Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

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 caus...

Full description

Saved in:

Bibliographic Details
Published in:	Annals of the rheumatic diseases 2022, Vol.81 (8), p.1085-1095
Main Authors:	Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C, Sorensen, Signe Bek, Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Bank, Steffen, Bjorkman, Lena I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F, Gudjonsson, Sigurjon A, Halldorsson, Gisli H, Hillert, Jan, Hogdall, Estrid, Jacobsen, Søren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H, 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, Olsson, Tomas, 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, Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole BV, Jonsdottir, Ingileif, Stefansson, Kari, Andersen, Steffen, Banasik, Karina, Burgdorf, Kristoffer, Hansen, Thomas Folkmann, Hjalgrim, Henrik, Jemec, Gregor, Jennum, Poul, Johansson, Pär Ingemar, Nielsen, Kasper Rene, Nyegaard, Mette, Brun, Mie Topholm, Pedersen, Ole Birger, Mikkelsen, Susan, Dinh, Khoa Manh, Ostrowski, Sisse Rye, Werge, Thomas, Gudbjartsson, Daniel, Stefánsson, Hreinn, Þorsteinsdóttir, Unnur, Larsen, Margit Anita Hørup, Didriksen, Maria, Sækmose, Susanne, Andersen, Paal Skytt, Dessau, Ram Benny, Andersen, Malene Rohr, Hoffmann, Hans Jürgen, Brasen, Claus Lohman, Kastbom, Alf, Rantapaa-Dahlqvist, Solbritt
Format:	Article
Language:	eng ; nor
Subjects:	Arthritis, Rheumatoid - genetics association autoantibodies Biobanks cells classification Clinical Medicine criteria DNA-binding fms Gene expression Genes genetic Genetic Predisposition to Disease - genetics Genetics Genome-wide association studies Genome-Wide Association Study Genomes Glutamic acid Histocompatibility antigen HLA Humans Hydrophobicity inhibitor Interferon-alpha Interleukin 12 Janus kinase Janus Kinases - genetics Klinisk medicin Medical and Health Sciences Medicin och hälsovetenskap Plasma levels Plasma proteins polymorphism polymorphism, genetic Population Protein Tyrosine Phosphatase, Non-Receptor Type 22 - genetics Protein-tyrosine-phosphatase Proteins Proteomics Reumatologi och inflammation Rheumatoid Arthritis Rheumatology Rheumatology and Autoimmunity Signal Transduction - genetics STAT Transcription Factors - genetics stat4 Stat4 protein Transcriptomics Tyk2 protein Valine α-Interferon
Online Access:	Request full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
ISSN:	0003-4967 1468-2060 1468-2060