Citations 2
The genetic determinants of recurrent somatic mutations in 43,693 blood genomes
Weinstock, Joshua S. , Laurie, Cecelia , Broome, Jai , Taylor, Kent D. , Guo, Xiuqing , Shuldiner, Alan R. , O’Connell, Jeffrey R. , Lewis, Joshua P. , Boerwinkle, Eric , Barnes, Kathleen C. , Chami, Nathalie , Loos, Ruth J. F. , Fornage, Myriam , Redline, Susan , Cade, Brian E. , Chen, Zhanghua , Gauderman, W. James , Schleimer, Robert P. , Bis, Joshua C. , Brody, Jennifer A. , Silverman, Edwin K. , Qiao, Dandi , Lasky‐Su, Jessica , DeMeo, Dawn L. , Palmer, Nicholette D. , Bowden, Donald W. , Johnson, Andrew D. , Yanek, Lisa R. , Becker, Lewis C. , Kardia, Sharon L.R., Kaplan, Robert C. , Heckbert, Susan R. , Smith, Nicholas L. , Arnett, Donna K. , Irvin, Marguerite R. , Tiwari, Hemant K., Raffield, Laura M. , Gao, Yan , Rotter, Jerome I. , Wheeler, Marsha M. , Duggirala, Ravindranath , Xiao, Shujie, Williams, L. Keoki , Meyers, Deborah A. , Ortega, Victor E. , McGarvey, Stephen T. , Chen, Yii‐Der Ida , Lee, Wen‐Jane , Shoemaker, M. Benjamin , Roden, Dan M. , Blackwell, Thomas W. , Smith, Albert V. , Kang, Hyun Min , Mathias, Rasika A. , Natarajan, Pradeep , Jaiswal, Siddhartha , Reiner, Alex P. , Bick, Alexander G. , Kaplan, Robert C. , Broome, Jai , Kenny, Eimear E , Loos, Ruth J F , Fornage, Myriam , Redline, Susan , Cade, Brian E , Gauderman, W James , Grammer, Leslie , Schleimer, Robert P , Bis, Joshua C , Brody, Jennifer A , Silverman, Edwin K , Yun, Jeong H , Qiao, Dandi , Weiss, Scott T , Palmer, Nicholette D , Freedman, Barry I , Cho, Michael H , Vasan, Ramachandran S , Johnson, Andrew D , Yanek, Lisa R , Becker, Lewis C , He, Jiang , Heckbert, Susan R , Wiggins, Kerri L , Arnett, Donna K , Correa, Adolfo , Raffield, Laura M , Gao, Yan , Rotter, Jerome I , Rich, Stephen S , Manichaikul, Ani W , Konkle, Barbara A , Johnsen, Jill M , Custer, Brian S , Duggirala, Ravindranath , Curran, Joanne E , Li, Xingnan , McGarvey, Stephen T , Gu, C Charles , Lee, Wen-Jane , Darbar, Dawood , Roden, Dan M. , Kooperberg, Charles , Desai, Pinkal M , Smith, Albert V , Kang, Hyun M , Mathias, Rasika A , Natarajan, Pradeep , Jaiswal, Siddhartha , Bick, Alexander G , Weinstock, Joshua S , Shuldiner, Alan R , Taylor, Kent D , Guo, Xiuqing , Lasky-Su, Jessica , Gilliland, Frank D. , Kumar, Rajesh , Psaty, Bruce M. , Yun, Jeong H. , Weiss, Scott T. , Freedman, Barry I. , Cho, Michael H. , Vasan, Ramachandran S. , He, Jiang , Wiggins, Kerri L. , Andrade, Mariza de , Rich, Stephen S. , Manichaikul, Ani , Konkle, Barbara A. , Custer, Brian , Curran, Joanne E. , Blangero, John , Gui, Hongsheng , Li, Xingnan , Darbar, Dawood , Albert, Christine M. , Kooperberg, Charles , Desai, Pinkal , Abecasis, Gonçalo R.
Science Advances | April 26, 2023 | Volume: 9 | Issue: 17 | Pages: No page available
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.
Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential
Nakao, Tetsushi , Bick, Alexander G. , Taub, Margaret A. , Uddin, Md Mesbah , Niroula, Abhishek , Carty, Cara L. , Lane, John , Honigberg, Michael C. , Weinstock, Joshua S. , Pampana, Akhil , Griffin, Gabriel K. , Bhattacharya, Romit , Assimes, Themistocles L. , Emery, Leslie S. , Wong, Quenna , Broome, Jai , Laurie, Cecelia , Khan, Alyna , Smith, Albert V. , Blackwell, Thomas W. , Nelson, Christopher P. , Yoneda, Zachary T. , Peralta, Juan M. , Bowden, Donald W. , Irvin, Marguerite R. , Boorgula, Meher Preethi, Zhao, Wei , Yanek, Lisa R. , Roden, Dan M. , Reupena, Muagututi‘a Sefuiva , DeMeo, Dawn L. , Kelly, Shannon , Musani, Solomon K., Bis, Joshua C. , Lloyd‐Jones, Donald M. , Peyser, Patricia A. , Qiao, Dandi , Tiwari, Hemant K., Smith, Jennifer A. , Smith, Nicholas L. , Kelly, Tanika N. , Hidalgo, Bertha , Weeks, Daniel E. , Group, The Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA), Deka, Ranjan , Naseri, Take, Fuentes, Lisa de las , Raffield, Laura M. , Morrison, Alanna C. , Vries, Paul S. de , Shoemaker, M. Benjamin , Palmer, Nicholette D. , Barnes, Kathleen C. , Redline, Susan , Kardia, Sharon L.R., Becker, Lewis C. , Heckbert, Susan R. , He, Jiang , Post, Wendy S. , Arnett, Donna K. , McGarvey, Stephen T. , Chen, Yii‐Der Ida , Kaplan, Robert C. , Meyers, Deborah A. , Fornage, Myriam , Boerwinkle, Eric , Loos, Ruth J. F. , Silverman, Edwin K. , Danesh, John , Samani, Nilesh J. , Jaiswal, Siddhartha , Ebert, Benjamin L. , Reiner, Alex P. , Mathias, Rasika A. , Do, Ron , Natarajan, Pradeep , Zhao, Wei , Zekavat, Seyedeh M , Uddin, Md M , Niroula, Abhishek , Lane, John , Honigberg, Michael C , Weinstock, Joshua S , Pampana, Akhil , Griffin, Gabriel K , Clarke, Shoa L , Bhattacharya, Romit , Assimes, Themistocles L , Emery, Leslie S , Stilp, Adrienne M , Wong, Quenna , Broome, Jai , Khan, Alyna T , Smith, Albert V , Codd, Veryan , Nelson, Christopher P , Yoneda, Zachary T , Peralta, Juan M , Yanek, Lisa R , Wiggins, Kerri L , Gu, C Charles , Peloso, Gina M , Roden, Dan M. , Hwu, Chii-Min , North, Kari E. , Bis, Joshua C , Lloyd-Jones, Donald M , Johnsen, Jill M , Preuss, Michael , Tracy, Russell P , Peyser, Patricia A , Qiao, Dandi , Curran, Joanne E , Freedman, Barry I , Chavan, Sameer , Smith, Jennifer A , Kelly, Tanika N , Hidalgo, Bertha , Weeks, Daniel E , Hawley, Nicola L , Minster, Ryan L , de las Fuentes, Lisa , Raffield, Laura M , Ballantyne, Christie M , Kenny, Eimear E , Rich, Stephen S , Whitsel, Eric A , Cho, Michael H , Palmer, Nicholette D , Mitchell, Braxton D , Shuldiner, Alan R , Redline, Susan , Heckbert, Susan R , He, Jiang , Post, Wendy , Arnett, Donna K , Vasan, Ramachandran S , Weiss, Scott T , McGarvey, Stephen T , Custer, Brian S , Correa, Adolfo , Manson, JoAnn E , Konkle, Barbara A , Loos, Ruth J F , Rotter, Jerome I , Silverman, Edwin K , Kooperberg, Charles , Samani, Nilesh J , Jaiswal, Siddhartha , Libby, Peter , Ellinor, Patrick T , Pankratz, Nathan , Ebert, Benjamin L , Mathias, Rasika A , Do, Ron , Natarajan, Pradeep , Morrison, Alanna C , Bick, Alexander G , Gibson, Christopher James , Clarke, Shoa L. , Codd, Veryan , Wiggins, Kerri L. , Hixson, James E. , Peloso, Gina M. , Tracy, Russell P. , Desai, Pinkal , Curran, Joanne E. , Freedman, Barry I. , Cupples, L. Adrienne , Group, The Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA), Naseri, Take K. , Ballantyne, Christie M. , Rich, Stephen S. , Cho, Michael H. , Pace, Betty S. , Blangero, John , Mitchell, Braxton D. , Shuldiner, Alan R. , Abecasis, Gonçalo R. , Vasan, Ramachandran S. , Darbar, Dawood , Weiss, Scott T. , Andrade, Mariza de , Custer, Brian , Psaty, Bruce M. , Manson, JoAnn E. , Konkle, Barbara A. , Rotter, Jerome I. , Kooperberg, Charles , Libby, Peter , Ellinor, Patrick T. , Pankratz, Nathan
Science Advances | April 6, 2022 | Volume: 8 | Issue: 14 | Pages: No page available
Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.