Determinants of mosaic chromosomal alteration fitness

Yash Pershad; Taralynn Mack; Hannah Poisner; Yasminka A. Jakubek; Adrienne M. Stilp; Braxton D. Mitchell; Joshua P. Lewis; Eric Boerwinkle; Ruth J.F. Loos; Nathalie Chami; Zhe Wang; Kathleen Barnes; Nathan Pankratz; Myriam Fornage; Susan Redline; Bruce M. Psaty; Joshua C. Bis; Ali Shojaie; Edwin K. Silverman; Michael H. Cho; Jeong H. Yun; Dawn DeMeo; Daniel Levy; Andrew D. Johnson; Rasika A. Mathias; Margaret A. Taub; Donna Arnett; Kari E. North; Laura M. Raffield; April P. Carson; Margaret F. Doyle; Stephen S. Rich; Jerome I. Rotter; Xiuqing Guo; Nancy J. Cox; Dan M. Roden; Nora Franceschini; Pinkal Desai; Alex P. Reiner; Paul L. Auer; Paul A. Scheet; Siddhartha Jaiswal; Joshua S. Weinstock; Alexander G. Bick

doi:10.1038/s41467-024-48190-8

Determinants of mosaic chromosomal alteration fitness

Yash Pershad, Taralynn Mack, Hannah Poisner, Yasminka A. Jakubek, Adrienne M. Stilp, Braxton D. Mitchell, Joshua P. Lewis, Eric Boerwinkle, Ruth J.F. Loos, Nathalie Chami, Zhe Wang, Kathleen Barnes, Nathan Pankratz, Myriam Fornage, Susan Redline, Bruce M. Psaty, Joshua C. Bis, Ali Shojaie, Edwin K. Silverman, Michael H. ChoJeong H. Yun, Dawn DeMeo, Daniel Levy, Andrew D. Johnson, Rasika A. Mathias, Margaret A. Taub, Donna Arnett, Kari E. North, Laura M. Raffield, April P. Carson, Margaret F. Doyle, Stephen S. Rich, Jerome I. Rotter, Xiuqing Guo, Nancy J. Cox, Dan M. Roden, Nora Franceschini, Pinkal Desai, Alex P. Reiner, Paul L. Auer, Paul A. Scheet, Siddhartha Jaiswal, Joshua S. Weinstock, Alexander G. Bick

Research output: Contribution to journal › Article › peer-review

Abstract

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R² = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Original language	English
Article number	3800
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-48190-8
State	Published - Dec 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

We thank the studies and participants who provided biological samples and data for the NHLBI TOPMed Consortium. WGS for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample identity quality control, and general study coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). The full study-specific acknowledgments are included in the Supplementary Materials. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. We wish to acknowledge the contributions of the consortium working on the development of the NHLBI BioData Catalyst ecosystem. This work was supported by National Institutes of Health grant R01AG083736 (A.G.B., P.L.A., P.A.S.), National Institutes of Health grant R01HL117626, National Institutes of Health contract HHSN268201800002I, National Institutes of Health grant R01HL120393, National Institutes of Health grant U01HL120393, National Institutes of Health contract HHSN268201800001I, National Institutes of Health grant DP5OD029586 (A.G.B.), Burroughs Wellcome Foundation Career Award for Medical Scientists (A.G.B. and S.J.), NHLBI BioData Catalyst Fellowship (J.S.W.), and National Institutes of Health grant T32GM007347 (Y.P.).

Funders	Funder number
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
U.S. Department of Health and Human Services	U01HL-120393, R01AG083736, R01HL120393, DP5OD029586, R01HL117626
U.S. Department of Health and Human Services
TOPMed Informatics Research Center	HHSN268201800001I, HHSN268201800002I, 3R01HL-117626-02S1
Burroughs Wellcome Fund	T32GM007347
Burroughs Wellcome Fund

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-024-48190-8

Cite this

Pershad, Y., Mack, T., Poisner, H., Jakubek, Y. A., Stilp, A. M., Mitchell, B. D., Lewis, J. P., Boerwinkle, E., Loos, R. J. F., Chami, N., Wang, Z., Barnes, K., Pankratz, N., Fornage, M., Redline, S., Psaty, B. M., Bis, J. C., Shojaie, A., Silverman, E. K., ... Bick, A. G. (2024). Determinants of mosaic chromosomal alteration fitness. Nature Communications, 15(1), Article 3800. https://doi.org/10.1038/s41467-024-48190-8

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title = "Determinants of mosaic chromosomal alteration fitness",

abstract = "Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.",

author = "Yash Pershad and Taralynn Mack and Hannah Poisner and Jakubek, {Yasminka A.} and Stilp, {Adrienne M.} and Mitchell, {Braxton D.} and Lewis, {Joshua P.} and Eric Boerwinkle and Loos, {Ruth J.F.} and Nathalie Chami and Zhe Wang and Kathleen Barnes and Nathan Pankratz and Myriam Fornage and Susan Redline and Psaty, {Bruce M.} and Bis, {Joshua C.} and Ali Shojaie and Silverman, {Edwin K.} and Cho, {Michael H.} and Yun, {Jeong H.} and Dawn DeMeo and Daniel Levy and Johnson, {Andrew D.} and Mathias, {Rasika A.} and Taub, {Margaret A.} and Donna Arnett and North, {Kari E.} and Raffield, {Laura M.} and Carson, {April P.} and Doyle, {Margaret F.} and Rich, {Stephen S.} and Rotter, {Jerome I.} and Xiuqing Guo and Cox, {Nancy J.} and Roden, {Dan M.} and Nora Franceschini and Pinkal Desai and Reiner, {Alex P.} and Auer, {Paul L.} and Scheet, {Paul A.} and Siddhartha Jaiswal and Weinstock, {Joshua S.} and Bick, {Alexander G.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41467-024-48190-8",

language = "English",

volume = "15",

number = "1",

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Pershad, Y, Mack, T, Poisner, H, Jakubek, YA, Stilp, AM, Mitchell, BD, Lewis, JP, Boerwinkle, E, Loos, RJF, Chami, N, Wang, Z, Barnes, K, Pankratz, N, Fornage, M, Redline, S, Psaty, BM, Bis, JC, Shojaie, A, Silverman, EK, Cho, MH, Yun, JH, DeMeo, D, Levy, D, Johnson, AD, Mathias, RA, Taub, MA, Arnett, D, North, KE, Raffield, LM, Carson, AP, Doyle, MF, Rich, SS, Rotter, JI, Guo, X, Cox, NJ, Roden, DM, Franceschini, N, Desai, P, Reiner, AP, Auer, PL, Scheet, PA, Jaiswal, S, Weinstock, JS & Bick, AG 2024, 'Determinants of mosaic chromosomal alteration fitness', Nature Communications, vol. 15, no. 1, 3800. https://doi.org/10.1038/s41467-024-48190-8

TY - JOUR

T1 - Determinants of mosaic chromosomal alteration fitness

AU - Pershad, Yash

AU - Mack, Taralynn

AU - Poisner, Hannah

AU - Jakubek, Yasminka A.

AU - Stilp, Adrienne M.

AU - Mitchell, Braxton D.

AU - Lewis, Joshua P.

AU - Boerwinkle, Eric

AU - Loos, Ruth J.F.

AU - Chami, Nathalie

AU - Wang, Zhe

AU - Barnes, Kathleen

AU - Pankratz, Nathan

AU - Fornage, Myriam

AU - Redline, Susan

AU - Psaty, Bruce M.

AU - Bis, Joshua C.

AU - Shojaie, Ali

AU - Silverman, Edwin K.

AU - Cho, Michael H.

AU - Yun, Jeong H.

AU - DeMeo, Dawn

AU - Levy, Daniel

AU - Johnson, Andrew D.

AU - Mathias, Rasika A.

AU - Taub, Margaret A.

AU - Arnett, Donna

AU - North, Kari E.

AU - Raffield, Laura M.

AU - Carson, April P.

AU - Doyle, Margaret F.

AU - Rich, Stephen S.

AU - Rotter, Jerome I.

AU - Guo, Xiuqing

AU - Cox, Nancy J.

AU - Roden, Dan M.

AU - Franceschini, Nora

AU - Desai, Pinkal

AU - Reiner, Alex P.

AU - Auer, Paul L.

AU - Scheet, Paul A.

AU - Jaiswal, Siddhartha

AU - Weinstock, Joshua S.

AU - Bick, Alexander G.

PY - 2024/12

Y1 - 2024/12

N2 - Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

AB - Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

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DO - 10.1038/s41467-024-48190-8

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VL - 15

JO - Nature Communications

JF - Nature Communications

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M1 - 3800

ER -

Determinants of mosaic chromosomal alteration fitness

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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