Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset
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Published:2022-04-25
Issue:8
Volume:81
Page:1085-1095
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ISSN:0003-4967
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Container-title:Annals of the Rheumatic Diseases
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language:en
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Short-container-title:Ann Rheum Dis
Author:
Saevarsdottir SaedisORCID, Stefansdottir Lilja, Sulem Patrick, Thorleifsson Gudmar, Ferkingstad Egil, Rutsdottir Gudrun, Glintborg BenteORCID, Westerlind HelgaORCID, Grondal Gerdur, Loft Isabella C, Sorensen Signe Bek, Lie Benedicte A, Brink Mikael, Ärlestig Lisbeth, Arnthorsson Asgeir Orn, Baecklund Eva, Banasik Karina, Bank Steffen, Bjorkman Lena I, Ellingsen TorkellORCID, Erikstrup Christian, Frei Oleksandr, Gjertsson IngerORCID, Gudbjartsson Daniel F, Gudjonsson Sigurjon A, Halldorsson Gisli H, Hendricks Oliver, Hillert Jan, Hogdall Estrid, Jacobsen SørenORCID, Jensen Dorte Vendelbo, Jonsson Helgi, Kastbom AlfORCID, Kockum Ingrid, Kristensen SalomeORCID, Kristjansdottir Helga, Larsen Margit H, Linauskas Asta, Hauge Ellen-Margrethe, Loft Anne G, Ludviksson Bjorn R, Lund Sigrun H, Markusson Thorsteinn, Masson Gisli, Melsted Pall, Moore Kristjan H S, Munk HeidiORCID, Nielsen Kaspar R, Norddahl Gudmundur L, Oddsson Asmundur, Olafsdottir Thorunn A, Olason Pall I, Olsson Tomas, Ostrowski Sisse Rye, Hørslev-Petersen Kim, Rognvaldsson Solvi, Sanner Helga, Silberberg Gilad N, Stefansson Hreinn, Sørensen Erik, Sørensen Inge J, Turesson CarlORCID, Bergman Thomas, Alfredsson Lars, Kvien Tore K, Brunak Søren, Steinsson Kristján, Andersen VibekeORCID, Andreassen Ole A, Rantapää-Dahlqvist SolbrittORCID, Hetland Merete LundORCID, Klareskog LarsORCID, Askling JohanORCID, Padyukov Leonid, Pedersen Ole BV, Thorsteinsdottir Unnur, Jonsdottir Ingileif, Stefansson Kari, ,
Abstract
ObjectivesTo find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets.MethodsWe performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ~1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen).ResultsWe found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1×10−9), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3×10−160). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6×10−11). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63–0.87, p=10−9–10−27) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4.ConclusionSequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
Funder
Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Novo Nordisk Research Council of Norway Knud and Edith Eriksens Mindefond Laege Sofus Carl Emil Friis and Hustru Olga Doris Friis' Legat Region Stockholm-Karolinska Institutet Region of Southern Denmark Department of Rheumatology, Frederiksberg Hospital University of Aarhus Norges Forskningsråd VINNOVA Novo Nordisk Fonden NordForsk Trond Mohn stiftelse Health Research Fund of Central Denmark Region Aase og Ejnar Danielsens Fond Vetenskapsrådet Nils and Bibbi Jensens Foundation South-Eastern Heath Region of Norway Region of Southern Denmark’s PhD Fund Augustinus Fonden Karolinska Institutet Hjärnfonden Psoriasis Forskningsfonden A.P. Moller Foundation for the Advancement of Medical Science Beckett-Fonden Margaretha af Ugglas Foundation European Research Council AdG project Stiftelsen Kristian Gerhard Jebsen Knut och Alice Wallenbergs Stiftelse Universitetet i Bergen Gigtforeningen Colitis-Crohn Foreningen
Subject
General Biochemistry, Genetics and Molecular Biology,Immunology,Immunology and Allergy,Rheumatology
Cited by
22 articles.
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