A practical approach to curate clonal hematopoiesis of indeterminate potential in human genetic datasets

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is a common form of age-related somatic mosaicism that is associated with significant morbidity and mortality. CHIP mutations can be identified in peripheral blood samples sequenced using approaches that cover the whole genome, whole exome or targeted genetic regions; however, differentiating true CHIP mutations from sequencing artifacts and germline variants is a considerable bioinformatic challenge. We present a stepwise method that combines filtering based on sequencing metrics, variant annotation, and population-based associations to increase the accuracy of CHIP calls. We apply this approach to ascertain CHIP in ~550,000 individuals in the UK Biobank complete whole exome cohort and the All of Us Research Program initial whole genome release cohort. CHIP ascertainment on this scale unmasks recurrent artifactual variants and highlights the importance of specialized filtering approaches for several genes including TET2 and ASXL1. We show how small changes in filtering parameters can considerably increase CHIP misclassification and reduce the effect size of epidemiological associations. Our high-fidelity call set refines prior population-based associations of CHIP with incident outcomes. For example, the annualized incidence of myeloid malignancy in individuals with small CHIP clones is 0.03%/year, which increases to 0.5%/year amongst individuals with very large CHIP clones. We also find a significantly lower prevalence of CHIP in individuals of self-reported Latino or Hispanic ethnicity in All of Us, highlighting the importance of including diverse populations. The standardization of CHIP calling will increase the fidelity of CHIP epidemiological work and is required for clinical CHIP diagnostic assays.

BRCC3-Mediated NLRP3 Deubiquitylation Promotes Inflammasome Activation and Atherosclerosis in Tet2 Clonal Hematopoiesis

“…TET2 CH represents a common somatic genetic variation promoting atherosclerotic CVD especially in the elderly, similarly affecting men and women and groups of different ancestry in the United States. 40 Our study provides new insight into the mechanisms of NLRP3 inflammasome activation in TET2-deficient murine and human macrophages, and in Tet2 CH mice, mediated by a JNK1/BRCC3 NLRP3 deubiquitylation pathway that increases NLRP3 inflammasome activation. This mechanism of NLRP3 inflammasome activation has not previously been implicated in accelerated atherosclerosis.…”

Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection

“…To examine the potential impacts of other types of CH on mLOX associations with leukemia, we performed sensitivity analyses in UKBB where we had available calls on autosomal mosaic chromosomal alterations (mCAs) as well as CH mutations in driver genes, commonly referred to as clonal hematopoiesis of indeterminate potential (CHIP) 36 . We observed attenuations in associations for expanded mLOX when removing individuals with autosomal mCAs (HR=3.8 [1.6-9.3], P=2.7×10 −3 ), CHIP (HR=6.2 [3.1-12.4], P=3.1×10 −7 ) and both mCAs and CHIP (HR=4.5 [1.9-10.8], P=8.6×10 −4 ) ( Supplementary Table S7 ); however, significant associations with expanded mLOX and overall leukemia risk remained indicating mLOX is independently associated with leukemia risk.…”

Inflammasomes and Atherosclerosis: a Mixed Picture

“…100 However, risk estimates in UKB are attenuated by the much healthier status of UKB subjects than the general UK population 101 and likely in this study 100 by insufficient depth of sequencing and mutation mis-calling. 101,102 Moreover, the Mendelian randomization analysis mainly used SNPs near the DNMT3A gene that were not associated with CVD risk and thus represent a weak instrument as acknowledged by the authors. 100…”