Genome-wide analysis defines genetic determinants of MPN subtypes and identifies a sex-specific association at CDH22/CD40.
Tapper, William J Dawoud, Ahmed A Z Score, Joannah Chase, Andrew J Baxter, E Joanna Ewing, Joanne Wallis, Louise Guglielmelli, Paola Colomer, Dolors Bellosillo, Beatriz
Tapper, William J
Dawoud, Ahmed A Z
Score, Joannah
Chase, Andrew J
Baxter, E Joanna
Ewing, Joanne
Wallis, Louise
Guglielmelli, Paola
Colomer, Dolors
Bellosillo, Beatriz
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Publication date
2025-09-30
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Abstract
To identify genetic variants that influence myeloproliferative neoplasm (MPN) phenotype, we undertook a two-stage case-only genome-wide association study using cohorts from the UK (including UK Biobank), Spain, Germany and Italy. MPN subtype [essential thrombocythemia (ET); polycythemia vera (PV)] were compared to each other, to healthy controls and stratified analyses was performed based on chromosome 9p aberrations, JAK2 V617F mutation burden and sex. The ET versus PV analysis identified known associations: (i) at HBS1L-MYB that increased ET risk (PMETA=7.93x10-6, OR=1.28) and reduced PV risk (PMETA=9.43x10-5, OR=0.81) and (ii) at GFI1B-GTF3C5 that predisposed to PV only (PMETA=1.43x10-9, OR=1.38). Two further linked intronic SNPs, rs2425786 and rs2425788, at CDH22/CD40 were significant in females only (PMETA=2.67x10-8) with predisposition to PV (PMETA=0.0006, OR=1.3) and reduction of ET risk (PMETA=7.82x10-5, OR=0.75). Associations with JAK2, TERT, ATM, TET2, PINT, GFI1B and SH2B3 were confirmed (PMETA<5x10-8) and nine further loci were replicated (PMETA<0.05). A polygenic risk score consisting of 48 SNPs from 31 loci demonstrated moderate discriminative performance for ET and PV (AUC=0.718) and was improved by optimization for disease subtype (AUCET=0.724 and AUCPV=0.755). Overall, our results reveal that multiple germline variants influence MPN phenotype with HBS1L-MYB and a novel sex-specific association with CDH22/CD40 being the strongest determinants.
Citation
Tapper WJ, Dawoud AAZ, Score J, Chase AJ, Baxter EJ, Ewing J, Wallis L, Guglielmelli P, Colomer D, Bellosillo B, Gomez M, Hernandez-Boluda JC, Besses C, Cervantes F, Koschmieder S, Green AR, Reiter A, Vannucchi AM, Harrison CN, Cross NCP. Genome-wide analysis defines genetic determinants of MPN subtypes and identifies a sex-specific association at CDH22/CD40. Blood. 2025 Sep 30:blood.2025028489. doi: 10.1182/blood.2025028489. Epub ahead of print.
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Article