Genome-wide analysis defines genetic determinants of MPN subtypes and identifies a sex-specific association at <i>CDH22</i> / <i>CD40</i>
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.
Article Details
Authors (20)
William J. Tapper
1Faculty of Medicine, University of Southampton, Southampton, United Kingdom
Ahmed A. Z. Dawoud
1Faculty of Medicine, University of Southampton, Southampton, United Kingdom
Joannah Score
1Faculty of Medicine, University of Southampton, Southampton, United Kingdom
Andrew J. Chase
1Faculty of Medicine, University of Southampton, Southampton, United Kingdom
E. Joanna Baxter
Joanne Ewing
3Department of Haematology, Heartlands Hospital, Birmingham, United Kingdom
Louise Wallis
4Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom
Paola Guglielmelli
3Center for Research and Innovation of Myeloproliferative Neoplasms, AOU Careggi, University of Florence, Florence, Italy
Dolors Colomer
Beatriz Bellosillo
7Hospital del Mar, Hospital del Mar Research Institute, Barcelona, Spain
Montse Gomez
8Hospital Clínico Universitario, Instituto de Investigación Sanitaria, University of Valencia, Valencia, Spain
Juan Carlos Hernández-Boluda
8Hospital Clínico Universitario, Instituto de Investigación Sanitaria, University of Valencia, Valencia, Spain
Carlos Besses
7Hospital del Mar, Hospital del Mar Research Institute, Barcelona, Spain
Francisco Cervantes
10Hematology Department, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain
Steffen Koschmieder
Anthony R. Green
Andreas Reiter
Alessandro Vannucchi
5Center Research and Innovation of Myeloproliferative Neoplasms, Dipartimento di Medicina Sperimentale e Clinica, Azienda Ospedaliero Universitaria Careggi, University of Florence, Florence, Italy
Claire Harrison
11Department of Haematology, Guy’s and St Thomas’ National Health Service Foundation Trust, London, United Kingdom
Nicholas C. P. Cross