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

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; Sisse Rye Ostrowski; Erik Sørensen; Inge J Sørensen; Merete Lund Hetland; Ole Bv Pedersen; Kristoffer Sølvsten Burgdorf; Thomas Folkmann Hansen; Poul Jørgen Jennum; Erik Sørensen; Henrik Ullum; Margit Anita Hørup Larsen; Malene Rohr Andersen; Members of the DBDS Genomic Consortium; Pär Ingemar Johansson

doi:10.1136/annrheumdis-2021-221754

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

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 EllingsenChristian 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, Sisse Rye Ostrowski, Erik Sørensen, Inge J Sørensen, Merete Lund Hetland, Ole Bv Pedersen, Kristoffer Sølvsten Burgdorf (Member of study group), Thomas Folkmann Hansen (Member of study group), Poul Jørgen Jennum (Member of study group), Erik Sørensen (Member of study group), Henrik Ullum (Member of study group), Margit Anita Hørup Larsen (Member of study group), Malene Rohr Andersen (Member of study group), Members of the DBDS Genomic Consortium, Pär Ingemar Johansson (Member of study group)

^*Corresponding author for this work

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.

Original language	English
Article number	221754
Journal	Annals of the Rheumatic Diseases
Volume	81
Issue number	8
Pages (from-to)	1085-1095
Number of pages	11
ISSN	0003-4967
DOIs	https://doi.org/10.1136/annrheumdis-2021-221754
Publication status	Published - Aug 2022

Keywords

Arthritis, Rheumatoid/genetics
Genetic Predisposition to Disease/genetics
Genome-Wide Association Study
Humans
Interferon-alpha
Janus Kinases/genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics
Proteomics
STAT Transcription Factors/genetics
Signal Transduction/genetics

Access to Document

10.1136/annrheumdis-2021-221754

Cite this

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., ... Johansson, P. I. (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. Article 221754. https://doi.org/10.1136/annrheumdis-2021-221754

Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset. / Saevarsdottir, Saedis; Stefansdottir, Lilja; Sulem, Patrick et al.
In: Annals of the Rheumatic Diseases, Vol. 81, No. 8, 221754, 08.2022, p. 1085-1095.

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

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, Markusson, T, Masson, G, Melsted, P, Ostrowski, SR , Sørensen, E , Sørensen, IJ , Hetland, ML, Pedersen, OB, Burgdorf, KS, Hansen, TF , Jennum, PJ , Sørensen, E, Ullum, H, Larsen, MAH, Andersen, MR, Members of the DBDS Genomic Consortium & Johansson, PI 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, 221754, pp. 1085-1095. https://doi.org/10.1136/annrheumdis-2021-221754

@article{cb9bfd45f98f48b683b2586d16f25e91,

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.",

keywords = "Arthritis, Rheumatoid/genetics, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study, Humans, Interferon-alpha, Janus Kinases/genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics, Proteomics, STAT Transcription Factors/genetics, Signal Transduction/genetics",

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 Thorsteinn Markusson and Gisli Masson and Pall Melsted and Ostrowski, {Sisse Rye} and Erik S{\o}rensen and S{\o}rensen, {Inge J} and Hetland, {Merete Lund} and Pedersen, {Ole Bv} and Burgdorf, {Kristoffer S{\o}lvsten} and Hansen, {Thomas Folkmann} and Jennum, {Poul J{\o}rgen} and Erik S{\o}rensen and Henrik Ullum and Larsen, {Margit Anita H{\o}rup} and Andersen, {Malene Rohr} and {Members of the DBDS Genomic Consortium} and Johansson, {P{\"a}r Ingemar}",

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. COPECARE",

year = "2022",

month = aug,

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",

}

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 - Markusson, Thorsteinn

AU - Masson, Gisli

AU - Melsted, Pall

AU - Ostrowski, Sisse Rye

AU - Sørensen, Erik

AU - Sørensen, Inge J

AU - Hetland, Merete Lund

AU - Pedersen, Ole Bv

AU - Members of the DBDS Genomic Consortium

A2 - Burgdorf, Kristoffer Sølvsten

A2 - Hansen, Thomas Folkmann

A2 - Jennum, Poul Jørgen

A2 - Sørensen, Erik

A2 - Ullum, Henrik

A2 - Larsen, Margit Anita Hørup

A2 - Andersen, Malene Rohr

A2 - Johansson, Pär Ingemar

PY - 2022/8

Y1 - 2022/8

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.

KW - Arthritis, Rheumatoid/genetics

KW - Genetic Predisposition to Disease/genetics

KW - Genome-Wide Association Study

KW - Humans

KW - Interferon-alpha

KW - Janus Kinases/genetics

KW - Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics

KW - Proteomics

KW - STAT Transcription Factors/genetics

KW - Signal Transduction/genetics

UR - http://www.scopus.com/inward/record.url?scp=85130778612&partnerID=8YFLogxK

U2 - 10.1136/annrheumdis-2021-221754

DO - 10.1136/annrheumdis-2021-221754

M3 - Journal article

C2 - 35470158

SN - 0003-4967

VL - 81

SP - 1085

EP - 1095

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

IS - 8

M1 - 221754

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this