Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

Gyda Bjornsdottir; Lilja Stefansdottir; DBDS Genetic Consortium; GO Consortium; Gudmar Thorleifsson; Patrick Sulem; Kristjan Norland; Egil Ferkingstad; Asmundur Oddsson; Florian Zink; Sigrun H. Lund; Muhammad S. Nawaz; G. Bragi Walters; Astros Th Skuladottir; Sigurjon A. Gudjonsson; Gudmundur Einarsson; Gisli H. Halldorsson; Valgerdur Bjarnadottir; Gardar Sveinbjornsson; Anna Helgadottir; Unnur Styrkarsdottir; Larus J. Gudmundsson; Ole Birger Pedersen; Thomas Folkmann Hansen; Thomas Werge; Karina Banasik; Anders Troelsen; Soren T. Skou; Lise Wegner Thørner; Christian Erikstrup; Kaspar Rene Nielsen; Susan Mikkelsen; Steffen Andersen; Søren Brunak; Kristoffer Burgdorf; Henrik Hjalgrim; Gregor Jemec; Poul Jennum; Per Ingemar Johansson; Kasper Rene Nielsen; Mette Nyegaard; Mie Topholm Bruun; Ole Birger Pedersen; Khoa Manh Dinh; Erik Sørensen; Sisse Ostrowski; Thorgeir E. Thorgeirsson; Kari Stefansson

doi:10.1038/s41467-022-28167-1

Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

Gyda Bjornsdottir^*, Lilja Stefansdottir, DBDS Genetic Consortium, GO Consortium, Gudmar Thorleifsson, Patrick Sulem, Kristjan Norland, Egil Ferkingstad, Asmundur Oddsson, Florian Zink, Sigrun H. Lund, Muhammad S. Nawaz, G. Bragi Walters, Astros Th Skuladottir, Sigurjon A. Gudjonsson, Gudmundur Einarsson, Gisli H. Halldorsson, Valgerdur Bjarnadottir, Gardar Sveinbjornsson, Anna HelgadottirUnnur Styrkarsdottir, Larus J. Gudmundsson, Ole Birger Pedersen, Thomas Folkmann Hansen, Thomas Werge, Karina Banasik, Anders Troelsen, Soren T. Skou, Lise Wegner Thørner, Christian Erikstrup, Kaspar Rene Nielsen, Susan Mikkelsen, Steffen Andersen, Søren Brunak, Kristoffer Burgdorf, Henrik Hjalgrim, Gregor Jemec, Poul Jennum, Per Ingemar Johansson, Kasper Rene Nielsen, Mette Nyegaard, Mie Topholm Bruun, Ole Birger Pedersen, Khoa Manh Dinh, Erik Sørensen, Sisse Ostrowski, Thorgeir E. Thorgeirsson, Kari Stefansson

^*Corresponding author for this work

Internal Medicine

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Abstract

Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (OR_IDD = 0.92, P = 1.6 × 10⁻³⁹; OR_dorsalgia = 0.92, P = 7.2 × 10⁻¹⁵) is with a 3’UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 − 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10⁻¹¹); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.

Original language	English
Article number	634
Journal	Nature Communications
Volume	13
Issue number	1
Early online date	2 Feb 2022
DOIs	https://doi.org/10.1038/s41467-022-28167-1
Publication status	Published - 1 Dec 2022

Bibliographical note

Funding Information:
We thank all participants in the various studies included here, for their valuable contribution to research. We thank all investigators and colleagues in Iceland who contributed to data collection, phenotypic characterization of clinical samples, genotyping and analysis of the whole-genome association data. We acknowledge participants and investigators of the FinnGen study in Finland, the DBDS-CHB studies in Denmark, and the UK Biobank in Great Britain. This research has been conducted using the UK Biobank Resource under Application Number 24898. The financial support from the European Commission to the painFACT project (H2020-2020-848099, T.E.T.) is acknowledged. K.B., T.F.H., and S.B. acknowledge the Novo Nordisk Foundation (grants NNF17OC0027594 K.B., T.F.H., S.B., and NNF14CC0001 K.B., T.F.H., S.B.).

Funding Information:
We thank all participants in the various studies included here, for their valuable contribution to research. We thank all investigators and colleagues in Iceland who contributed to data collection, phenotypic characterization of clinical samples, genotyping and analysis of the whole-genome association data. We acknowledge participants and investigators of the FinnGen study in Finland, the DBDS-CHB studies in Denmark, and the UK Biobank in Great Britain. This research has been conducted using the UK Biobank Resource under Application Number 24898. The financial support from the European Commission to the painFACT project (H2020-2020-848099, T.E.T.) is acknowledged. K.B., T.F.H., and S.B. acknowledge the Novo Nordisk Foundation (grants NNF17OC0027594 K.B., T.F.H., S.B., and NNF14CC0001 K.B., T.F.H., S.B.).

Publisher Copyright:
© 2022, The Author(s).

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Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathologyFinal published version, 2.3 MBLicence: CC BY

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Bjornsdottir, G., Stefansdottir, L., DBDS Genetic Consortium, GO Consortium, Thorleifsson, G., Sulem, P., Norland, K., Ferkingstad, E., Oddsson, A., Zink, F., Lund, S. H., Nawaz, M. S., Bragi Walters, G., Skuladottir, A. T., Gudjonsson, S. A., Einarsson, G., Halldorsson, G. H., Bjarnadottir, V., Sveinbjornsson, G., ... Stefansson, K. (2022). Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology. Nature Communications, 13(1), Article 634. https://doi.org/10.1038/s41467-022-28167-1

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title = "Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology",

abstract = "Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10−39; ORdorsalgia = 0.92, P = 7.2 × 10−15) is with a 3{\textquoteright}UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 − 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10−11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.",

author = "Gyda Bjornsdottir and Lilja Stefansdottir and {DBDS Genetic Consortium} and {GO Consortium} and Gudmar Thorleifsson and Patrick Sulem and Kristjan Norland and Egil Ferkingstad and Asmundur Oddsson and Florian Zink and Lund, {Sigrun H.} and Nawaz, {Muhammad S.} and {Bragi Walters}, G. and Skuladottir, {Astros Th} and Gudjonsson, {Sigurjon A.} and Gudmundur Einarsson and Halldorsson, {Gisli H.} and Valgerdur Bjarnadottir and Gardar Sveinbjornsson and Anna Helgadottir and Unnur Styrkarsdottir and Gudmundsson, {Larus J.} and Pedersen, {Ole Birger} and Hansen, {Thomas Folkmann} and Thomas Werge and Karina Banasik and Anders Troelsen and Skou, {Soren T.} and Th{\o}rner, {Lise Wegner} and Christian Erikstrup and Nielsen, {Kaspar Rene} and Susan Mikkelsen and Steffen Andersen and S{\o}ren Brunak and Kristoffer Burgdorf and Henrik Hjalgrim and Gregor Jemec and Poul Jennum and Johansson, {Per Ingemar} and Nielsen, {Kasper Rene} and Mette Nyegaard and Bruun, {Mie Topholm} and Pedersen, {Ole Birger} and Dinh, {Khoa Manh} and Erik S{\o}rensen and Sisse Ostrowski and {van Meurs}, {Joyce B.J.} and Boer, {Cindy G.} and Uitterlinden, {Andr{\'e} G.} and Thorgeirsson, {Thorgeir E.} and Kari Stefansson",

note = "Funding Information: We thank all participants in the various studies included here, for their valuable contribution to research. We thank all investigators and colleagues in Iceland who contributed to data collection, phenotypic characterization of clinical samples, genotyping and analysis of the whole-genome association data. We acknowledge participants and investigators of the FinnGen study in Finland, the DBDS-CHB studies in Denmark, and the UK Biobank in Great Britain. This research has been conducted using the UK Biobank Resource under Application Number 24898. The financial support from the European Commission to the painFACT project (H2020-2020-848099, T.E.T.) is acknowledged. K.B., T.F.H., and S.B. acknowledge the Novo Nordisk Foundation (grants NNF17OC0027594 K.B., T.F.H., S.B., and NNF14CC0001 K.B., T.F.H., S.B.). Funding Information: We thank all participants in the various studies included here, for their valuable contribution to research. We thank all investigators and colleagues in Iceland who contributed to data collection, phenotypic characterization of clinical samples, genotyping and analysis of the whole-genome association data. We acknowledge participants and investigators of the FinnGen study in Finland, the DBDS-CHB studies in Denmark, and the UK Biobank in Great Britain. This research has been conducted using the UK Biobank Resource under Application Number 24898. The financial support from the European Commission to the painFACT project (H2020-2020-848099, T.E.T.) is acknowledged. K.B., T.F.H., and S.B. acknowledge the Novo Nordisk Foundation (grants NNF17OC0027594 K.B., T.F.H., S.B., and NNF14CC0001 K.B., T.F.H., S.B.). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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doi = "10.1038/s41467-022-28167-1",

language = "English",

volume = "13",

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Bjornsdottir, G, Stefansdottir, L, DBDS Genetic Consortium, GO Consortium, Thorleifsson, G, Sulem, P, Norland, K, Ferkingstad, E, Oddsson, A, Zink, F, Lund, SH, Nawaz, MS, Bragi Walters, G, Skuladottir, AT, Gudjonsson, SA, Einarsson, G, Halldorsson, GH, Bjarnadottir, V, Sveinbjornsson, G, Helgadottir, A, Styrkarsdottir, U, Gudmundsson, LJ, Pedersen, OB, Hansen, TF, Werge, T, Banasik, K, Troelsen, A, Skou, ST, Thørner, LW, Erikstrup, C, Nielsen, KR, Mikkelsen, S, Andersen, S, Brunak, S, Burgdorf, K, Hjalgrim, H, Jemec, G, Jennum, P, Johansson, PI, Nielsen, KR, Nyegaard, M, Bruun, MT, Pedersen, OB, Dinh, KM, Sørensen, E, Ostrowski, S, Thorgeirsson, TE & Stefansson, K 2022, 'Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology', Nature Communications, vol. 13, no. 1, 634. https://doi.org/10.1038/s41467-022-28167-1

TY - JOUR

T1 - Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

AU - Bjornsdottir, Gyda

AU - Stefansdottir, Lilja

AU - DBDS Genetic Consortium

AU - GO Consortium

AU - Thorleifsson, Gudmar

AU - Sulem, Patrick

AU - Norland, Kristjan

AU - Ferkingstad, Egil

AU - Oddsson, Asmundur

AU - Zink, Florian

AU - Lund, Sigrun H.

AU - Nawaz, Muhammad S.

AU - Bragi Walters, G.

AU - Skuladottir, Astros Th

AU - Gudjonsson, Sigurjon A.

AU - Einarsson, Gudmundur

AU - Halldorsson, Gisli H.

AU - Bjarnadottir, Valgerdur

AU - Sveinbjornsson, Gardar

AU - Helgadottir, Anna

AU - Styrkarsdottir, Unnur

AU - Gudmundsson, Larus J.

AU - Pedersen, Ole Birger

AU - Hansen, Thomas Folkmann

AU - Werge, Thomas

AU - Banasik, Karina

AU - Troelsen, Anders

AU - Skou, Soren T.

AU - Thørner, Lise Wegner

AU - Erikstrup, Christian

AU - Nielsen, Kaspar Rene

AU - Mikkelsen, Susan

AU - Andersen, Steffen

AU - Brunak, Søren

AU - Burgdorf, Kristoffer

AU - Hjalgrim, Henrik

AU - Jemec, Gregor

AU - Jennum, Poul

AU - Johansson, Per Ingemar

AU - Nielsen, Kasper Rene

AU - Nyegaard, Mette

AU - Bruun, Mie Topholm

AU - Pedersen, Ole Birger

AU - Dinh, Khoa Manh

AU - Sørensen, Erik

AU - Ostrowski, Sisse

AU - van Meurs, Joyce B.J.

AU - Boer, Cindy G.

AU - Uitterlinden, André G.

AU - Thorgeirsson, Thorgeir E.

AU - Stefansson, Kari

N1 - Funding Information: We thank all participants in the various studies included here, for their valuable contribution to research. We thank all investigators and colleagues in Iceland who contributed to data collection, phenotypic characterization of clinical samples, genotyping and analysis of the whole-genome association data. We acknowledge participants and investigators of the FinnGen study in Finland, the DBDS-CHB studies in Denmark, and the UK Biobank in Great Britain. This research has been conducted using the UK Biobank Resource under Application Number 24898. The financial support from the European Commission to the painFACT project (H2020-2020-848099, T.E.T.) is acknowledged. K.B., T.F.H., and S.B. acknowledge the Novo Nordisk Foundation (grants NNF17OC0027594 K.B., T.F.H., S.B., and NNF14CC0001 K.B., T.F.H., S.B.). Funding Information: We thank all participants in the various studies included here, for their valuable contribution to research. We thank all investigators and colleagues in Iceland who contributed to data collection, phenotypic characterization of clinical samples, genotyping and analysis of the whole-genome association data. We acknowledge participants and investigators of the FinnGen study in Finland, the DBDS-CHB studies in Denmark, and the UK Biobank in Great Britain. This research has been conducted using the UK Biobank Resource under Application Number 24898. The financial support from the European Commission to the painFACT project (H2020-2020-848099, T.E.T.) is acknowledged. K.B., T.F.H., and S.B. acknowledge the Novo Nordisk Foundation (grants NNF17OC0027594 K.B., T.F.H., S.B., and NNF14CC0001 K.B., T.F.H., S.B.). Publisher Copyright: © 2022, The Author(s).

PY - 2022/12/1

Y1 - 2022/12/1

N2 - Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10−39; ORdorsalgia = 0.92, P = 7.2 × 10−15) is with a 3’UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 − 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10−11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.

AB - Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10−39; ORdorsalgia = 0.92, P = 7.2 × 10−15) is with a 3’UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 − 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10−11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.

UR - http://www.scopus.com/inward/record.url?scp=85123973763&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-28167-1

DO - 10.1038/s41467-022-28167-1

M3 - Article

C2 - 35110524

AN - SCOPUS:85123973763

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 634

ER -

Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

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