Niroula, Abhishek
Mayo Clinic
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Citations 2
Genomic and phenomic landscape of clonal hematopoiesis in over a million ancestrally diverse participants
Uddin, Md Mesbah , Weinstock, Joshua S. , Niroula, Abhishek , Vlasschaert, Caitlyn , Koyama, Satoshi , Nakao, Tetsushi , Urbut, Sarah , Paruchuri, Kaavya , Silver, Alexander J. , Mack, Taralynn , Wong, Megan , Bhattacharya, Romit , Jorshery, Saman Doroodgar , Raddatz, Michael A. , Hornsby, Whitney , Kresge, Hailey A. , Cho, Kelly , Sun, Yan V. , Pyarajan, Saiju , Chen, Yii‐Der Ida , Sheu, Wayne H-H , Hung, Yi‐Jen , Hidalgo, Bertha , Fornage, Myriam , Kaplan, Robert C., Williams, L. Keoki , Province, Mike , Kardia, Sharon, Peyser, Patricia A., Yanek, Lisa R. , Becker, Lewis C. , Meyers, Deborah A. , Naseri, Take, Barnes, Kathleen C. , Redline, S S, Schwartz, D A, Shoemaker, M. Benjamin , Palmer, Nicholette D., Bowden, Donald W., Kumar, Rajesh, Nj, Smith, Floyd, James, Tracy, Russell, Bis, Joshua C. , SS, Rich, Boerwinkle, Eric, Wang, Zhe, Silverman, Edwin K. , Auer, Paul L. , Reiner, Alexander P. , Ebert, Benjamin L. , Natarajan, Pradeep , Uddin, Md M , Niroula, Abhishek , Weinstock, Joshua S , Bhattacharya, Romit , Ebert, Benjamin L , Natarajan, Pradeep , Yu, Zhi , Zekavat, Seyedeh M , Truong, Buu Minh Thanh , Haidermota, Sara , Honigberg, Michael C. , Zhang, Martin Jinye , Dron, Jacqueline S. , Heimlich, Jonathan Brett , Sankaran, Vijay G. , Griffin, Gabriel K. , Gibson, Christopher James , Wilson, Peter W.F. , Genovese, Giulio , Xu, Yaomin , Savona, Michael R. , Raffield, Laura M. , Arnett, Donna K. , Konkle, Barbara A. , Peyser, Patricia A. , Smith, Jennifer A. , Mathias, Rasika A. , Andrade, Mariza de , Darbar, Dawood , He, Jiang , Blangero, John , Weiss, Scott T. , Custer, Brian , Minster, Ryan L , Viali, Satupaitea , Mitchell, Braxton D. , Palmer, Nicholette D , Freedman, Barry I. , Bowden, Donald W. , Albert, Christine M. , Smith, Nicholas, Tracy, Russell P. , Psaty, Bruce M. , Taylor, Kent D. , Rotter, Jerome I. , Boerwinkle, Eric , Vasan, Ramachandran S. , Lubitz, Steven A. , Ellinor, Patrick T. , Loos, Ruth J. F. , Yun, Jeong H. , Cho, Michael H. , Abecasis, Gonçalo R. , Kooperberg, Charles , Reiner, Alex P. , Jaiswal, Siddhartha , Bick, Alexander G.
No container title available | July 31, 2022 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract With aging, somatic mutations in hematopoietic stem and progenitor cells (HSPC) can give rise to clonal hematopoiesis of indeterminate potential (CHIP), a premalignant state associated with diverse age-related diseases. Here we report the largest multi-ancestry genome-wide analysis of CHIP to date (N = 1,018,305), including individuals of African (N = 85,978), Admixed American (N = 191,371), East Asian (N = 13,532), European (N = 694,015), and South Asian (N = 13,193) ancestry. Multi-ancestry meta-analyses identified 72 genome-wide significant loci, including 44 novel associations implicating genes such as AFF1 , ATF7IP , ATP8B4 , BCL2 , CEBPA , CYRIA , DNM2 , ELF1 , NKX2-3 , PIK3CB , PRDM16 , RPN1 , TERC , and TRIM4 . Notably, variants at MECOM and PHF20L1 showed opposite allelic effects between DNMT3A - and non- DNMT3A -driven CHIP, highlighting driver-specific germline influences. Implicated loci converge on pathways regulating telomere maintenance, cell-cycle control, hematopoietic transcription, DNA damage response and immune signaling. These findings support a model in which germline variation both expands the HSPC pool and biases clonal selection in a driver-dependent manner, providing a mechanistic basis for inter-individual heterogeneity in CHIP. Phenome-wide association analyses further linked CHIP to hematologic, neoplastic, and circulatory traits, with enrichment across hematopoietic and non-hematopoietic cell types. Together, this work expands the genomic and phenomic landscape of CHIP and reveals germline–somatic interactions that shape clonal evolution during aging.
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.