Genome-wide analysis defines genetic determinants of MPN subtypes and identifies a sex-specific association at CDH22 / CD40
Year: 2025
Type: article
Study design: Observational Study
Abstract: ABSTRACT: To identify genetic variants that influence myeloproliferative neoplasm (MPN) phenotypes, we undertook a 2-stage patient-only genome-wide association study. MPN subtypes (essential thrombocythemia [ET]; polycythemia vera [PV]) were compared with each other to healthy controls and stratified analyses was performed for chromosome 9p aberrations, JAK2 V617F mutation burden, and sex. The ET vs PV analysis identified known associations: (1) at HBS1L-MYB that increased ET risk (Pmeta = 7.93 × 10-6, odds ratio [OR] = 1.28) and reduced PV risk (Pmeta = 9.43 × 10-5, OR = 0.81) and (2) at GFI1B-GTF3C5 that predisposed to PV only (Pmeta = 1.43 × 10-9, OR = 1.38). Two further linked intronic variants, rs2425786 and rs2425788, at CDH22/CD40 were significant in females only (Pmeta = 2.67 × 10-8), with predisposition to PV (Pmeta = .0006, OR = 1.3) and reduction of ET risk (Pmeta = 7.82 × 10-5, OR = 0.75). A polygenic risk score consisting of 48 variants from 31 loci demonstrated moderate discriminative performance for ET and PV (area under the curve [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.
Source: Blood
Authors: William J. Tapper, Ahmed A. Z. Dawoud, Joannah Score, Andrew J. Chase, E. Joanna Baxter, Joanne Ewing, Louise Wallis, Paola Guglielmelli, Dolors Colomer, Beatriz Bellosillo, Montse Gomez, Juan Carlos Hernández-Boluda, Carlos Besses, Francisco Cervantes, Steffen Koschmieder, Anthony R. Green, Andreas Reiter, Alessandro Vannucchi, Claire Harrison, Nicholas C. P. Cross
Institutions: University of Southampton, University of Cambridge, Heart of England NHS Foundation Trust, Heartlands Hospital, Royal Bournemouth Hospital, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Cáncer, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona, Hospital Del Mar, Hospital del Mar Research Institute, Universitat de València, Hospital Clínico Universitario de Valencia, RWTH Aachen University, Heidelberg University, University Medical Centre Mannheim, National Health Service, Guy's and St Thomas' NHS Foundation Trust
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,500
Funder: North Carolina Pork Council
OpenAlex ID: W4414644210