Germline risk of clonal haematopoiesis

Abstract

Clonal haematopoiesis (CH) is a common, age-related expansion of blood cells with somatic mutations that is associated with an increased risk of haematological malignancies, cardiovascular disease and all-cause mortality. CH may be caused by point mutations in genes associated with myeloid neoplasms, chromosomal copy number changes and loss of heterozygosity events. How inherited and environmental factors shape the incidence of CH is incompletely understood. Even though the several varieties of CH may have distinct phenotypic consequences, recent research points to an underlying genetic architecture that is highly overlapping. Moreover, there are numerous commonalities between the inherited variation associated with CH and that which has been linked to age-associated biomarkers and diseases. In this Review, we synthesize what is currently known about how inherited variation shapes the risk of CH and how this genetic architecture intersects with the biology of diseases that occur with ageing.

Fig. 1. Types of clonal haematopoiesis.

Clonal haematopoiesis refers to a clonal expansion of blood cells that are often identified based on shared genetic mutations. a | An especially common type of clonal haematopoiesis is the mosaic loss of the Y chromosome (mLOY), an entity that is often studied separately from other large chromosomal events. b | When large segments of one or more chromosomes are gained, lost or recombine resulting in the loss of heterozygosity, this may result in clonal haematopoiesis with mosaic chromosomal alterations (mCAs). c | Clonal haematopoiesis may also occur through mutations in myeloid-associated genes, termed clonal haematopoiesis of indeterminate potential (CHIP).

Fig. 2. CH subtypes have shared and unique risk variants.

Many germline risk loci have been linked to the development of clonal haematopoiesis (CH). The three subtypes of CH that have received the greatest scrutiny in this area are mosaic loss of the Y chromosome (mLOY), mosaic chromosomal alterations (mCAs) and clonal haematopoiesis of indeterminate potential (CHIP). These three subtypes are enriched for several of the same germline variants such as those affecting DNA damage response genes CHEK2 and ATM, proliferation factor TCL1A, and telomerase component TERT. However, each of these entities also retains risk loci unique to it alone. Considering the spectrum of variants, one notable pattern is a rarity of mitosis-specific genes in CHIP compared to their relative abundance in mLOY and mCAs. Another broad theme is the high prevalence of previously identified associations between these germline loci and diseases of ageing, including malignancies, cardiovascular disease and dementia. The degree to which CH is involved in these known links to disease remains to be determined. Note: over 150 loci have been associated with mLOY, only a small number of which are depicted in this figure.

Fig. 3. CHIP has polygenic risk.

Genetic association studies have demonstrated that the inherited risk landscape for clonal haematopoiesis of indeterminate potential (CHIP) is characterized by numerous common variants with modest effect sizes and several rare variants associated with strong effects. Associations with the TERT locus have been replicated among numerous studies of individuals with CHIP as well as clonal haematopoiesis (CH) identified by high somatic mutational burden in whole-genome sequencing (WGS-outlier). Furthermore, CH by WGS-outlier is strongly correlated with CHIP and mosaic loss of the Y chromosome, highlighting a robust association between telomere biology and CHIP. Where studies have examined single genes affected by a somatic CHIP mutation, the results point to heterogeneity in their germline associations, both in terms of associated variants (for example, germline TCL1A variation is associated with DNMT3A-CH but not JAK2-CH) and the degree of association (for example, a stronger association of germline TERT variants with JAK2-CH than with CH overall).

Fig. 4. Using germline variation to study causal associations of CH.

Certain situations in which germline variants affect the risk of developing clonal haematopoiesis (CH) can be used to determine whether CH has a causal contribution to a given phenotype. A Mendelian randomization (MR) approach takes advantage of the fact that individuals acquire their germline allelic composition by chance. Any change in CH frequency or clone size due to germline variation can then be treated as the result of a random genetic assignment and used to estimate a causal association between CH and the phenotype. Current evidence suggests that some germline variants may affect CH but do not independently influence the associated phenotypes — such variants are the most likely to be appropriate for MR analyses. For example, TCL1A is known to increase the risk of DNMT3A-CH but is not known to have direct effects on cardiovascular disease (CVD) (part a). However, there is substantial overlap in the genetic architecture of CH and diseases of ageing, so some inherited variants may affect both CH and observed phenotypes. In such cases, MR estimates of causality are confounded by the direct association of the germline variant with the outcome. A good example of this is germline variation in SH2B3, which is associated with both the risk of JAK2-CH and CVD (part b). Unless this latter association can be properly accounted for, a typical MR approach would overestimate the effect of JAK2 on CVD.