Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis

John Bowes; Ashley Budu-Aggrey; Ulrike Huffmeier; Steffen Uebe; Kathryn Steel; Harry L Hebert; Chris Wallace; Jonathan Massey; Ian N Bruce; James Bluett; Marie Feletar; Ann W Morgan; Helena Marzo-Ortega; Gary Donohoe; Derek W Morris; Philip Helliwell; Anthony W Ryan; David Kane; Richard B Warren; Eleanor Korendowych; Gerd-Marie Alenius; Emiliano Giardina; Jonathan Packham; Ross McManus; Oliver FitzGerald; Neil McHugh; Matthew A Brown; Pauline Ho; Frank Behrens; Harald Burkhardt; Andre Reis; Anne Barton

doi:10.1038/ncomms7046

Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis

Nat Commun. 2015 Feb 5:6:6046. doi: 10.1038/ncomms7046.

Authors

John Bowes¹, Ashley Budu-Aggrey², Ulrike Huffmeier³, Steffen Uebe³, Kathryn Steel¹, Harry L Hebert⁴, Chris Wallace⁵, Jonathan Massey¹, Ian N Bruce⁶, James Bluett⁶, Marie Feletar⁷, Ann W Morgan⁸, Helena Marzo-Ortega⁸, Gary Donohoe⁹, Derek W Morris⁹, Philip Helliwell⁸, Anthony W Ryan¹⁰, David Kane¹¹, Richard B Warren¹², Eleanor Korendowych¹³, Gerd-Marie Alenius¹⁴, Emiliano Giardina¹⁵, Jonathan Packham¹⁶, Ross McManus¹⁰, Oliver FitzGerald¹⁷, Neil McHugh¹³, Matthew A Brown¹⁸, Pauline Ho⁶, Frank Behrens¹⁹, Harald Burkhardt¹⁹, Andre Reis³, Anne Barton²

Affiliations

¹ Arthritis Research UK Centre for Genetics and Genomics, The University of Manchester, Manchester M13 9PT, UK.
² 1] Arthritis Research UK Centre for Genetics and Genomics, The University of Manchester, Manchester M13 9PT, UK [2] NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester Foundation Trust and University of Manchester, Manchester Academy of Health Sciences, Manchester M13 9WU, UK.
³ Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
⁴ 1] Arthritis Research UK Centre for Genetics and Genomics, The University of Manchester, Manchester M13 9PT, UK [2] The Dermatology Centre, Salford Royal NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester M6 8HD, UK.
⁵ 1] JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK [2] Centre for Biostatistics, Institute of Population Health, The University of Manchester, Jean McFarlane Building, Oxford Road, Manchester M13 9PL, UK.
⁶ 1] Arthritis Research UK Centre for Genetics and Genomics, The University of Manchester, Manchester M13 9PT, UK [2] The Kellgren Centre for Rheumatology, Central Manchester Foundation Trust, NIHR Manchester Biomedical Research Centre, Manchester M13 9WL, UK.
⁷ Monash University, Melbourne, Victoria 3800, Australia.
⁸ NIHR-Leeds Musculoskeletal Biomedical Research Unit, Leeds Institute of Molecular Medicine, University of Leeds, Leeds LS7 4SA, UK.
⁹ CogGene Group, Discipline of Biochemistry and School of Psychology, National University of Ireland, Galway, Ireland.
¹⁰ Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland.
¹¹ Adelaide and Meath Hospital and Trinity College Dublin, Dublin 24, Ireland.
¹² The Dermatology Centre, Salford Royal NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester M6 8HD, UK.
¹³ Royal National Hospital for Rheumatic Diseases and Department of Pharmacy and Pharmacology, University of Bath, Bath BA1 1RL, UK.
¹⁴ Department of Public Health and Clinical Medicine, Rheumatology, University Hospital, Umeå 901 87, Sweden.
¹⁵ Department of Biopathology, Centre of Excellence for Genomic Risk Assessment in Multifactorial and Complex Diseases, School of Medicine, University of Rome 'Tor Vergata' and Fondazione PTV 'Policlinico Tor Vergata', Rome 18-00173, Italy.
¹⁶ Rheumatology Department, Haywood Hospital, Health Services Research Unit, Institute of Science and Technology in Medicine, Keele University, Keele ST5 5BG, UK.
¹⁷ Department of Rheumatology, St. Vincent's University Hospital, UCD School of Medicine and Medical Sciences and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland.
¹⁸ The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland QLD 4102, Australia.
¹⁹ Division of Rheumatology and Fraunhofer IME-Project-Group Translational Medicine and Pharmacology, Goethe University, Frankfurt 60590, Germany.

Abstract

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis and, despite the larger estimated heritability for PsA, the majority of genetic susceptibility loci identified to date are shared with psoriasis. Here, we present results from a case-control association study on 1,962 PsA patients and 8,923 controls using the Immunochip genotyping array. We identify eight loci passing genome-wide significance, secondary independent effects at three loci and a distinct PsA-specific variant at the IL23R locus. We report two novel loci and evidence of a novel PsA-specific association at chromosome 5q31. Imputation of classical HLA alleles, amino acids and SNPs across the MHC region highlights three independent associations to class I genes. Finally, we find an enrichment of associated variants to markers of open chromatin in CD8(+) memory primary T cells. This study identifies key insights into the genetics of PsA that could begin to explain fundamental differences between psoriasis and PsA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Alleles
Arthritis, Psoriatic / genetics*
Arthritis, Psoriatic / immunology
Arthritis, Psoriatic / metabolism
Arthritis, Psoriatic / pathology
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
CD4-Positive T-Lymphocytes / pathology
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism*
CD8-Positive T-Lymphocytes / pathology
Case-Control Studies
Chromatin / chemistry
Chromatin / immunology
Chromosomes, Human, Pair 5
Female
Genetic Predisposition to Disease
Genotype
Genotyping Techniques
Histocompatibility Antigens Class I / genetics*
Histocompatibility Antigens Class I / immunology
Humans
Immunologic Memory
Male
Microarray Analysis
Middle Aged
Polymorphism, Single Nucleotide
Psoriasis / genetics*
Psoriasis / immunology
Psoriasis / metabolism
Psoriasis / pathology
Quantitative Trait Loci / immunology*
Receptors, Interleukin / genetics*
Receptors, Interleukin / immunology

Substances

Chromatin
Histocompatibility Antigens Class I
IL23R protein, human
Receptors, Interleukin

Abstract

Publication types

MeSH terms

Substances

Grants and funding