Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset. Issue 8 (25th April 2022)

• Record Type: Journal Article
• Authors: Saevarsdottir, Saedis; Stefansdottir, Lilja; Sulem, Patrick; Thorleifsson, Gudmar; Ferkingstad, Egil; Rutsdottir, Gudrun; Glintborg, Bente; Westerlind, Helga; 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, Torkell; Erikstrup, Christian; Frei, Oleksandr; Gjertsson, Inger; Gudbjartsson, Daniel F; Gudjonsson, Sigurjon A; Halldorsson, Gisli H; Hendricks, Oliver; Hillert, Jan; Hogdall, Estrid; Jacobsen, Søren; Jensen, Dorte Vendelbo; Jonsson, Helgi; Kastbom, Alf; Kockum, Ingrid; Kristensen, Salome; 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, Heidi; 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, Carl; Bergman, Thomas; Alfredsson, Lars; Kvien, Tore K; Brunak, Søren; Steinsson, Kristján; Andersen, Vibeke; Andreassen, Ole A; Rantapää-Dahlqvist, Solbritt; Hetland, Merete Lund; Klareskog, Lars; Askling, Johan; Padyukov, Leonid; Pedersen, Ole BV; Thorsteinsdottir, Unnur; Jonsdottir, Ingileif; Stefansson, Kari;
• Other Names: author non-byline.; Andersen Steffen author non-byline.; Banasik Karina author non-byline.; Brunak Søren author non-byline.; Burgdorf Kristoffer author non-byline.; Erikstrup Christian author non-byline.; Hansen Thomas Folkmann author non-byline.; Hjalgrim Henrik author non-byline.; Jemec Gregor author non-byline.; Jennum Poul author non-byline.; Johansson Pär Ingemar author non-byline.; Nielsen Kasper Rene author non-byline.; Nyegaard Mette author non-byline.; Brun Mie Topholm author non-byline.; Pedersen Ole Birger author non-byline.; Mikkelsen Susan author non-byline.; Dinh Khoa Manh author non-byline.; Sørensen Erik author non-byline.; Ullum Henrik author non-byline.; Ostrowski Sisse Rye author non-byline.; Werge Thomas author non-byline.; Gudbjartsson Daniel author non-byline.; Stefansson Kari author non-byline.; Stefánsson Hreinn author non-byline.; Þorsteinsdóttir Unnur author non-byline.; Larsen Margit Anita Hørup author non-byline.; Didriksen Maria author non-byline.; Sækmose Susanne author non-byline.; author non-byline.; Andersen Paal Skytt author non-byline.; Dessau Ram Benny author non-byline.; Andersen Malene Rohr author non-byline.; Hoffmann Hans Jürgen author non-byline.; Brasen Claus Lohman author non-byline.; author non-byline.; Askling Johan author non-byline.; Baecklund Eva author non-byline.; Bjorkman Lena author non-byline.; Kastbom Alf author non-byline.; Rantapaa-Dahlqvist Solbritt author non-byline.; Turesson Carl author non-byline.;
• Is Part Of: Annals of the rheumatic diseases. Volume 81:Issue 8(2022)
• Page Start: 1085
• Page End: 1095
• Publication Date: 2022-04-25
• Subjects: rheumatoid arthritis -- autoantibodies -- polymorphism, genetic; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2021-221754
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Objectives: To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods: We 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). Results: We 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. Conclusion: Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.