| Title: | Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset |
| Journal: | Annals of the Rheumatic Diseases |
| Published: | 25 Apr 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35470158/ |
| DOI: | https://doi.org/10.1136/annrheumdis-2021-221754 |
| URL: | https://ard.bmj.com/content/annrheumdis/81/8/1085.full.pdf |
Publication 13911
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Abstract
OBJECTIVES: To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets.</p>
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).</p>
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.</p>
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.</p>
10 Keywords
- Arthritis, Rheumatoid
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Interferon-alpha
- Janus Kinases
- Protein Tyrosine Phosphatase, Non-Receptor Type 22
- Proteomics
- STAT Transcription Factors
- Signal Transduction
116 Authors
- Saedis Saevarsdottir
- Lilja Stefansdottir
- Patrick Sulem
- Gudmar Thorleifsson
- Egil Ferkingstad
- Gudrun Rutsdottir
- Bente Glintborg
- Helga Westerlind
- Gerdur Grondal
- Isabella C Loft
- Signe Bek Sorensen
- Benedicte A Lie
- Mikael Brink
- Lisbeth Ärlestig
- Asgeir Orn Arnthorsson
- Eva Baecklund
- Karina Banasik
- Steffen Bank
- Lena I Bjorkman
- Torkell Ellingsen
- Christian Erikstrup
- Oleksandr Frei
- Inger Gjertsson
- Daniel F Gudbjartsson
- Sigurjon A Gudjonsson
- Gisli H Halldorsson
- Oliver Hendricks
- Jan Hillert
- Estrid Hogdall
- Søren Jacobsen
- Dorte Vendelbo Jensen
- Helgi Jonsson
- Alf Kastbom
- Ingrid Kockum
- Salome Kristensen
- Helga Kristjansdottir
- Margit H Larsen
- Asta Linauskas
- Ellen-Margrethe Hauge
- Anne G Loft
- Bjorn R Ludviksson
- Sigrun H Lund
- Thorsteinn Markusson
- Gisli Masson
- Pall Melsted
- Kristjan H S Moore
- Heidi Munk
- Kaspar R Nielsen
- Gudmundur L Norddahl
- Asmundur Oddsson
- Thorunn A Olafsdottir
- Pall I Olason
- Tomas Olsson
- Sisse Rye Ostrowski
- Kim Hørslev-Petersen
- Solvi Rognvaldsson
- Helga Sanner
- Gilad N Silberberg
- Hreinn Stefansson
- Erik Sørensen
- Inge J 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 BV Pedersen
- Unnur Thorsteinsdottir
- Ingileif Jonsdottir
- Kari Stefansson
- Steffen Andersen
- Karina Banasik
- Søren Brunak
- Kristoffer Burgdorf
- Christian Erikstrup
- Thomas Folkmann Hansen
- Henrik Hjalgrim
- Gregor Jemec
- Poul Jennum
- Pär Ingemar Johansson
- Kasper Rene Nielsen
- Mette Nyegaard
- Mie Topholm Brun
- Ole Birger Pedersen
- Susan Mikkelsen
- Khoa Manh Dinh
- Erik Sørensen
- Henrik Ullum
- Sisse Rye Ostrowski
- Thomas Werge
- Daniel Gudbjartsson
- Kari Stefansson
- Hreinn Stefánsson
- Unnur Þorsteinsdóttir
- Margit Anita Hørup Larsen
- Maria Didriksen
- Susanne Sækmose
- Paal Skytt Andersen
- Ram Benny Dessau
- Malene Rohr Andersen
- Hans Jürgen Hoffmann
- Claus Lohman Brasen
- Johan Askling
- Eva Baecklund
- Lena Bjorkman
- Alf Kastbom
- Solbritt Rantapaa-Dahlqvist
- Carl Turesson
1 Application
| Application ID | Title |
|---|---|
| 24898 | Genetics of lumbar disc disease and associated sciatica |
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