Novel Germline Loci Are Associated with Clonal Hematopoiesis Risk

Somatic mutations that arise in blood cells can enhance cellular fitness, leading to clonal expansion of hematopoietic stem cells. This phenomenon of clonal hematopoiesis (CH) increases with age and is associated with a higher risk of blood cancers, as well as various nonhematologic diseases. Although driver mutations are known to occur in genes such as DNMT3A and TET2, which encode epigenetic regulators and distinguish the two most common CH subtypes, the mechanisms that underlie clonal expansion and the increased risk of cancer are not well characterized. To address this, Kar, Quiros, and colleagues investigated the genetic and phenotypic associations of CH in a cohort of over 200,000 individuals in the UK Biobank. Logistic regression analyses indicated that age, hypertension, and smoking status were associated with development of CH, whereas a phenome-wide association study demonstrated that CH was strongly associated with development of myeloid malignancies, as well as lymphoma, lung cancer, and kidney cancer. A genome-wide association study of individuals with genetically inferred European ancestry identified seven germline variants associated with CH risk, including four novel variants in ENPP6, TERT, CD164, and ATM. In addition, stratification of CH subtypes uncovered previously unreported variants associated with subtype-specific risk, including variants in CD164, CHEK2, PARP1, and SETBP1 for DNMT3A-mutant CH, in TMEM209 and TCL1A for TET2-mutant CH, and in LINC02064 for small clone CH—each of which was prioritized as putative functional target genes that implicates the role of DNA damage repair, stem cell migration, and oncogene signaling. Notably, the TCL1A and CD164 variants had opposite effects on DNMT3A- versus TET2-mutant CH, potentially reflecting the role of these loci in CH subtype development. Mendelian randomization analyses further highlighted multiple causal risk factors, including smoking and leukocyte telomere length, as well as consequences of CH, including myeloproliferative neoplasms and various solid tumors. In summary, this work comprehensively analyzes germline loci associated with CH and uncovers multiple novel insights into clonal CH.

Kar SP, Quiros PM, Gu M, Jiang T, Mitchell J, Langdon R, et al. Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis. Nat Genet 2022;54:1155–66.

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