@article {9742,
	title = {Epigenome-wide DNA Methylation Association Study of CHIP Provides Insight into Perturbed Gene Regulation.},
	journal = {Res Sq},
	year = {2024},
	month = {2024 Jul 16},
	abstract = {<p>With age, hematopoietic stem cells can acquire somatic mutations in leukemogenic genes that confer a proliferative advantage in a phenomenon termed "clonal hematopoiesis of indeterminate potential" (CHIP). How these mutations confer a proliferative advantage and result in increased risk for numerous age-related diseases remains poorly understood. We conducted a multiracial meta-analysis of epigenome-wide association studies (EWAS) of CHIP and its subtypes in four cohorts (N=8196) to elucidate the molecular mechanisms underlying CHIP and illuminate how these changes influence cardiovascular disease risk. The EWAS findings were functionally validated using human hematopoietic stem cell (HSC) models of CHIP. A total of 9615 CpGs were associated with any CHIP, 5990 with DNMT3A CHIP, 5633 with TET2 CHIP, and 6078 with ASXL1 CHIP (P <1{\texttimes}10). CpGs associated with CHIP subtypes overlapped moderately, and the genome-wide DNA methylation directions of effect were opposite for TET2 and DNMT3A CHIP, consistent with their opposing effects on global DNA methylation. There was high directional concordance between the CpGs shared from the meta-EWAS and human edited CHIP HSCs. Expression quantitative trait methylation analysis further identified transcriptomic changes associated with CHIP-associated CpGs. Causal inference analyses revealed 261 CHIP-associated CpGs associated with cardiovascular traits and all-cause mortality (FDR adjusted p-value <0.05). Taken together, our study sheds light on the epigenetic changes impacted by CHIP and their associations with age-related disease outcomes. The novel genes and pathways linked to the epigenetic features of CHIP may serve as therapeutic targets for preventing or treating CHIP-mediated diseases.</p>},
	issn = {2693-5015},
	doi = {10.21203/rs.3.rs-4656898/v1},
	author = {Levy, Daniel and Kirmani, Sara and Huan, Tianxiao and Van Amburg, Joseph and Joehanes, Roby and Uddin, Md Mesbah and Nguyen, Ngoc Quynh and Yu, Bing and Brody, Jennifer and Fornage, Myriam and Bressler, Jan and Sotoodehnia, Nona and Ong, David and Puddu, Fabio and Floyd, James and Ballantyne, Christie and Psaty, Bruce and Raffield, Laura and Natarajan, Pradeep and Conneely, Karen and Carson, April and Lange, Leslie and Ferrier, Kendra and Heard-Costa, Nancy and Murabito, Joanne and Bick, Alexander}
}
@article {9749,
	title = {The Genetic Determinants and Genomic Consequences of Non-Leukemogenic Somatic Point Mutations.},
	journal = {medRxiv},
	year = {2024},
	month = {2024 Aug 26},
	abstract = {<p>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 (  ,  ,  ), and one locus associated with a sex-associated mutation pathway (  . We performed a secondary analysis excluding individuals with mCAs, finding that the genetic architecture was largely unaffected by their inclusion. Functional analyses of  and  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.</p>},
	doi = {10.1101/2024.08.22.24312319},
	author = {Weinstock, Joshua S and Chaudhry, Sharjeel A and Ioannou, Maria and Viskadourou, Maria and Reventun, Paula and Jakubek, Yasminka A and Alexander Liggett, L and Laurie, Cecelia and Broome, Jai G and Khan, Alyna and Taylor, Kent D and Guo, Xiuqing and Peyser, Patricia A and Boerwinkle, Eric and Chami, Nathalie and Kenny, Eimear E and Loos, Ruth J and Psaty, Bruce M and Russell, Tracy P and Brody, Jennifer A and Yun, Jeong H and Cho, Michael H and Vasan, Ramachandran S and Kardia, Sharon L and Smith, Jennifer A and Raffield, Laura M and Bidulescu, Aurelian and O{\textquoteright}Brien, Emily and de Andrade, Mariza and Rotter, Jerome I and Rich, Stephen S and Tracy, Russell P and Chen, Yii Der Ida and Gu, C Charles and Hsiung, Chao A and Kooperberg, Charles and Haring, Bernhard and Nassir, Rami and Mathias, Rasika and Reiner, Alex and Sankaran, Vijay and Lowenstein, Charles J and Blackwell, Thomas W and Abecasis, Goncalo R and Smith, Albert V and Kang, Hyun M and Natarajan, Pradeep and Jaiswal, Siddhartha and Bick, Alexander and Post, Wendy S and Scheet, Paul and Auer, Paul and Karantanos, Theodoros and Battle, Alexis and Arvanitis, Marios}
}
