Polygenic germline loci are a major contributor to population variation in common blood cell traits, but little is known about how such predisposition influences clonal selection and cancer. Myeloproliferative neoplasms (MPN) are rare chronic haematological cancers characterised by the abnormal overproduction of mature blood cells leading to elevated blood cells parameters, and are driven by somatic mutations, e.g. JAK2V617F. JAK2 mutations result in a spectrum of phenotypes from asymptomatic clonal haematopoiesis (CH) to distinct MPN subtypes characterised by increased red blood cells (polycythaemia vera; PV) and platelets (essential thrombocythaemia; ET) respectively. Compared to MPN, mutant JAK2 is much more common in the population, the vast majority of whom do not meet, or go on to develop, disease defining characteristics of MPN. Little is understood about why only a minority of individuals with mutated JAK2 develop more severe haematological manifestations that fulfil the clinical criteria of MPN and the factors that influence blood count heterogeneity in MPN. We assessed how polygenic germline scores (PGS), based on associated genetic variants, for 29 haematological traits drive JAK2V617F positivity in UK Biobank (UKBB) (n=540 mutation carriers, 161,994 non-carriers). Accounting for the recognised predisposition towards MPN driven by the JAK2 46/1 haplotype and other known germline variants associated with MPN, we found significant positive associations with JAK2V617Fclones for the PGSs of plateletcrit (PGS PCT) and monocyte count (PGS MONO) ( P =9.510 -4 and 0.0036 respectively with FDR<0.05 for small clones [VAF <0.1, n=397]; 0.033 and 0.0022 with FDR adjusted P = 0.31 and 0.064 for large clones [VAF 0.1 or greater, n=143]). Empowered by genome-wide association study data associated with JAK2V617F positivity in the full UKBB data (n = 1,125 mutation carriers, 338,919 non-carriers), we identified strong evidence that genetically predicted monocytes (odds ratio [OR] 1.31, 95% confidence interval [CI]=1.15-1.49, P=4.610 -5) and plateletcrit (OR 1.52, CI=1.29-1.78; P=3.010 -7) are causal risk factors for JAK2V617F clonal expansion. We genotyped genome-wide SNPs in 761 MPN patients whom had detailed somatic mutation data, and built PGSs for blood cell traits in patients and 30,305 healthy controls. Germline predisposition to several higher red-cell traits increased the odds of PV (OR 1.22, CI=1.01-1.47 to 1.57, CI=1.34-1.86]), while high PGSs for two platelet traits predisposed to ET (OR 1.56, CI=1.44-1.70; OR 1.72, CI=1.44-2.02). Results were validated in MPN and healthy controls from UKBB. Importantly, extreme PGS for blood cell traits associated with an MPN diagnosis in the absence of somatic driver mutations in both patients and UKBB, potentially mimicking the haematological phenotype of clonal disease. We confirmed that the heritability of MPN subtype via polygenic predisposition to normal blood traits was independent of known germline MPN and CH risk loci. In summary, by analysing two large MPN disease cohorts and UKBB, we provide new insights into the interaction between germline polygenic variation involved in basic haematopoiesis and clonal selection on somatic driver mutations in blood. We demonstrate that genetically predicted haematological traits can causally influence clonal selection on mutant JAK2, and the polygenic predisposition of blood cell traits influences the phenotype of subsequent blood cancer. Our results highlight an independent and causal new component of the overall susceptibility to clonal disease and provide a novel framework for considering an individual's genetic background in the context of their clinical presentation.
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