Project Summary Age is the dominant risk factor for most chronic diseases; yet mechanisms by which aging confers risk are largely unknown. One unifying feature of aging diseases as diverse as cardiovascular disease and cancer is the acquisition of somatic mutations in hematopoietic stem cells (frequently DNMT3A, TET2, JAK2), termed Clonal Hematopoiesis of Indeterminate Potential (CHIP). I will leverage human genomics to identify pathways underlying CHIP acquisition, clonal expansion and disease. Why only some individuals develop CHIP, why only some CHIP clones expand, and why only a minority of CHIP carriers develop disease is presently unknown. I hypothesize that germline genetic variation contributes to CHIP acquisition, clonal expansion and disease. I propose to (1) identify CHIP in existing genome sequencing data and perform genetic association analyses of CHIP in >800,000 individuals and evaluate how CHIP-associated variants alter human hematopoietic stem cell function in in-vitro follow-up experiments. (2) Define the determinants of CHIP clonal expansion and association with disease. (3) Identify gene expression programs that cause clonal expansion and disease. Successful execution of these aims will highlight therapeutic targets for the prevention of CHIP, clonal expansion and disease for which no therapies currently exist. Such a CHIP therapeutic would potentially be an intervention for multiple aging diseases. To succeed in these aims, I will receive significant institutional support from MGH including funding, space, protected time and mentorship to establish my research group. The Broad Institute will provide access to leading-edge genomic resources. I will leverage my unique position at the interface of these two scientific communities to establish a leading research program focused on CHIP. Having completed rigorous training in genomics, cardiovascular biology, and clinical medicine, I am now poised to leverage these skills, resources and mentorship to embark on my own independent research career without delay.

Project Narrative More than 10% of adults over 70, have a somatic mutation in their blood stem cells, a newly identified disease termed ‘Clonal Hematopoiesis of Indeterminate Potential’ (CHIP), which increases blood cancer risk by 10-fold, heart attack risk by 2-fold and risk of death by 1.5-fold. To understand the fundamental causes and disease consequences of CHIP, we will perform human genomic analyses of hundreds of thousands of individuals with and without CHIP. Our work identifying the causes of CHIP may lead to the first treatment for patients with CHIP that would prevent multiple age-associated diseases.