Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over a third of people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14. Genes at new loci implicate DNA damage repair (PARP1, ATM, CHEK2), hematopoietic stem cell migration/homing (CD164) and myeloid oncogenesis (SETBP1). Several associations were CH-subtype-specific including variants at TCL1A and CD164 that had opposite associations with DNMT3A- versus TET2-mutant CH, the two most common CH subtypes, proposing key roles for these two loci in CH development. Mendelian randomization analyses showed that smoking and longer leukocyte telomere length are causal risk factors for CH and that genetic predisposition to CH increases risks of myeloproliferative neoplasia, nonhematological malignancies, atrial fibrillation and blood epigenetic ageing.
The pervasive effects of ageing and somatic mutation shape the landscape of human disease in later life1. A ubiquitous feature of ageing is the development of somatic mutation-driven clonal expansions in aged tissues2,3. In blood, somatic mutations that enhance cellular fitness of individual hematopoietic stem cells (HSCs) and their progeny give rise to the common age-related phenomenon of CH4,5,6,7. CH becomes increasingly prevalent with age4,5,6 and is associated with an increased risk of hematological cancers4,5,8,9 and some nonhematological conditions5,10,11. However, our understanding of the biological basis for these associations remains limited, as does our ability to explain how CH driver mutations promote clonal expansion of mutant HSCs12. In fact, whilst CH is defined by its association with somatic mutations, its development is influenced by nonmutation factors13,14,15,16 and by the heritable genome17,18, in ways that remain poorly understood.
We present an observational and genetic epidemiological analysis of CH in 200,453 individuals in the UKB and report a series of insights into the causes and consequences of this common aging-associated phenomenon. We increase the number of germline associations with CH in European-ancestry populations from 4 (ref. 17) to 14, reveal heterogeneity of associations by CH driver gene and clone size, and implicate putative new CH susceptibility genes, including CD164, ATM and SETBP1, through functional annotation. We also demonstrate that the CH GWAS signal is enriched at epigenetic marks specific to the hematopoietic system, particularly in open chromatin regions of hematopoietic stem/progenitor cells. The robustness of our GWAS is supported by replication of the vast majority of associations in an additional set of 221,285 individuals from the UKB and further affirmed by our replication of previous European-ancestry-specific CH associations17, the consistency of our estimates of CH heritability with previous reports17,79 and the fact that many of our lead variants are associated with related traits29,31,60,80.
Abstract:This study presents the characteristics and performance of a motor at the operating point based on pulse-width modulation (PWM). PWM is used in modulating the output voltage of a three-phase inverter. The PWM technique has advantages and disadvantages depending on the system size and operating range. For example, some discontinuous pulse-width modulation (DPWM) techniques are advantageous in low-cost systems because they can reduce the number of switches. Some PWM techniques are complicated for software construction and require a lot of computation. In this paper, PWM techniques were constructed by using the offset voltage injection method. Therefore, the construction of the PWM technique is simplified by the method. In an experimental setup, an interior permanent-magnet synchronous motor (IPMSM) and a three-phase inverter were implemented to test motor control performance depending on the PWM technique. In addition, the current control characteristics and inverter efficiency were analyzed and compared depending on the speed and load of the motor. According to the results of this paper, it is possible to compare the motor and inverter control characteristics using various types of PWM rapidly. Additionally, it will help to select an appropriate PWM technique for a specific system.Keywords: pulse-width modulation; inverter efficiency; IPMSM driver; offset voltage; CPWM; DPWM 781b155fdc