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

Nat Commun. 2024 May 7;15(1):3800. doi: 10.1038/s41467-024-48190-8.

Authors

Yash Pershad^#¹, Taralynn Mack^#¹, Hannah Poisner¹, Yasminka A Jakubek², Adrienne M Stilp³, Braxton D Mitchell⁴, Joshua P Lewis⁴, Eric Boerwinkle⁵, Ruth J F Loos⁶, Nathalie Chami⁶, Zhe Wang⁶, Kathleen Barnes⁷, Nathan Pankratz⁸, Myriam Fornage^{5

9}, Susan Redline¹⁰, Bruce M Psaty¹¹, Joshua C Bis¹², Ali Shojaie¹³, Edwin K Silverman¹⁴, Michael H Cho¹⁴, Jeong H Yun¹⁴, Dawn DeMeo¹⁴, Daniel Levy¹⁵, Andrew D Johnson¹⁵, Rasika A Mathias¹⁶, Margaret A Taub¹⁷, Donna Arnett¹⁸, Kari E North¹⁹, Laura M Raffield²⁰, April P Carson²¹, Margaret F Doyle²², Stephen S Rich²³, Jerome I Rotter²⁴, Xiuqing Guo²⁴, Nancy J Cox²⁵, Dan M Roden²⁶, Nora Franceschini¹⁹, Pinkal Desai²⁷, Alex P Reiner²⁸, Paul L Auer²⁹, Paul A Scheet³⁰, Siddhartha Jaiswal³¹, Joshua S Weinstock³², Alexander G Bick³³

Affiliations

¹ Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.
² Internal Medicine, Biomedical Informatics, University of Kentucky, Lexington, KY, USA.
³ Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
⁴ Dept of Medicine, Endocrinology, Diabetes, and Nutrition, University of Maryland, Baltimore, Baltimore, MD, USA.
⁵ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁶ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷ Division of Biomedical Informatics & Personalized Medicine, University of Colorado Anschutz, Aurora, CO, USA.
⁸ Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA.
⁹ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
¹⁰ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
¹¹ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, WA, USA.
¹² Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
¹³ Biostatistics, University of Washington, Seattle, WA, USA.
¹⁴ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁵ National Heart, Lung and Blood Institute, Population Sciences Branch, Framingham, MA, USA.
¹⁶ Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MA, USA.
¹⁷ Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MA, USA.
¹⁸ Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
¹⁹ Department of Epidemiology, University of North Carolina Chapel-Hill, Chapel Hill, NC, USA.
²⁰ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²¹ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
²² Department of Pathology & Laboratory Medicine, The University of Vermont Larner College of Medicine, Colchester, VT, USA.
²³ Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA.
²⁴ Pediatrics, Genomic Outcomes, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
²⁵ Division of Genetic Medicine, Department of Medicine, Vanderbilt University and Vanderbilt University Medical Center, Nashville, TN, USA.
²⁶ Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁷ Weill Cornell Medical College, New York, NY, USA.
²⁸ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
²⁹ Division of Biostatistics, Insitute for Health & Equity and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
³⁰ Dept of Epidemiology, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
³¹ Department of Pathology, Stanford University, Stanford, CA, USA.
³² Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³³ Division of Genetic Medicine, Department of Medicine, Vanderbilt University and Vanderbilt University Medical Center, Nashville, TN, USA. alexander.bick@vumc.org.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Chromosome Aberrations*
Clonal Hematopoiesis* / genetics
Cross-Sectional Studies
Female
Genome-Wide Association Study
Hematopoietic Stem Cells / metabolism
Humans
Janus Kinase 2 / genetics
Loss of Heterozygosity
Male
Middle Aged
Mosaicism*
Mutation
Polymorphism, Single Nucleotide
Telomerase / genetics
Telomerase / metabolism

Substances

Janus Kinase 2
Telomerase
JAK2 protein, human
TERT protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding