Genetic predisposition to myeloproliferative neoplasms implicates hematopoietic stem cell biology

Abstract

3Myeloproliferative neoplasms (MPNs) are blood cancers characterized by excessive production of mature myeloid cells that result from the acquisition of somatic driver mutations in hematopoietic stem cells (HSCs) 1 . While substantial progress has been made to define the causal somatic mutation profile for MPNs 2 , epidemiologic studies indicate a significant heritable component for the disease that is among the highest known for all cancers 3 . However, only a limited set of genetic risk loci have been identified, and the underlying biological mechanisms leading to MPN acquisition remain unexplained. Here, to define the inherited risk profile, we conducted the largest genome-wide association study of MPNs to date (978,913 individuals with 3,224 cases) and identified 14 genome-wide significant loci, as well as a polygenic signature that increases the odds for disease acquisition by nearly 3-fold between the top and median deciles. Interestingly, we find a shared genetic architecture between MPN risk and several hematopoietic traits spanning distinct lineages, as well as an association between increased MPN risk and longer leukocyte telomere length, collectively implicating HSC function and self-renewal. Strikingly, we find a significant enrichment for risk variants mapping to accessible chromatin in HSCs compared with other hematopoietic populations. Finally, gene mapping identifies modulators of HSC biology and targeted variant-to-function analyses suggest likely roles for CHEK2 and GFI1B in altering HSC function to confer disease risk. Overall, we demonstrate the power of human genetic studies to illuminate a previously unappreciated mechanism for MPN risk through modulation of HSC function. 4 Main Text:We initially sought to characterize the germline genetic architecture that confers risk for MPNs, and therefore conducted a genome-wide association study (GWAS) meta-analysis using three population-based cohorts (UK Biobank (UKBB), 23andMe, and FinnGen). The combined sample size comprised 2,627 MPN cases and 755,476 controls, more than doubling the number of cases from prior studies (Supplementary Table 1, Extended Data Fig. 1). We tested 7,329,649 well-represented variants passing central and studyspecific quality control measures. Linkage disequilibrium score regression (LDSC) 4 showed negligible inflation in test statistics due to population structure, with an intercept of 1.005 and genomic control factor of 1.0255. We estimate the narrow-sense heritability for MPN risk to be 0.0717 (s.e. = 0.0306) on the liability scale, suggesting that ~7% of variance in MPN risk can be attributed to common genetic variation (MAF > 1%), assuming a disease prevalence of 0.0328%, as reported in population studies 5,6 .Analysis of GWAS signals using GCTA 7 revealed 12 linkage disequilibrium (LD)independent loci at genome-wide significance (p < 5 x 10 -8 ) and an additional 16 loci with suggestive associations (p < 1 x 10 -6 ) ( Fig. 1a, Supplementary Table 2). Previous studies have shown that carriers of the somatic JAK2 V617...

Unraveling Hematopoiesis through the Lens of Genomics

“…With an ever-growing ability to more precisely track individual clones at single-cell resolution (Nam et al, 2019), it is likely to become more apparent why CHIP occurs in some individuals but not others and why it predominantly appears to be limited to the elderly population. Moreover, recent work has identified several genetic loci that confer a risk of developing CHIP and myeloproliferative disorders with age, suggesting that alterations in fundamental cellular processes may promote clonal expansion (Bao et al, 2019a;Bick et al, 2019b). New genomic tools may help to interrogate the functional consequences of these genetic risk factors and define the effect of disease in disrupting the HSC population in a manner that promotes development of clonal hematopoiesis.…”

“…In addition, beyond studies of blood cell traits, there are likely to be important opportunities to study cryptic phenotypes that might occur because of altered hematopoiesis. For instance, although clonal blood disorders and cancers are thought to arise primarily because of the acquisition of somatic mutations in HSCs or other hematopoietic cells, it is clear that inherited genetic variation can alter this risk significantly (Bao et al, 2019a;Bick et al, 2019b;Vijayakrishnan et al, 2018;Went et al, 2018). Understanding the mechanisms that underlie such germline genetic predisposition for common and rare genetic variants will undoubtedly advance our knowledge of how genetic variation can influence hematopoiesis in different ways.…”

Combining genome-wide studies of breast, prostate, ovarian and endometrial cancers maps cross-cancer susceptibility loci and identifies new genetic associations

“…Some loci associated with blood cell traits, in particular blood cell counts, likely represent cell-type agnostic biomarkers of cellular turnover and proliferative potential -biological processes that, in turn, may link them to solid tumor risk. Indeed, common genetic variants at SH2B3, ATM, TERT, TET2, and CHEK2 are associated with multiple blood cell traits 55 and with myeloproliferative neoplasms 56,57 , and were the genes nearest to five cross-cancer lead SNPs identified in the current study. For example, our lead SNP rs7310615 that maps to SH2B3 (Pbreast = 3 x 10 -7 and Pendometrial = 1.3 x 10 -10 ) is a genome-wide significant lead SNP associated with white blood cell, red blood cell and platelet counts and other blood cell traits 55 , and with myeloproliferative neoplasms 56,57 .…”

“…Indeed, common genetic variants at SH2B3, ATM, TERT, TET2, and CHEK2 are associated with multiple blood cell traits 55 and with myeloproliferative neoplasms 56,57 , and were the genes nearest to five cross-cancer lead SNPs identified in the current study. For example, our lead SNP rs7310615 that maps to SH2B3 (Pbreast = 3 x 10 -7 and Pendometrial = 1.3 x 10 -10 ) is a genome-wide significant lead SNP associated with white blood cell, red blood cell and platelet counts and other blood cell traits 55 , and with myeloproliferative neoplasms 56,57 . Rare germline missense variants in SH2B3 and ATM are also associated with the blood cell (somatic) acquisition of loss-ofheterozygosity (LOH) in the chromosomal arms where these genes reside, which may result in the aberrant clonal expansion of the blood cells acquiring these LOH events or clonal hematopoeisis 58 .…”