Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset
Saedís Saevarsdóttir, Lilja Stefánsdóttir, Patrick Sulem, Guðmar Þorleifsson, Egil Ferkingstad, Gudrun Rutsdottir, Bente Glintborg, Helga Westerlind, Gerður Gröndal, Isabella Loft, Signe Bek Sørensen, Benedicte A. Lie, Mikael Brink, Lisbeth Ärlestig, Asgeir Ö. Arnthórsson, Eva Baecklund, Karina Banasik, Steffen Bank, Lena Björkman, Torkell Ellingsen, Christian Erikstrup, Oleksandr Frei, Inger Gjertsson, Daníel F. Guðbjartsson, Sigurjón A. Guðjónsson, Gísli H. Halldórsson, Oliver Hendricks, Jan Hillert, Estrid Høgdall, Søren Jacobsen, Dorte Vendelbo Jensen, Helgi Jónsson, Alf Kastbom, Ingrid Kockum, Salome Kristensen, Helga Kristjánsdóttir, Margit Hørup Larsen, Asta Linauskas, Ellen‐Margrethe Hauge, Anne Gitte Loft, Björn R. Lúdvíksson, Sigrún H. Lund, Thorsteinn Markusson, Gísli Másson, Páll Melsted, Kristjan H. S. Moore, Heidi Lausten Munk, Kaspar René Nielsen, Gudmundur L. Norddahl, Ásmundur Oddsson, Thorunn A. Olafsdottir, Pall I. Olason, Tomas Olsson, Sisse Rye Ostrowski, Kim Hørslev‐Petersen, Sölvi Rögnvaldsson, Helga Sanner, Gilad N Silberberg, Hreinn Stefánsson, Erik Sørensen, Inge Juul Sørensen, Carl Turesson, Thomas Bergman, Lars Alfredsson, Tore K Kvien, Søren Brunak, Kristján Steinsson, Vibeke Andersen, Ole A. Andreassen, Solbritt Rantapää‐Dahlqvist, Merete Lund Hetland, Lars Klareskog, Johan Askling, Leonid Padyukov, Ole Birger Pedersen, Unnur Thorsteinsdottir, Ingileif Jónsdóttir, Kāri Stefánsson, Steffen Andersen, Karina Banasik, Søren Brunak, Kristoffer Sølvsten Burgdorf, Christian Erikstrup, Thomas Folkmann Hansen, Henrik Hjalgrim, Gregor B. E. Jemec, Poul Jennum, Pär I. Johansson, Kasper Nielsen, Mette Nyegaard, Mie Topholm Brun, Ole Birger Pedersen, Susan Mikkelsen, Khoa Manh Dinh, Erik Sørensen, Henrik Ullum, Sisse Rye Ostrowski, Thomas Werge, Daníel F. Guðbjartsson, Kāri Stefánsson
Abstract
<h3>Objectives</h3> To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. <h3>Methods</h3> 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). <h3>Results</h3> 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 <i>STAT4</i> (rs140675301-A) that is independent of reported non-coding <i>STAT4</i>-variants, increases the risk of seropositive RA 2.27-fold (p=2.1×10<sup>−9</sup>), more than the rs2476601-A missense variant in <i>PTPN22</i> (OR=1.59, p=1.3×10<sup>−160</sup>). <i>STAT4</i> rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in <i>FLT3</i> increases seropositive RA risk (OR=1.35, p=6.6×10<sup>−11</sup>). Independent missense variants in <i>TYK2</i> (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63–0.87, p=10<sup>−9</sup>–10<sup>−27</sup>) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. <h3>Conclusion</h3> Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.