GWAS meta-analysis of psoriasis identifies new susceptibility alleles impacting disease mechanisms and therapeutic targets

Nick Dand; Philip E Stuart; John Bowes; David Ellinghaus; Joanne Nititham; Jake R Saklatvala; Maris Teder-Laving; Laurent F Thomas; Tanel Traks; Steffen Uebe; Gunter Assmann; David Baudry; Frank Behrens; Allison C Billi; Matthew A Brown; Harald Burkhardt; Francesca Capon; Raymond Chung; Charles J Curtis; Michael Duckworth; Eva Ellinghaus; Oliver FitzGerald; Sascha Gerdes; Christopher E M Griffiths; Susanne Gulliver; Philip Helliwell; Pauline Ho; Per Hoffmann; Oddgeir L Holmen; Zhi-Ming Huang; Kristian Hveem; Deepak Jadon; Michaela Köhm; Cornelia Kraus; Céline Lamacchia; Sang Hyuck Lee; Feiyang Ma; Satveer K Mahil; Neil McHugh; Ross McManus; Ellen H Modalsli; Michael J Nissen; Markus Nöthen; Vinzenz Oji; Jorge R Oksenberg; Matthew T Patrick; Bethany E Perez-White; Andreas Ramming; Jürgen Rech; Cheryl Rosen; Mrinal K Sarkar; Georg Schett; Börge Schmidt; Trilokraj Tejasvi; Heiko Traupe; John J Voorhees; Eike Matthias Wacker; Richard B Warren; Rachael Wasikowski; Stephan Weidinger; Xiaoquan Wen; Zhaolin Zhang; BSTOP study group; Estonian Biobank research team; Anne Barton; Vinod Chandran; Tõnu Esko; John Foerster; Andre Franke; Dafna D Gladman; Johann E Gudjonsson; Wayne Gulliver; Ulrike Hüffmeier; Külli Kingo; Sulev Kõks; Wilson Liao; Mari Løset; Reedik Mägi; Rajan P Nair; Proton Rahman; André Reis; Catherine H Smith; Paola Di Meglio; Jonathan N Barker; Lam C Tsoi; Michael A Simpson; James T Elder

doi:10.1101/2023.10.04.23296543

GWAS meta-analysis of psoriasis identifies new susceptibility alleles impacting disease mechanisms and therapeutic targets

medRxiv [Preprint]. 2023 Oct 5:2023.10.04.23296543. doi: 10.1101/2023.10.04.23296543.

Authors

Nick Dand^{1

2}, Philip E Stuart³, John Bowes^{4

5}, David Ellinghaus⁶, Joanne Nititham⁷, Jake R Saklatvala¹, Maris Teder-Laving⁸, Laurent F Thomas^{9

10

11

12}, Tanel Traks¹³, Steffen Uebe¹⁴, Gunter Assmann^{15

16}, David Baudry¹⁷, Frank Behrens^{18

19

20

21}, Allison C Billi³, Matthew A Brown^{1

22}, Harald Burkhardt^{21

19

20}, Francesca Capon¹, Raymond Chung^{23

24}, Charles J Curtis^{23

24}, Michael Duckworth¹⁷, Eva Ellinghaus⁶, Oliver FitzGerald²⁵, Sascha Gerdes²⁶, Christopher E M Griffiths^{27

17

28}, Susanne Gulliver²⁹, Philip Helliwell^{30

31}, Pauline Ho^{4

5

32}, Per Hoffmann³³, Oddgeir L Holmen^{34

35}, Zhi-Ming Huang⁷, Kristian Hveem^{10

34

35}, Deepak Jadon³⁶, Michaela Köhm^{18

19

20

21}, Cornelia Kraus¹⁴, Céline Lamacchia³⁷, Sang Hyuck Lee^{23

24}, Feiyang Ma^{3

38}, Satveer K Mahil^{17

39}, Neil McHugh⁴⁰, Ross McManus⁴¹, Ellen H Modalsli^{9

42}, Michael J Nissen³⁷, Markus Nöthen³³, Vinzenz Oji⁴³, Jorge R Oksenberg⁴⁴, Matthew T Patrick³, Bethany E Perez-White⁴⁵, Andreas Ramming^{46

47}, Jürgen Rech^{46

47}, Cheryl Rosen⁴⁸, Mrinal K Sarkar³, Georg Schett^{46

47}, Börge Schmidt⁴⁹, Trilokraj Tejasvi^{3

50}, Heiko Traupe⁴³, John J Voorhees³, Eike Matthias Wacker⁶, Richard B Warren^{51

52}, Rachael Wasikowski³, Stephan Weidinger²⁶, Xiaoquan Wen⁵³, Zhaolin Zhang³; BSTOP study group; Estonian Biobank research team; Anne Barton^{4

5

32}, Vinod Chandran⁵⁴, Tõnu Esko⁸, John Foerster⁵⁵, Andre Franke⁶, Dafna D Gladman⁵⁴, Johann E Gudjonsson³, Wayne Gulliver^{29

56}, Ulrike Hüffmeier¹⁴, Külli Kingo^{13

57}, Sulev Kõks^{58

59}, Wilson Liao⁷, Mari Løset^{10

42}, Reedik Mägi⁶⁰, Rajan P Nair³, Proton Rahman⁶¹, André Reis¹⁴, Catherine H Smith^{17

39}, Paola Di Meglio¹⁷, Jonathan N Barker^{17

39}, Lam C Tsoi^{3

38

53}, Michael A Simpson¹, James T Elder^{3

50}

Affiliations

¹ Department of Medical & Molecular Genetics, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
² Health Data Research UK, London, UK.
³ Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁴ Centre for Genetics and Genomics Versus Arthritis, The University of Manchester, Manchester, UK.
⁵ National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre, The University of Manchester, Manchester, UK.
⁶ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
⁷ Deparment of Dermatology, University of California San Francisco, San Francisco, CA, USA.
⁸ Institute of Genomics, University of Tartu, Tartu, Estonia.
⁹ Department of Clinical and Molecular Medicine, NTNU - Norwegian University of Science and Technology, Trondheim, Norway.
¹⁰ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU - Norwegian University of Science and Technology, Trondheim, Norway.
¹¹ BioCore - Bioinformatics Core Facility, NTNU - Norwegian University of Science and Technology, Trondheim, Norway.
¹² Clinic of Laboratory Medicine, St.Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
¹³ Department of Dermatology and Venereology, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
¹⁴ Institute of Human Genetics, Universitätsklinikum Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany.
¹⁵ RUB University Hospital JWK Minden, Department of Rheumatology, Minden, Germany.
¹⁶ Jose-Carreras Centrum for Immuno- and Gene Therapy, University of Saarland Medical School, Homburg, Germany.
¹⁷ St John's Institute of Dermatology, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
¹⁸ Division of Translational Rheumatology, Immunology - Inflammation Medicine, University Hospital, Goethe University, Frankfurt am Main, Germany.
¹⁹ Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany.
²⁰ Fraunhofer Cluster of Excellence Immune-mediated Diseases CIMD, Frankfurt am Main, Germany.
²¹ Division of Rheumatology, University Hospital, Goethe University, Frankfurt am Main, Germany.
²² Genomics England, Canary Wharf, London, UK.
²³ Institute of Psychiatry, Psychology and Neuroscience, King's College London, Denmark Hill, Camberwell, London, UK.
²⁴ National Institute for Health and Care Research (NIHR) Biomedical Research Centre, South London and Maudsley Hospital, London, UK.
²⁵ UCD School of Medicine and Medical Sciences and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Ireland.
²⁶ Department of Dermatology, Venereology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
²⁷ Centre for Dermatology Research, University of Manchester, NIHR Manchester Biomedical Research Centre, Manchester, UK.
²⁸ Department of Dermatology, King's College Hospital NHS Foundation Trust, London, UK.
²⁹ Newlab Clinical Research Inc, St. John's, NL, Canada.
³⁰ National Institute for Health and Care Research (NIHR) Leeds Biomedical Research Centre, Leeds Teaching Hospitals Trust, UK.
³¹ Leeds Institute of Rheumatic and Musculoskeletal Disease, University of Leeds, UK.
³² The Kellgren Centre for Rheumatology, Manchester University NHS Foundation Trust, Manchester, UK.
³³ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
³⁴ HUNT Research Centre, Department of Public Health and Nursing, NTNU - Norwegian University of Science and Technology, Levanger, Norway.
³⁵ Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.
³⁶ Department of Medicine, University of Cambridge, Cambridge, UK.
³⁷ Division of Rheumatology, Geneva University Hospital, Geneva, Switzerland.
³⁸ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
³⁹ St John's Institute of Dermatology, Guy's and St Thomas' National Health Service (NHS) Foundation Trust, London, UK.
⁴⁰ Royal National Hospital for Rheumatic Diseases and Dept Pharmacy and Pharmacology, University of Bath, UK.
⁴¹ Department of Clinical Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Ireland.
⁴² Department of Dermatology, Clinic of Orthopedy, Rheumatology and Dermatology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
⁴³ Department of Dermatology, University of Münster, Münster, Germany.
⁴⁴ Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA, USA.
⁴⁵ Department of Dermatology, Northwestern University, Evanston, IL, USA.
⁴⁶ Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Ulmenweg 18, 91054, Erlangen, Germany.
⁴⁷ Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
⁴⁸ Division of Dermatology, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.
⁴⁹ Institute of Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
⁵⁰ Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI, USA.
⁵¹ Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK.
⁵² Centre for Dermatology Research, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M6 8HD, UK.
⁵³ Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
⁵⁴ Schroeder Arthritis Institute, Krembil Research Institute, and Toronto Western Hospital, University Health Network and University of Toronto, Toronto, Ontario, Canada.
⁵⁵ College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee, UK.
⁵⁶ Department of Dermatology, Discipline of Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
⁵⁷ Dermatology Clinic, Tartu University Hospital, Tartu, Estonia.
⁵⁸ Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia.
⁵⁹ Centre for Molecular Medicine and Innovative Therapeutics, Health Futures Institute, Murdoch University, Perth, WA 6150, Australia.
⁶⁰ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
⁶¹ Memorial University of Newfoundland, St. John's, NL, Canada.

Abstract

Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci. To move towards a saturation map of psoriasis susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls and identified 109 distinct psoriasis susceptibility loci, including 45 that have not been previously reported. These include susceptibility variants at loci in which the therapeutic targets IL17RA and AHR are encoded, and deleterious coding variants supporting potential new drug targets (including in STAP2, CPVL and POU2F3). We conducted a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants and cross-referenced these against single cell expression profiles in psoriasis-affected skin, highlighting roles for the transcriptional regulation of haematopoietic cell development and epigenetic modulation of interferon signalling in psoriasis pathobiology.

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Abstract

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