Common and rare variant associations with clonal haematopoiesis phenotypes

Abstract

Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes 1 – 5 . Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75 , which are associated with reduced incidence of CHIP. We also identify novel rare variant associations with clonal haematopoiesis and telomere length. Analysis of 5,041 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID-19 outcomes, cardiovascular disease, haematologic traits, malignancy, smoking, obesity, infection and all-cause mortality. Longitudinal and Mendelian randomization analyses revealed that CHIP is associated with solid cancers, including non-melanoma skin cancer and lung cancer, and that CHIP linked to DNMT3A is associated with the subsequent development of myeloid but not lymphoid leukaemias. Additionally, contrary to previous findings from the initial 50,000 UKB exomes 6 , our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogeneous phenotypes with shared and unique germline genetic causes and varied clinical implications.

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

“…The X chromosome, particularly the inactive X, is more frequently mutated in cancer genomes 19 and is late replicating relative to autosomes, potentially increasing susceptibility to chromosomal alterations 20 . While few genome-wide association studies (GWAS) of mLOX have been reported to date 14,21 , GWAS of mosaic loss of the Y chromosome (mLOY) in men has identified hundreds of susceptibility loci 11-13,22 , many of which highlight genes involved in cell cycle regulation and cancer susceptibility. Here we describe insights from epidemiologic and genetic analyses of X chromosome loss from a combined meta-analysis of 904,524 women.…”

Genetic causes and cardiovascular consequences of clonal hematopoiesis in the UK Biobank

“…Fig. 1 | CH is associated with health outcomes across many organ systems.Boxes shaded green highlight associations between CH and diseases that were replicated by Kessler et al9 . COPD, chronic obstructive pulmonary disease.…”

“…The most common being loss of Y or X chromosomes, otherwise known as mosaic loss of Y and X (mLOY and mLOX, respectively). Similar to the gene-specific analyses, the authors Boxes shaded green highlight associations between CH and diseases that were replicated by Kessler et al 9 . COPD, chronic obstructive pulmonary disease.…”

“…Differences in filtering after variant calling, even among groups using the same variant caller, can lead to differences in the frequency of CH in the UKB. For example, CH was detected in 5.5% of individuals by Kar et al 15 , 6% by Kessler et al 9 and 3.4% by Vlasschaert et al 8 in the UKB. There is no consensus about best practices for CH variant calling, and variation in methodology influences association results.…”

“…In a recent issue of Nature, Kessler et al 9 analyze whole-exome sequencing data from 628,388 individuals in the UK Biobank (UKB) and the Geisinger MyCode Community Health Initiative to identify 40,208 individuals with CH. They identified several new germline genetic loci associated with CH, and studied the effect of CH on a wide variety of health outcomes.…”