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Inherited Causes of Clonal Hematopoiesis of Indeterminate Potential in TOPMed Whole Genomes

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

Posted 27 Sep 2019
bioRxiv DOI: 10.1101/782748

Age is the dominant risk factor for most chronic human diseases; yet the mechanisms by which aging confers this risk are largely unknown. Recently, the age-related acquisition of somatic mutations in regenerating hematopoietic stem cell populations was associated with both hematologic cancer incidence and coronary heart disease prevalence. Somatic mutations with leukemogenic potential may confer selective cellular advantages leading to clonal expansion, a phenomenon termed 'Clonal Hematopoiesis of Indeterminate Potential' (CHIP). Simultaneous germline and somatic whole genome sequence analysis now provides the opportunity to identify root causes of CHIP. Here, we analyze high-coverage whole genome sequences from 97,691 participants of diverse ancestries in the NHLBI TOPMed program and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid, and inflammatory traits specific to different CHIP genes. Association of a genome-wide set of germline genetic variants identified three genetic loci associated with CHIP status, including one locus at TET2 that was African ancestry specific. In silico-informed in vitro evaluation of the TET2 germline locus identified a causal variant that disrupts a TET2 distal enhancer. Aggregates of rare germline loss-of-function variants in CHEK2, a DNA damage repair gene, predisposed to CHIP acquisition. Overall, we observe that germline genetic variation altering hematopoietic stem cell function and the fidelity of DNA-damage repair increase the likelihood of somatic mutations leading to CHIP.

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