
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.08.22.24312319
preprint
2
Article
The Genetic Determinants and Genomic Consequences of Non-Leukemogenic Somatic Point Mutations
Weinstock Joshua S. http://orcid.org/0000-0001-7013-1899

Chaudhry Sharjeel A. http://orcid.org/0000-0001-8701-3979

Ioannou Maria
Viskadourou Maria
Reventun Paula http://orcid.org/0000-0002-6221-8780

Jakubek Yasminka A. http://orcid.org/0000-0003-1427-1015

Alexander Liggett L. http://orcid.org/0000-0001-6152-8456

Laurie Cecelia
Broome Jai G.
Khan Alyna
Taylor Kent D. http://orcid.org/0000-0002-2756-4370

Guo Xiuqing http://orcid.org/0000-0002-5264-5068

Peyser Patricia A.
Boerwinkle Eric
Chami Nathalie http://orcid.org/0000-0002-8547-6424

Kenny Eimear E. http://orcid.org/0000-0001-9198-759X

Loos Ruth J. http://orcid.org/0000-0002-8532-5087

Psaty Bruce M.
Russell Tracy P.
Brody Jennifer A. http://orcid.org/0000-0001-8509-148X

Yun Jeong H. http://orcid.org/0000-0002-4361-8295

Cho Michael H. http://orcid.org/0000-0002-4907-1657

Vasan Ramachandran S.
Kardia Sharon L. http://orcid.org/0000-0002-9853-3379

Smith Jennifer A. http://orcid.org/0000-0002-3575-5468

Raffield Laura M. http://orcid.org/0000-0002-7892-193X

Bidulescu Aurelian
O’Brien Emily
de Andrade Mariza
Rotter Jerome I. http://orcid.org/0000-0001-7191-1723

Rich Stephen S. http://orcid.org/0000-0003-3872-7793

Tracy Russell P.
Chen Yii Der Ida http://orcid.org/0000-0003-1741-3517

Gu C. Charles http://orcid.org/0000-0002-8527-8145

Hsiung Chao A. http://orcid.org/0000-0002-8209-9627

Kooperberg Charles http://orcid.org/0000-0002-7986-8560

Haring Bernhard
Nassir Rami
Mathias Rasika
Reiner Alex
Sankaran Vijay http://orcid.org/0000-0003-0044-443X

Lowenstein Charles J.
Blackwell Thomas W.
Abecasis Goncalo R.
Smith Albert V. http://orcid.org/0000-0003-1942-5845

Kang Hyun M. http://orcid.org/0000-0002-3631-3979

Natarajan Pradeep http://orcid.org/0000-0001-8402-7435

Jaiswal Siddhartha
Bick Alexander
Post Wendy S.
Scheet Paul
Auer Paul
Karantanos Theodoros http://orcid.org/0000-0002-6792-8298

Battle Alexis
Arvanitis Marios
26 8 2024
2024.08.22.24312319https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://medrxiv.org/lookup/doi/10.1101/2024.08.22.24312319
nihpp-2024.08.22.24312319.pdf
Abstract

Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as point mutations or mosaic chromosomal alterations (mCAs) in genes associated with hematologic malignancy, are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we used 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic point mutations (LPM), which we term CH-LPMneg. We quantified CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we developed a novel statistical method, the Genomic and Epigenomic informed Mutation (GEM) rate, that uses external genomic and epigenomic data sources to distinguish artifactual signals from true somatic mutations. We performed a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. After fine-mapping and variant-to-gene analyses, we identified seven genes associated with CH-LPMneg ( TCL1A, TERT, SMC4, NRIP1, PRDM16 , MSRA , SCARB1 ), and one locus associated with a sex-associated mutation pathway ( SRGAP2C) . We performed a secondary analysis excluding individuals with mCAs, finding that the genetic architecture was largely unaffected by their inclusion. Functional analyses of SMC4 and NRIP1 implicated altered HSC self-renewal and proliferation as the primary mediator of mutation burden in blood. We then performed comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we performed phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count and increased risk for incident peripheral artery disease, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS without a paired-tissue sample and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg.
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