Journal article

Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Paul A Lyons, James E Peters, Federico Alberici, James Liley, Richard MR Coulson, William Astle, Chiara Baldini, Francesco Bonatti, Maria C Cid, Heather Elding, Giacomo Emmi, Joerg Epplen, Loic Guillevin, David RW Jayne, Tao Jiang, Iva Gunnarsson, Peter Lamprecht, Stephen Leslie, Mark A Little, Davide Martorana Show all

Nature Communications | NATURE PUBLISHING GROUP | Published : 2019

Abstract

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratif..

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Grants

Awarded by Arthritis Research UK


Awarded by British Heart Foundation


Awarded by Medical Research Council Programme Grant


Awarded by Wellcome Trust


Awarded by Medical Research Council


Awarded by UK Research Innovation Fellowship


Awarded by Science Foundation Ireland


Awarded by Career Development Fellowship


Awarded by Victorian Life Sciences Computation Initiative (VLSCI) on its Peak Computing Facility at the University of Melbourne, an initiative of the Victorian Government, Australia


Awarded by Ministry of Health of Czech Republic


Awarded by Ministerio de Economia y Competitividad


Awarded by Instituto de Salud Carlos III


Funding Acknowledgements

This work was funded primarily by Project Grants from Arthritis Research UK (20593 to Drs. Smith and Lyons) and the British Heart Foundation (PG/13/64/30435 to Drs. Smith and Lyons). Additional support was provided by the NIHR Cambridge Biomedical Research Centre, the West Anglia Comprehensive Research Network, a Medical Research Council Programme Grant (MR/L019027/1 to Dr. Smith), a Wellcome Trust Investigator Award (200871/Z/16/Z to Dr. Smith), a NIHR Senior Investigator Award (to Dr. Smith), a Wellcome Trust Senior Research Fellowship (WT107881 to Dr. Wallace), a Medical Research Council grant (MC_UU_00002/4 to Dr. Wallace), a Wellcome Trust Mathematical Genomics and Medicine Programme Studentship (to Dr. Liley), a Career Development Award from the Cambridge British Heart Foundation Centre for Research Excellence and a UK Research Innovation Fellowship (RE/13/6/30180 and MR/S004068/1 to Dr. Peters). Additional aspects of this work were supported by the following funding: a Science Foundation Ireland Grant (11/Y/B2093 to Dr Little); an Australian National Health and Medical Research Council (NH&MRC), Career Development Fellowship (ID 1053756) and a Victorian Life Sciences Computation Initiative (VLSCI) grant number (VR0240) on its Peak Computing Facility at the University of Melbourne, an initiative of the Victorian Government, Australia (to Dr Leslie); Research at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program; Project RVO 64 165 of the Ministry of Health of Czech Republic (to Dr Tesar); Ministerio de Economia y Competitividad (SAF SAF 2017-88275-R), FEDER una manera de hacer Europa) and CERCA programme (to Drs Cid and Hernandez-Rodriguez) and Instituto de Salud Carlos III (PI 18/00461) (to Drs Espigol-Frigole and Prieto-Gonzalez); Prof Bruce is an NIHR Senior Investigator and is supported by Versus Arthritis, the National Institute for Health Research Manchester Biomedical Research Centre and the NIHR Manchester Clinical Research Facility. We thank the Centre for Integrated Genomic Medical Research Biobank for sample storage and preparation, and AROS Applied Biotechnology (Aarhus, Denmark) and Cambridge Genomic Services (Cambridge, UK) for genotyping.