%0 Journal Article %J Nature %D 2020 %T Inherited causes of clonal haematopoiesis in 97,691 whole genomes. %A Bick, Alexander G %A Weinstock, Joshua S %A Nandakumar, Satish K %A Fulco, Charles P %A Bao, Erik L %A Zekavat, Seyedeh M %A Szeto, Mindy D %A Liao, Xiaotian %A Leventhal, Matthew J %A Nasser, Joseph %A Chang, Kyle %A Laurie, Cecelia %A Burugula, Bala Bharathi %A Gibson, Christopher J %A Lin, Amy E %A Taub, Margaret A %A Aguet, Francois %A Ardlie, Kristin %A Mitchell, Braxton D %A Barnes, Kathleen C %A Moscati, Arden %A Fornage, Myriam %A Redline, Susan %A Psaty, Bruce M %A Silverman, Edwin K %A Weiss, Scott T %A Palmer, Nicholette D %A Vasan, Ramachandran S %A Burchard, Esteban G %A Kardia, Sharon L R %A He, Jiang %A Kaplan, Robert C %A Smith, Nicholas L %A Arnett, Donna K %A Schwartz, David A %A Correa, Adolfo %A de Andrade, Mariza %A Guo, Xiuqing %A Konkle, Barbara A %A Custer, Brian %A Peralta, Juan M %A Gui, Hongsheng %A Meyers, Deborah A %A McGarvey, Stephen T %A Chen, Ida Yii-Der %A Shoemaker, M Benjamin %A Peyser, Patricia A %A Broome, Jai G %A Gogarten, Stephanie M %A Wang, Fei Fei %A Wong, Quenna %A Montasser, May E %A Daya, Michelle %A Kenny, Eimear E %A North, Kari E %A Launer, Lenore J %A Cade, Brian E %A Bis, Joshua C %A Cho, Michael H %A Lasky-Su, Jessica %A Bowden, Donald W %A Cupples, L Adrienne %A Mak, Angel C Y %A Becker, Lewis C %A Smith, Jennifer A %A Kelly, Tanika N %A Aslibekyan, Stella %A Heckbert, Susan R %A Tiwari, Hemant K %A Yang, Ivana V %A Heit, John A %A Lubitz, Steven A %A Johnsen, Jill M %A Curran, Joanne E %A Wenzel, Sally E %A Weeks, Daniel E %A Rao, Dabeeru C %A Darbar, Dawood %A Moon, Jee-Young %A Tracy, Russell P %A Buth, Erin J %A Rafaels, Nicholas %A Loos, Ruth J F %A Durda, Peter %A Liu, Yongmei %A Hou, Lifang %A Lee, Jiwon %A Kachroo, Priyadarshini %A Freedman, Barry I %A Levy, Daniel %A Bielak, Lawrence F %A Hixson, James E %A Floyd, James S %A Whitsel, Eric A %A Ellinor, Patrick T %A Irvin, Marguerite R %A Fingerlin, Tasha E %A Raffield, Laura M %A Armasu, Sebastian M %A Wheeler, Marsha M %A Sabino, Ester C %A Blangero, John %A Williams, L Keoki %A Levy, Bruce D %A Sheu, Wayne Huey-Herng %A Roden, Dan M %A Boerwinkle, Eric %A Manson, JoAnn E %A Mathias, Rasika A %A Desai, Pinkal %A Taylor, Kent D %A Johnson, Andrew D %A Auer, Paul L %A Kooperberg, Charles %A Laurie, Cathy C %A Blackwell, Thomas W %A Smith, Albert V %A Zhao, Hongyu %A Lange, Ethan %A Lange, Leslie %A Rich, Stephen S %A Rotter, Jerome I %A Wilson, James G %A Scheet, Paul %A Kitzman, Jacob O %A Lander, Eric S %A Engreitz, Jesse M %A Ebert, Benjamin L %A Reiner, Alexander P %A Jaiswal, Siddhartha %A Abecasis, Goncalo %A Sankaran, Vijay G %A Kathiresan, Sekar %A Natarajan, Pradeep %X

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

%B Nature %V 586 %P 763-768 %8 2020 10 %G eng %N 7831 %R 10.1038/s41586-020-2819-2 %0 Journal Article %J Blood Cancer Discov %D 2021 %T is mutated in clonal hematopoiesis and myelodysplastic syndromes and impacts RNA splicing. %A Beauchamp, Ellen M %A Leventhal, Matthew %A Bernard, Elsa %A Hoppe, Emma R %A Todisco, Gabriele %A Creignou, Maria %A Gallì, Anna %A Castellano, Cecilia A %A McConkey, Marie %A Tarun, Akansha %A Wong, Waihay %A Schenone, Monica %A Stanclift, Caroline %A Tanenbaum, Benjamin %A Malolepsza, Edyta %A Nilsson, Björn %A Bick, Alexander G %A Weinstock, Joshua S %A Miller, Mendy %A Niroula, Abhishek %A Dunford, Andrew %A Taylor-Weiner, Amaro %A Wood, Timothy %A Barbera, Alex %A Anand, Shankara %A Psaty, Bruce M %A Desai, Pinkal %A Cho, Michael H %A Johnson, Andrew D %A Loos, Ruth %A MacArthur, Daniel G %A Lek, Monkol %A Neuberg, Donna S %A Lage, Kasper %A Carr, Steven A %A Hellstrom-Lindberg, Eva %A Malcovati, Luca %A Papaemmanuil, Elli %A Stewart, Chip %A Getz, Gad %A Bradley, Robert K %A Jaiswal, Siddhartha %A Ebert, Benjamin L %X

Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader, , as well as in , , and . We also identified these mutations at low frequency in myelodysplastic syndrome patients. edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage and increased genome-wide intron retention. mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and MDS.

%B Blood Cancer Discov %V 2 %P 500-517 %8 2021 Sep %G eng %N 5 %R 10.1158/2643-3230.BCD-20-0224 %0 Journal Article %J J Am Coll Cardiol %D 2021 %T Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure. %A Yu, Bing %A Roberts, Mary B %A Raffield, Laura M %A Zekavat, Seyedeh Maryam %A Nguyen, Ngoc Quynh H %A Biggs, Mary L %A Brown, Michael R %A Griffin, Gabriel %A Desai, Pinkal %A Correa, Adolfo %A Morrison, Alanna C %A Shah, Amil M %A Niroula, Abhishek %A Uddin, Md Mesbah %A Honigberg, Michael C %A Ebert, Benjamin L %A Psaty, Bruce M %A Whitsel, Eric A %A Manson, JoAnn E %A Kooperberg, Charles %A Bick, Alexander G %A Ballantyne, Christie M %A Reiner, Alex P %A Natarajan, Pradeep %A Eaton, Charles B %K Aged %K Clonal Hematopoiesis %K Correlation of Data %K Demography %K DNA-Binding Proteins %K Female %K Heart Failure %K Humans %K Janus Kinase 2 %K Male %K Middle Aged %K Mutation %K Proportional Hazards Models %K Proto-Oncogene Proteins %K Repressor Proteins %K Risk Factors %K Stroke Volume %K Ventricular Dysfunction, Left %K Whole Exome Sequencing %X

BACKGROUND: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF).

OBJECTIVES: This study sought to evaluate whether CHIP is associated with incident HF.

METHODS: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses.

RESULTS: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction.

CONCLUSIONS: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.

%B J Am Coll Cardiol %V 78 %P 42-52 %8 2021 07 06 %G eng %N 1 %R 10.1016/j.jacc.2021.04.085 %0 Journal Article %J Nat Commun %D 2022 %T Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program. %A Wheeler, Marsha M %A Stilp, Adrienne M %A Rao, Shuquan %A Halldorsson, Bjarni V %A Beyter, Doruk %A Wen, Jia %A Mihkaylova, Anna V %A McHugh, Caitlin P %A Lane, John %A Jiang, Min-Zhi %A Raffield, Laura M %A Jun, Goo %A Sedlazeck, Fritz J %A Metcalf, Ginger %A Yao, Yao %A Bis, Joshua B %A Chami, Nathalie %A de Vries, Paul S %A Desai, Pinkal %A Floyd, James S %A Gao, Yan %A Kammers, Kai %A Kim, Wonji %A Moon, Jee-Young %A Ratan, Aakrosh %A Yanek, Lisa R %A Almasy, Laura %A Becker, Lewis C %A Blangero, John %A Cho, Michael H %A Curran, Joanne E %A Fornage, Myriam %A Kaplan, Robert C %A Lewis, Joshua P %A Loos, Ruth J F %A Mitchell, Braxton D %A Morrison, Alanna C %A Preuss, Michael %A Psaty, Bruce M %A Rich, Stephen S %A Rotter, Jerome I %A Tang, Hua %A Tracy, Russell P %A Boerwinkle, Eric %A Abecasis, Goncalo R %A Blackwell, Thomas W %A Smith, Albert V %A Johnson, Andrew D %A Mathias, Rasika A %A Nickerson, Deborah A %A Conomos, Matthew P %A Li, Yun %A Þorsteinsdottir, Unnur %A Magnússon, Magnús K %A Stefansson, Kari %A Pankratz, Nathan D %A Bauer, Daniel E %A Auer, Paul L %A Reiner, Alex P %K Blood Cells %K Genome-Wide Association Study %K Humans %K Whole Genome Sequencing %X

Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.

%B Nat Commun %V 13 %P 7592 %8 2022 Dec 08 %G eng %N 1 %R 10.1038/s41467-022-35354-7 %0 Journal Article %J Nature %D 2023 %T Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis. %A Weinstock, Joshua S %A Gopakumar, Jayakrishnan %A Burugula, Bala Bharathi %A Uddin, Md Mesbah %A Jahn, Nikolaus %A Belk, Julia A %A Bouzid, Hind %A Daniel, Bence %A Miao, Zhuang %A Ly, Nghi %A Mack, Taralynn M %A Luna, Sofia E %A Prothro, Katherine P %A Mitchell, Shaneice R %A Laurie, Cecelia A %A Broome, Jai G %A Taylor, Kent D %A Guo, Xiuqing %A Sinner, Moritz F %A von Falkenhausen, Aenne S %A Kääb, Stefan %A Shuldiner, Alan R %A O'Connell, Jeffrey R %A Lewis, Joshua P %A Boerwinkle, Eric %A Barnes, Kathleen C %A Chami, Nathalie %A Kenny, Eimear E %A Loos, Ruth J F %A Fornage, Myriam %A Hou, Lifang %A Lloyd-Jones, Donald M %A Redline, Susan %A Cade, Brian E %A Psaty, Bruce M %A Bis, Joshua C %A Brody, Jennifer A %A Silverman, Edwin K %A Yun, Jeong H %A Qiao, Dandi %A Palmer, Nicholette D %A Freedman, Barry I %A Bowden, Donald W %A Cho, Michael H %A DeMeo, Dawn L %A Vasan, Ramachandran S %A Yanek, Lisa R %A Becker, Lewis C %A Kardia, Sharon L R %A Peyser, Patricia A %A He, Jiang %A Rienstra, Michiel %A van der Harst, Pim %A Kaplan, Robert %A Heckbert, Susan R %A Smith, Nicholas L %A Wiggins, Kerri L %A Arnett, Donna K %A Irvin, Marguerite R %A Tiwari, Hemant %A Cutler, Michael J %A Knight, Stacey %A Muhlestein, J Brent %A Correa, Adolfo %A Raffield, Laura M %A Gao, Yan %A de Andrade, Mariza %A Rotter, Jerome I %A Rich, Stephen S %A Tracy, Russell P %A Konkle, Barbara A %A Johnsen, Jill M %A Wheeler, Marsha M %A Smith, J Gustav %A Melander, Olle %A Nilsson, Peter M %A Custer, Brian S %A Duggirala, Ravindranath %A Curran, Joanne E %A Blangero, John %A McGarvey, Stephen %A Williams, L Keoki %A Xiao, Shujie %A Yang, Mao %A Gu, C Charles %A Chen, Yii-Der Ida %A Lee, Wen-Jane %A Marcus, Gregory M %A Kane, John P %A Pullinger, Clive R %A Shoemaker, M Benjamin %A Darbar, Dawood %A Roden, Dan M %A Albert, Christine %A Kooperberg, Charles %A Zhou, Ying %A Manson, JoAnn E %A Desai, Pinkal %A Johnson, Andrew D %A Mathias, Rasika A %A Blackwell, Thomas W %A Abecasis, Goncalo R %A Smith, Albert V %A Kang, Hyun M %A Satpathy, Ansuman T %A Natarajan, Pradeep %A Kitzman, Jacob O %A Whitsel, Eric A %A Reiner, Alexander P %A Bick, Alexander G %A Jaiswal, Siddhartha %K Alleles %K Animals %K Clonal Hematopoiesis %K Genome-Wide Association Study %K Hematopoiesis %K Hematopoietic Stem Cells %K Humans %K Mice %K Mutation %K Promoter Regions, Genetic %X

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

%B Nature %V 616 %P 755-763 %8 2023 Apr %G eng %N 7958 %R 10.1038/s41586-023-05806-1 %0 Journal Article %J medRxiv %D 2023 %T Determinants of mosaic chromosomal alteration fitness. %A Pershad, Yash %A Mack, Taralynn %A Poisner, Hannah %A Jakubek, Yasminka A %A Stilp, Adrienne M %A Mitchell, Braxton D %A Lewis, Joshua P %A Boerwinkle, Eric %A Loos, Ruth J %A Chami, Nathalie %A Wang, Zhe %A Barnes, Kathleen %A Pankratz, Nathan %A Fornage, Myriam %A Redline, Susan %A Psaty, Bruce M %A Bis, Joshua C %A Shojaie, Ali %A Silverman, Edwin K %A Cho, Michael H %A Yun, Jeong %A DeMeo, Dawn %A Levy, Daniel %A Johnson, Andrew %A Mathias, Rasika %A Taub, Margaret %A Arnett, Donna %A North, Kari %A Raffield, Laura M %A Carson, April %A Doyle, Margaret F %A Rich, Stephen S %A Rotter, Jerome I %A Guo, Xiuqing %A Cox, Nancy %A Roden, Dan M %A Franceschini, Nora %A Desai, Pinkal %A Reiner, Alex %A Auer, Paul L %A Scheet, Paul %A Jaiswal, Siddhartha %A Weinstock, Joshua S %A Bick, Alexander G %X

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 for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our estimates of mCA fitness were correlated (R = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using a theoretical probability distribution. Individuals with lymphoid-associated mCAs had a significantly higher white blood cell count and faster clonal expansion rate. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified , , and locus variants as modulators of mCA clonal expansion rate.

%B medRxiv %8 2023 Oct 21 %G eng %R 10.1101/2023.10.20.23297280 %0 Journal Article %J Sci Adv %D 2023 %T The genetic determinants of recurrent somatic mutations in 43,693 blood genomes. %A Weinstock, Joshua S %A Laurie, Cecelia A %A Broome, Jai G %A Taylor, Kent D %A Guo, Xiuqing %A Shuldiner, Alan R %A O'Connell, Jeffrey R %A Lewis, Joshua P %A Boerwinkle, Eric %A Barnes, Kathleen C %A Chami, Nathalie %A Kenny, Eimear E %A Loos, Ruth J F %A Fornage, Myriam %A Redline, Susan %A Cade, Brian E %A Gilliland, Frank D %A Chen, Zhanghua %A Gauderman, W James %A Kumar, Rajesh %A Grammer, Leslie %A Schleimer, Robert P %A Psaty, Bruce M %A Bis, Joshua C %A Brody, Jennifer A %A Silverman, Edwin K %A Yun, Jeong H %A Qiao, Dandi %A Weiss, Scott T %A Lasky-Su, Jessica %A DeMeo, Dawn L %A Palmer, Nicholette D %A Freedman, Barry I %A Bowden, Donald W %A Cho, Michael H %A Vasan, Ramachandran S %A Johnson, Andrew D %A Yanek, Lisa R %A Becker, Lewis C %A Kardia, Sharon %A He, Jiang %A Kaplan, Robert %A Heckbert, Susan R %A Smith, Nicholas L %A Wiggins, Kerri L %A Arnett, Donna K %A Irvin, Marguerite R %A Tiwari, Hemant %A Correa, Adolfo %A Raffield, Laura M %A Gao, Yan %A de Andrade, Mariza %A Rotter, Jerome I %A Rich, Stephen S %A Manichaikul, Ani W %A Konkle, Barbara A %A Johnsen, Jill M %A Wheeler, Marsha M %A Custer, Brian S %A Duggirala, Ravindranath %A Curran, Joanne E %A Blangero, John %A Gui, Hongsheng %A Xiao, Shujie %A Williams, L Keoki %A Meyers, Deborah A %A Li, Xingnan %A Ortega, Victor %A McGarvey, Stephen %A Gu, C Charles %A Chen, Yii-Der Ida %A Lee, Wen-Jane %A Shoemaker, M Benjamin %A Darbar, Dawood %A Roden, Dan %A Albert, Christine %A Kooperberg, Charles %A Desai, Pinkal %A Blackwell, Thomas W %A Abecasis, Goncalo R %A Smith, Albert V %A Kang, Hyun M %A Mathias, Rasika %A Natarajan, Pradeep %A Jaiswal, Siddhartha %A Reiner, Alexander P %A Bick, Alexander G %K Germ-Line Mutation %K Hematopoiesis %K Humans %K Middle Aged %K Mutation %K Mutation, Missense %K Phenotype %X

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

%B Sci Adv %V 9 %P eabm4945 %8 2023 Apr 28 %G eng %N 17 %R 10.1126/sciadv.abm4945 %0 Journal Article %J Nat Genet %D 2023 %T Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing. %A Jakubek, Yasminka A %A Zhou, Ying %A Stilp, Adrienne %A Bacon, Jason %A Wong, Justin W %A Ozcan, Zuhal %A Arnett, Donna %A Barnes, Kathleen %A Bis, Joshua C %A Boerwinkle, Eric %A Brody, Jennifer A %A Carson, April P %A Chasman, Daniel I %A Chen, Jiawen %A Cho, Michael %A Conomos, Matthew P %A Cox, Nancy %A Doyle, Margaret F %A Fornage, Myriam %A Guo, Xiuqing %A Kardia, Sharon L R %A Lewis, Joshua P %A Loos, Ruth J F %A Ma, Xiaolong %A Machiela, Mitchell J %A Mack, Taralynn M %A Mathias, Rasika A %A Mitchell, Braxton D %A Mychaleckyj, Josyf C %A North, Kari %A Pankratz, Nathan %A Peyser, Patricia A %A Preuss, Michael H %A Psaty, Bruce %A Raffield, Laura M %A Vasan, Ramachandran S %A Redline, Susan %A Rich, Stephen S %A Rotter, Jerome I %A Silverman, Edwin K %A Smith, Jennifer A %A Smith, Aaron P %A Taub, Margaret %A Taylor, Kent D %A Yun, Jeong %A Li, Yun %A Desai, Pinkal %A Bick, Alexander G %A Reiner, Alexander P %A Scheet, Paul %A Auer, Paul L %K Black People %K Genome, Human %K Genome-Wide Association Study %K Hispanic or Latino %K Humans %K Mosaicism %K Precision Medicine %X

Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.

%B Nat Genet %V 55 %P 1912-1919 %8 2023 Nov %G eng %N 11 %R 10.1038/s41588-023-01553-1