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

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Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset. / 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; Ostrowski, Sisse Rye; Sørensen, Erik; Sørensen, Inge J; Brunak, Søren; Andersen, Vibeke; Hetland, Merete Lund; Askling, Johan; Pedersen, Ole Bv; Members of the DBDS Genomic Consortium.

In: Annals of the Rheumatic Diseases, Vol. 81, No. 8, 2022, p. 1085-1095.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Saevarsdottir, S, Stefansdottir, L, Sulem, P, Thorleifsson, G, Ferkingstad, E, Rutsdottir, G, Glintborg, B, Westerlind, H, Grondal, G, Loft, IC, Sorensen, SB, Lie, BA, Brink, M, Ärlestig, L, Arnthorsson, AO, Baecklund, E, Banasik, K, Bank, S, Bjorkman, LI, Ellingsen, T, Erikstrup, C, Frei, O, Gjertsson, I, Gudbjartsson, DF, Gudjonsson, SA, Halldorsson, GH, Hendricks, O, Hillert, J, Hogdall, E, Jacobsen, S, Jensen, DV, Jonsson, H, Kastbom, A, Kockum, I, Kristensen, S, Kristjansdottir, H, Larsen, MH, Linauskas, A, Hauge, E-M, Loft, AG, Ludviksson, BR, Lund, SH, Ostrowski, SR, Sørensen, E, Sørensen, IJ, Brunak, S, Andersen, V, Hetland, ML, Askling, J, Pedersen, OB & Members of the DBDS Genomic Consortium 2022, 'Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset', Annals of the Rheumatic Diseases, vol. 81, no. 8, pp. 1085-1095. https://doi.org/10.1136/annrheumdis-2021-221754

APA

Saevarsdottir, S., Stefansdottir, L., Sulem, P., Thorleifsson, G., Ferkingstad, E., Rutsdottir, G., Glintborg, B., Westerlind, H., Grondal, G., Loft, I. C., Sorensen, S. B., Lie, B. A., Brink, M., Ärlestig, L., Arnthorsson, A. O., Baecklund, E., Banasik, K., Bank, S., Bjorkman, L. I., ... Members of the DBDS Genomic Consortium (2022). Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset. Annals of the Rheumatic Diseases, 81(8), 1085-1095. https://doi.org/10.1136/annrheumdis-2021-221754

Vancouver

Saevarsdottir S, Stefansdottir L, Sulem P, Thorleifsson G, Ferkingstad E, Rutsdottir G et al. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset. Annals of the Rheumatic Diseases. 2022;81(8):1085-1095. https://doi.org/10.1136/annrheumdis-2021-221754

Author

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 ; Ostrowski, Sisse Rye ; Sørensen, Erik ; Sørensen, Inge J ; Brunak, Søren ; Andersen, Vibeke ; Hetland, Merete Lund ; Askling, Johan ; Pedersen, Ole Bv ; Members of the DBDS Genomic Consortium. / Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset. In: Annals of the Rheumatic Diseases. 2022 ; Vol. 81, No. 8. pp. 1085-1095.

Bibtex

@article{ac8972ce49334e0888e52da877e76a2b,
title = "Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset",
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.",
author = "Saedis Saevarsdottir and Lilja Stefansdottir and Patrick Sulem and Gudmar Thorleifsson and Egil Ferkingstad and Gudrun Rutsdottir and Bente Glintborg and Helga Westerlind and Gerdur Grondal and Loft, {Isabella C} and Sorensen, {Signe Bek} and Lie, {Benedicte A} and Mikael Brink and Lisbeth {\"A}rlestig and Arnthorsson, {Asgeir Orn} and Eva Baecklund and Karina Banasik and Steffen Bank and Bjorkman, {Lena I} and Torkell Ellingsen and Christian Erikstrup and Oleksandr Frei and Inger Gjertsson and Gudbjartsson, {Daniel F} and Gudjonsson, {Sigurjon A} and Halldorsson, {Gisli H} and Oliver Hendricks and Jan Hillert and Estrid Hogdall and S{\o}ren Jacobsen and Jensen, {Dorte Vendelbo} and Helgi Jonsson and Alf Kastbom and Ingrid Kockum and Salome Kristensen and Helga Kristjansdottir and Larsen, {Margit H} and Asta Linauskas and Ellen-Margrethe Hauge and Loft, {Anne G} and Ludviksson, {Bjorn R} and Lund, {Sigrun H} and Ostrowski, {Sisse Rye} and Erik S{\o}rensen and S{\o}rensen, {Inge J} and S{\o}ren Brunak and Vibeke Andersen and Hetland, {Merete Lund} and Johan Askling and Pedersen, {Ole Bv} and {Members of the DBDS Genomic Consortium}",
note = "{\textcopyright} Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",
year = "2022",
doi = "10.1136/annrheumdis-2021-221754",
language = "English",
volume = "81",
pages = "1085--1095",
journal = "Annals of the Rheumatic Diseases",
issn = "0003-4967",
publisher = "B M J Group",
number = "8",

}

RIS

TY - JOUR

T1 - Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

AU - Saevarsdottir, Saedis

AU - Stefansdottir, Lilja

AU - Sulem, Patrick

AU - Thorleifsson, Gudmar

AU - Ferkingstad, Egil

AU - Rutsdottir, Gudrun

AU - Glintborg, Bente

AU - Westerlind, Helga

AU - Grondal, Gerdur

AU - Loft, Isabella C

AU - Sorensen, Signe Bek

AU - Lie, Benedicte A

AU - Brink, Mikael

AU - Ärlestig, Lisbeth

AU - Arnthorsson, Asgeir Orn

AU - Baecklund, Eva

AU - Banasik, Karina

AU - Bank, Steffen

AU - Bjorkman, Lena I

AU - Ellingsen, Torkell

AU - Erikstrup, Christian

AU - Frei, Oleksandr

AU - Gjertsson, Inger

AU - Gudbjartsson, Daniel F

AU - Gudjonsson, Sigurjon A

AU - Halldorsson, Gisli H

AU - Hendricks, Oliver

AU - Hillert, Jan

AU - Hogdall, Estrid

AU - Jacobsen, Søren

AU - Jensen, Dorte Vendelbo

AU - Jonsson, Helgi

AU - Kastbom, Alf

AU - Kockum, Ingrid

AU - Kristensen, Salome

AU - Kristjansdottir, Helga

AU - Larsen, Margit H

AU - Linauskas, Asta

AU - Hauge, Ellen-Margrethe

AU - Loft, Anne G

AU - Ludviksson, Bjorn R

AU - Lund, Sigrun H

AU - Ostrowski, Sisse Rye

AU - Sørensen, Erik

AU - Sørensen, Inge J

AU - Brunak, Søren

AU - Andersen, Vibeke

AU - Hetland, Merete Lund

AU - Askling, Johan

AU - Pedersen, Ole Bv

AU - Members of the DBDS Genomic Consortium

N1 - © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

U2 - 10.1136/annrheumdis-2021-221754

DO - 10.1136/annrheumdis-2021-221754

M3 - Journal article

C2 - 35470158

VL - 81

SP - 1085

EP - 1095

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

IS - 8

ER -

ID: 306112801