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; 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; Members of the DBDS Genomic Consortium; Mette Nyegaard

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, 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, Members of the DBDS Genomic Consortium, Mette Nyegaard (Medlem af forfattergruppering)

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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.

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.

Originalsprog	Engelsk
Artikelnummer	221754
Tidsskrift	Annals of the Rheumatic Diseases
Vol/bind	81
Udgave nummer	8
Sider (fra-til)	1085-1095
Antal sider	11
ISSN	0003-4967
DOI	https://doi.org/10.1136/annrheumdis-2021-221754
Status	Udgivet - aug. 2022

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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., ... Nyegaard, M. (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. Artikel 221754. https://doi.org/10.1136/annrheumdis-2021-221754

@article{239bab16e6074d16aa5db21a089d284f,

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 = "autoantibodies, polymorphism, genetic, rheumatoid arthritis, Genome-Wide Association Study, Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics, Interferon-alpha, Humans, Signal Transduction/genetics, Arthritis, Rheumatoid/genetics, Genetic Predisposition to Disease/genetics, Janus Kinases/genetics, Proteomics, STAT Transcription Factors/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 Moore, {Kristjan H S} and Heidi Munk and Nielsen, {Kaspar R} and Norddahl, {Gudmundur L} and Asmundur Oddsson and Olafsdottir, {Thorunn A} and Olason, {Pall I} and Tomas Olsson and Ostrowski, {Sisse Rye} and Kim H{\o}rslev-Petersen and Solvi Rognvaldsson and Helga Sanner and Silberberg, {Gilad N} and Hreinn Stefansson and Erik S{\o}rensen and S{\o}rensen, {Inge J} and Carl Turesson and Thomas Bergman and Lars Alfredsson and Kvien, {Tore K} and S{\o}ren Brunak and Kristj{\'a}n Steinsson and Vibeke Andersen and Andreassen, {Ole A} and Solbritt Rantap{\"a}{\"a}-Dahlqvist and Hetland, {Merete Lund} and Lars Klareskog and Johan Askling and Leonid Padyukov and Pedersen, {Ole Bv} and Unnur Thorsteinsdottir and Ingileif Jonsdottir and Kari Stefansson and {Members of the DBDS Genomic Consortium} and Mette Nyegaard",

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",

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",

}

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, Moore, KHS, Munk, H, Nielsen, KR, Norddahl, GL, Oddsson, A, Olafsdottir, TA, Olason, PI, Olsson, T, Ostrowski, SR, Hørslev-Petersen, K, Rognvaldsson, S, Sanner, H, Silberberg, GN, Stefansson, H, Sørensen, E, Sørensen, IJ, Turesson, C, Bergman, T, Alfredsson, L, Kvien, TK, Brunak, S, Steinsson, K, Andersen, V, Andreassen, OA, Rantapää-Dahlqvist, S, Hetland, ML, Klareskog, L, Askling, J, Padyukov, L, Pedersen, OB, Thorsteinsdottir, U, Jonsdottir, I, Stefansson, K, Members of the DBDS Genomic Consortium & Nyegaard, M 2022, 'Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset', Annals of the Rheumatic Diseases, bind 81, nr. 8, 221754, s. 1085-1095. https://doi.org/10.1136/annrheumdis-2021-221754

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 - Moore, Kristjan H S

AU - Munk, Heidi

AU - Nielsen, Kaspar R

AU - Norddahl, Gudmundur L

AU - Oddsson, Asmundur

AU - Olafsdottir, Thorunn A

AU - Olason, Pall I

AU - Olsson, Tomas

AU - Ostrowski, Sisse Rye

AU - Hørslev-Petersen, Kim

AU - Rognvaldsson, Solvi

AU - Sanner, Helga

AU - Silberberg, Gilad N

AU - Stefansson, Hreinn

AU - Sørensen, Erik

AU - Sørensen, Inge J

AU - Turesson, Carl

AU - Bergman, Thomas

AU - Alfredsson, Lars

AU - Kvien, Tore K

AU - Brunak, Søren

AU - Steinsson, Kristján

AU - Andersen, Vibeke

AU - Andreassen, Ole A

AU - Rantapää-Dahlqvist, Solbritt

AU - Hetland, Merete Lund

AU - Klareskog, Lars

AU - Askling, Johan

AU - Padyukov, Leonid

AU - Pedersen, Ole Bv

AU - Thorsteinsdottir, Unnur

AU - Jonsdottir, Ingileif

AU - Stefansson, Kari

AU - Members of the DBDS Genomic Consortium

A2 - Nyegaard, Mette

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 - autoantibodies

KW - polymorphism, genetic

KW - rheumatoid arthritis

KW - Genome-Wide Association Study

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

KW - Interferon-alpha

KW - Humans

KW - Signal Transduction/genetics

KW - Arthritis, Rheumatoid/genetics

KW - Genetic Predisposition to Disease/genetics

KW - Janus Kinases/genetics

KW - Proteomics

KW - STAT Transcription Factors/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

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