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

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 KorendowychGerd 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

Population Health and Genomics

Research output: Contribution to journal › Article › peer-review

158 Citations (Scopus)

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.

Original language	English
Article number	6046
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7046
Publication status	Published - Feb 2015

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms7046Licence: CC BY

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Bowes, J., Budu-Aggrey, A., Huffmeier, U., Uebe, S., Steel, K., Hebert, H. L., Wallace, C., Massey, J., Bruce, I. N., Bluett, J., Feletar, M., Morgan, A. W., Marzo-Ortega, H., Donohoe, G., Morris, D. W., Helliwell, P., Ryan, A. W., Kane, D., Warren, R. B., ... Barton, A. (2015). Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis. Nature Communications, 6, Article 6046. https://doi.org/10.1038/ncomms7046

@article{4eb6693124b5445c83503471691fb4a6,

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

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.",

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

note = "Funding Information: We acknowledge the assistance given by IT Services and the use of the Computational Shared Facility (CSF) at The University of Manchester. We thank Arthritis Research UK for their support (grant number 20385) and the NIHR Manchester Musculoskeletal Biomedical Research Unit. This report includes independent research funded by the National Institute for Health Research Biomedical Research Unit Funding Scheme. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. Genotyping of Irish samples was partially funded by Science Foundation Ireland grant number SFI09/IN.1/B2640. Support for the German component of the study was received from the German Federal Ministry of Education and Research ArthroMark (project 4, 01 EC 1009C), the Federal State of Hesse (LOEWE-project: IME Fraunhofer Project Group Translational Medicine & Pharmacology at the Goethe University), H.B. received funding from Pfizer Pharma, Germany (Forschungsf{\"o}rderpreis Rheumatologie 2012). Support for the Australian component of the study was received from Abbvie Plc. MAB is funded by an National Health and Medical Research Foundation (Australia) Senior Principal Research Fellowship. C.W. is funded by the Wellcome Trust (089989) and supported by grants awarded to the Diabetes and Inflammation Laboratory from JDRF (9-2011-253) and Wellcome Trust (091157). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140). Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

year = "2015",

month = feb,

doi = "10.1038/ncomms7046",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

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Bowes, J, Budu-Aggrey, A, Huffmeier, U, Uebe, S, Steel, K, Hebert, HL, Wallace, C, Massey, J, Bruce, IN, Bluett, J, Feletar, M, Morgan, AW, Marzo-Ortega, H, Donohoe, G, Morris, DW, Helliwell, P, Ryan, AW, Kane, D, Warren, RB, Korendowych, E, Alenius, GM, Giardina, E, Packham, J, McManus, R, Fitzgerald, O, McHugh, N, Brown, MA, Ho, P, Behrens, F, Burkhardt, H, Reis, A & Barton, A 2015, 'Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis', Nature Communications, vol. 6, 6046. https://doi.org/10.1038/ncomms7046

TY - JOUR

T1 - Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis

AU - Bowes, John

AU - Budu-Aggrey, Ashley

AU - Huffmeier, Ulrike

AU - Uebe, Steffen

AU - Steel, Kathryn

AU - Hebert, Harry L.

AU - Wallace, Chris

AU - Massey, Jonathan

AU - Bruce, Ian N.

AU - Bluett, James

AU - Feletar, Marie

AU - Morgan, Ann W.

AU - Marzo-Ortega, Helena

AU - Donohoe, Gary

AU - Morris, Derek W.

AU - Helliwell, Philip

AU - Ryan, Anthony W.

AU - Kane, David

AU - Warren, Richard B.

AU - Korendowych, Eleanor

AU - Alenius, Gerd Marie

AU - Giardina, Emiliano

AU - Packham, Jonathan

AU - McManus, Ross

AU - Fitzgerald, Oliver

AU - McHugh, Neil

AU - Brown, Matthew A.

AU - Ho, Pauline

AU - Behrens, Frank

AU - Burkhardt, Harald

AU - Reis, Andre

AU - Barton, Anne

N1 - Funding Information: We acknowledge the assistance given by IT Services and the use of the Computational Shared Facility (CSF) at The University of Manchester. We thank Arthritis Research UK for their support (grant number 20385) and the NIHR Manchester Musculoskeletal Biomedical Research Unit. This report includes independent research funded by the National Institute for Health Research Biomedical Research Unit Funding Scheme. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. Genotyping of Irish samples was partially funded by Science Foundation Ireland grant number SFI09/IN.1/B2640. Support for the German component of the study was received from the German Federal Ministry of Education and Research ArthroMark (project 4, 01 EC 1009C), the Federal State of Hesse (LOEWE-project: IME Fraunhofer Project Group Translational Medicine & Pharmacology at the Goethe University), H.B. received funding from Pfizer Pharma, Germany (Forschungsförderpreis Rheumatologie 2012). Support for the Australian component of the study was received from Abbvie Plc. MAB is funded by an National Health and Medical Research Foundation (Australia) Senior Principal Research Fellowship. C.W. is funded by the Wellcome Trust (089989) and supported by grants awarded to the Diabetes and Inflammation Laboratory from JDRF (9-2011-253) and Wellcome Trust (091157). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140). Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

PY - 2015/2

Y1 - 2015/2

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms7046

DO - 10.1038/ncomms7046

M3 - Article

C2 - 25651891

AN - SCOPUS:84923253404

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 6046

ER -

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

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Corrigendum: Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis (Nature Communications (2015) 6 (6046) DOI:10.1038/ncomms7046)

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