron Genetics Center
David J. Glass: Regeneron Pharmaceuticals
Luca A. Lotta: Regeneron Genetics Center
Michael N. Cantor: Regeneron Genetics Center
Gurinder S. Atwal: Regeneron Pharmaceuticals
Adam E. Locke: Regeneron Genetics Center
Manuel A. R. Ferreira: Regeneron Genetics Center
Raquel Deering: Regeneron Pharmaceuticals
Charles Paulding: Regeneron Genetics Center
Alan R. Shuldiner: Regeneron Genetics Center
Gavin Thurston: Regeneron Pharmaceuticals
Adolfo A. Ferrando: Regeneron Genetics Center
Will Salerno: Regeneron Genetics Center
Jeffrey G. Reid: Regeneron Genetics Center
John D. Overton: Regeneron Genetics Center
Jonathan Marchini: Regeneron Genetics Center
Hyun M. Kang: Regeneron Genetics Center
Aris Baras: Regeneron Genetics Center
Gonçalo R. Abecasis: Regeneron Genetics Center
Eric Jorgenson: Regeneron Genetics Center

Nature, 2022, vol. 612, issue 7939, 301-309

Abstract: Abstract Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes1–5. 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 exomes6, 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.

Date: 2022
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DOI: 10.1038/s41586-022-05448-9

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