Genome-wide analyses of 200,453 individuals yields new insights into the causes and consequences of clonal hematopoiesis

Abstract Clonal hematopoiesis (CH) is one of the most extensively studied somatic mutational phenomena, yet its causes and consequences remain poorly understood. We identify 10,924 individuals with CH amongst 200,453 whole-exome sequenced UK Biobank participants and use their linked genome-wide DNA genotypes to map the landscape of inherited predisposition to CH. We increase the number of European-ancestry genome-wide significant ( P <5×10 −8 ) germline associations with CH from four to 14 and identify one new transcriptome-wide significant ( P <3.2×10 −6 ) association. Genes at new loci implicate DNA damage repair ( PARP1, ATM , and CHEK2 ), hematopoietic stem cell migration/homing ( CD164 ), and myeloid oncogenesis ( SETBP1 ) in CH development. Several associations were CH-subtype specific and, strikingly, variants at TCL1A and CD164 had opposite associations with DNMT3A -versus TET2 -mutant CH, mirroring recently reported differences in lifelong behavior of these two most common CH subtypes and proposing important roles for these loci in CH pathogenesis. Using Mendelian randomization, we show, amongst other findings, that smoking and longer leukocyte telomere length are causal risk factors for CH and demonstrate that genetic predisposition to CH increases risks of myeloproliferative neoplasia, several non-hematological malignancies, atrial fibrillation, and blood epigenetic age acceleration.