Inherited Causes of Clonal Hematopoiesis of Indeterminate Potential in TOPMed Whole Genomes
Authors: Bick Alexander G , Weinstock Joshua S , Nandakumar Satish K , Fulco Charles P , Leventhal Matthew J , Bao Erik L , Nasser Joseph , Zekavat Seyedeh M , Szeto Mindy D , Laurie Cecelia , Taub Margaret A , Mitchell Braxton D , Barnes Kathleen C , Moscati Arden , Fornage Myriam , Redline Susan , Psaty Bruce M , Silverman Edwin K , Weiss Scott T , Palmer Nicholette D , Vasan Ramachandran S , Burchard Esteban G , Kardia Sharon LR , He Jiang , Kaplan Robert C , Smith Nicholas L , Arnett Donna K , Schwartz David A , Correa Adolfo , de Andrade Mariza , Guo Xiuqing , Konkle Barbara A , Custer Brian , Peralta Juan M , Gui Hongsheng , Meyers Deborah A , McGarvey Stephen T , Chen Ida Yii-Der , Shoemaker M. Benjamin , Peyser Patricia A , Broome Jai G , Gogarten Stephanie M , Wang Fei Fei , Wong Quenna , Montasser May E , Daya Michelle , Kenny Eimear E , North Kari , Launer Lenore J , Cade Brian E , Bis Joshua C , Cho Michael H , Lasky-Su Jessica , Bowden Donald W , Cupples L Adrienne , Mak Angel CY , Becker Lewis C , Smith Jennifer A , Kelly Tanika N , Aslibekyan Stella , Heckbert Susan R , Tiwari Hemant K , Yang Ivana V , Heit John A , Lubitz Steven A , Rich Stephen S , Johnsen Jill M , Curran Joanne E , Wenzel Sally , Weeks Daniel E , Rao Dabeeru C , Darbar Dawood , Moon Jee-Young , Tracy Russell P , Buth Erin J , Rafaels Nicholas , Loos Ruth JF , Hou Lifang , Lee Jiwon , Kachroo Priyadarshini , Freedman Barry I , Levy Daniel , Bielak Lawrence F , Hixson James E , Floyd James S , Whitsel Eric A , Ellinor Patrick , Irvin Marguerite R , Fingerlin Tasha E , Raffield Laura M , Armasu Sebastian M , Rotter Jerome I , Wheeler Marsha M , Sabino Ester C , Blangero John , Williams L. Keoki , Levy Bruce D , Sheu Wayne Huey-Herng , Roden Dan M , Boerwinkle Eric , Manson JoAnn E , Mathias Rasika A , Desai Pinkal , Taylor Kent D , Johnson Andrew , Auer Paul L , Kooperberg Charles , Laurie Cathy C , Blackwell Thomas W , Smith Albert V , Zhao Hongyu , Lange Ethan , Lange Leslie , Wilson James G , Lander Eric S , Engreitz Jesse M , Ebert Benjamin L , Reiner Alexander P , Sankaran Vijay G , Jaiswal Sidd , Abecasis Goncalo , Natarajan Pradeep , Kathiresan Sekar ,   on behalf of the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Published: September 2019

Age is the dominant risk factor for most chronic human diseases; yet the mechanisms by which aging confers this risk are largely unknown.1 Recently, the age-related acquisition of somatic mutations in regenerating hematopoietic stem cell populations was associated with both hematologic cancer incidence2–4 and coronary heart disease prevalence.5 Somatic mutations with leukemogenic potential may confer selective cellular advantages leading to clonal expansion, a phenomenon termed ‘Clonal Hematopoiesis of Indeterminate Potential’ (CHIP).6 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.