GWAS Meta-Analysis of Psoriasis Identifies New Susceptibility Alleles Impacting Disease Mechanisms and Therapeutic Targets

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. ### Competing Interest Statement FC reports grants and consultancy fees from Boehringer Ingelheim. SKM reports departmental income from Abbvie, Almirall, Eli Lilly, Janssen, Leo Pharma, Novartis, Pfizer, Sanofi and UCB, outside the submitted work. MJN has received consultancy fees and/or research funding from Abbvie, Amgen, Celgene, Eli Lilly, Janssen, Pfizer, Novartis and UCB. T.Tejasvi is a member of an advisory board for L'Oreal Teledermatology. VC has received research grants from AbbVie, Amgen, and Eli Lilly and has received honoraria for advisory board member roles from AbbVie, Amgen, BMS, Eli Lilly, Janssen, Novartis, Pfizer, and UCB. His spouse is an employee of AstraZeneca. JEG received research support from Eli Lilly, Kyowa Kirin, Janssen, Almirall, Celgene/BMS, Prometheus, Novartis, Galderma and AnaptysBio, and is a member of an advisory board for Novartis, AbbVie, Eli Lilly, Almirall, Galderma, Boehringer Ingelehim, Celgene/BMS, Sanofi, Janssen and AnaptysBio. SK is a founder of Prion OU, Geneto OU, Sportsgene OU and Genomic Therapeutics Pty Ltd. WL has received research grant funding from Abbvie, Amgen, Janssen, Leo, Novartis, Pfizer, Regeneron, and TRex Bio. PDM reports consultancy fees from Unilever and speaker's fees from Sanofi and BMS. LCT reports support from Janssen, Galderma, and Novartis. The remaining authors report no conflicts of interest. ### Funding Statement ND is funded by Health Data Research UK (MR/S003126/1). Support for the study was received from the Department of Health through the National Institute for Health and Care Research (NIHR) Bio-Resource Clinical Research Facility and comprehensive Biomedical Research Centre awards to Guy's and St Thomas' National Health Service Foundation Trust in partnership with King's College London and King's College Hospital National Health Service Foundation Trust (BRC\_1215\_20006). We acknowledge support from the Psoriasis Association in relation to Biomarkers of Systemic Treatment Outcomes in Psoriasis (RG2/10, RG2/10) and an award to PDM (ST1/19) and FC (ST3/20). This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement number 821511 (Biomarkers in Atopic Dermatitis and Psoriasis). The JU receives support from the European Union's Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). This publication reflects only the authors' views and the JU is not responsible for any use that may be made of the information it contains. SKM is funded by a NIHR Advanced Fellowship (NIHR302258). This study presents independent research supported by NIHR BioResource Centre Maudsley, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London. The BioResource gratefully acknowledge capital equipment funding from the Maudsley Charity (Grant Ref. 980) and Guy's and St Thomas's Charity (STR130505). PDM reports a Translational Research Grant (814364) from the National Psoriasis Foundation. LCT received funding from the National Institutes of Health (NIH) (K01 AR072129, P30 AR075043, UC2 AR081033). This work was supported by awards from NIH (R01AR042742, R01AR050511, R01AR054966, R01AR063611, R01AR065183), the National Psoriasis Foundation, and the Babcock Memorial Trust. JTE is supported by the Ann Arbor Veterans Hospital. MTP is supported by a Research Career Development Award from the Dermatology Foundation. XW is supported by NIH (R01ES033634, R35GM138121). MKS reports a Translational Research Grant from the National Psoriasis Foundation. ACB was supported by the University of Michigan A. Alfred Taubman Medical Research Institute via Taubman Emerging Scholar funds and the NIH (K08 AR078251, P30 AR075043). JEG is supported by NIH (P30AR075043) and the Taubman Medical Research Institute. Part of this study was funded by a grant to AR and UH from the Bundesministerium fur Bildung und Forschung (BMBF Metarthros 01EC1407A), by a grant to UH from the German Research Foundation (CRC1181-2, project A05) and by a grant to HB and FB from the Bundesministerium fuer Bildung und Forschung (BMBF ArthroMark 01EC1401C). The HNR study (Erlangen cohort) is supported by the Heinz Nixdorf Foundation (Germany). Additionally, the study is funded by the German Ministry of Education and Science and the German Research Council (DFG; Project SI 236/8-1, SI236/9-1, ER 155/6-1). The genotyping of the Illumina HumanOmni-1 Quad BeadChips of the HNR subjects was financed by the German Centre for Neurodegenerative Disorders (DZNE), Bonn. T.Traks and KK report support from the Estonian Research Council (PUT1465, PRG1189). SK is supported by MSWA, The Michael J. Fox Foundation, Shake It Up Australia, and Perron Institute for Neurological and Translational Science. MT-L was supported by the European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012). RM was supported by Estonian Research Council grant PRG1911. TE was supported by Estonian Research Council grant PRG1291. The Trondelag Health Study (The HUNT Study) is a collaboration between HUNT Research Center (Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology), Trondelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The genotyping in HUNT was financed by the National Institutes of Health; University of Michigan; the Research Council of Norway; the Liaison Committee for Education, Research, and Innovation in Central Norway; and the Joint Research Committee between St Olavs hospital and the Faculty of Medicine and Health Sciences, NTNU. LT, KH and ML work in a research unit funded by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology; The Liaison Committee for Education, Research and Innovation in Central Norway; the Joint Research Committee between St. Olavs Hospital (Trondheim, Norway) and the Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology. ML is supported by grants from the Liaison Committee for Education, Research and Innovation in Central Norway and the Joint Research Committee between St Olav's hospital and the Faculty of Medicine and Health Sciences, NTNU. The study received support from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Cluster of Excellence 2167 Precision Medicine in Chronic Inflammation (PMI) (EXC 2167-390884018). This work was supported by a grant from Versus Arthritis (21754). This research was co-funded by the NIHR Manchester Biomedical Research Centre (NIHR203308). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. DJ acknowledges that his research was supported by Cambridge Arthritis Research Endeavour (CARE) and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). WL acknowledges funding from NIH (R01AR065174, U01AI119125). The UCSF-MS DNA biorepository is supported by RG-1611-26299 from the National Multiple Sclerosis Society to JRO. VC is supported by a Pfizer Chair Research Award, Rheumatology, University of Toronto. The Schroeder Arthritis Institute Psoriatic Disease Program is supported by the Krembil Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: London - Westminster Research Ethics Committee gave ethical approval for this work (11/H0802/7). The research ethics committee of Friedich-Alexander-Universitaet Erlangen-Nuernberg gave ethical approval for this work. The institutional ethics committee of the University Hospital Essen gave ethical approval for this work. The Research Ethics Committee of the University of Tartu gave ethical approval for this work (265/T-21). The Estonian Council of Bioethics and Human Research gave ethical approval for this work (1.1-12/624). The the Data Inspectorate and the Regional Ethics Committee for Medical Research in Norway gave ethical approval for this work (REK 2014/144 and 2015/586). The Ethical review board of the Medical Faculty of the CAU (Christian-Albrechts-University of Kiel, Germany) gave ethical approval for this work. The North West Regional Ethics Committee gave ethical approval for this work (99/8/84). The Frenchay Regional Ethics Committee gave ethical approval for this work (12/SW/0110). The St Vincent's University Hospital ethics committee gave ethical approval for this work. The University Hospital of Geneva ethics committee gave ethical approval for this work (10-089). The Health Research Ethics Board (HREB), Newfoundland and Labrador gave ethical approval for this work. The East of Scotland Research Ethics Service gave ethical approval for this work (13/ES/0020). The University of California San Francisco institutional review board gave ethical approval for this work. The North West Multi-Centre Research Ethics Committee gave ethical approval for this work (11/NW/0382). 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Yes Data in the present study will be made publicly available on publication of the manuscript in a peer-reviewed journal.