Rare SLC13A1 Variants Associate with Intervertebral Disc Disorder Highlighting Role of Sulfate in Disc Pathology

Gyda  Bjornsdottir; Lilja Stefansdottir; Gudmar  Thorleifsson; Patrick Sulem; Kristjan Norland; Egil  Ferkingstad; Asmundur  Oddsson; Florian Zink; Sigrun H.  Lund; Muhammad S. Nawaz; Walters G. Bragi; Astros Th. Skuladottir; Larus J. Gudmundsson; Ole B. Pedersen; Thomas Folkmann Hansen; Thomas Werge; Karina Banasik; Anders Troelsen; Søren T.  Skou; Lise Wegner Thørner; Christian Erikstrup; Kaspar René Nielsen; Susan  Mikkelsen; Steffen Andersen; Søren Brunak; Kristoffer Sølvsten Burgdorf; Henrik Hjalgrim; Gregot Jemec; Poul Jennum; Per Ingemar Johansson; Rene Kasper Nielsen; Mette Nyegaard; Mie Topholm Bruun; Khoa Manh Dinh; Erik Sørensen; Sisse Rye Ostrowski; Pär Ingemar Johansson; Daniel F.  Gudbjartsson; Hreinn  Stefansson; Unnur  Thorsteinsdottir; Margit Anita Hørup Larsen; Maria Didriksen; Susanne Sækmose; Eleftheria Zeggini; Konstantinos Hatzikotoulas; Lorraine Southam; Arthur Gilly; Joyce B. J. van Meurs; Cindy G. Boer; André G. Uitterlinden; Helgi Jonsson; Thorvaldur Ingvarsson; Tõnu Esko; Reedik Mägi; Maris Teder-Laving; Shiro Ikegawa; Chikashi Terao; Hiroshi Takuwa; Ingrid Meulenbelt; Rodrigo Coutinho de Almeida; Margreet Kloppenburg; Margo Tuerlings; P. Eline Slagboom; Rob R. G. H. H. Nelissen; Ana M. Valdes; Massimo Mangino; Aspasia Tsezou; Eleni Zengini; George Alexiadis; George C. Babis; Kathryn S. E. Cheah; Tian T. Wu; Dino Samartzis; Pak Chung Sham; Peter Kraft; Jae Hee Kang; Kristian Hveem; John-Anker Zwart; Almut Lütge; Anne Heidi Skogholt; Marianne B. Johnsen; Laurent F. Thomas; Bendik Winsvold; Maiken E. Gabrielsen; Ming Ta Michael Lee; Yanfei Zhang; Steven A. Lietman; Manu Shivakumar; George Davey Smith; Jonathan H. Tobias; April Hartley; Tom R. Gaunt; Jie Zheng; J. Mark Wilkinson; Julia Steinberg; Andrew P. Morris; Ingileif  Jonsdottir; Aron Bjornsson; Ingvar H. Olafsson; Elfar Ulfarsson; Josep Blondal; Arnor Vikingsson; Sisse Rye Ostrowski; Henrik Ullum; Unnur  Thorsteinsdottir; Daniel F.  Gudbjartsson; Thorgeir E. Thorgeirsson; Kari  Stefansson; DBDS Genetic Consortium; GO Consortium

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, Gudmar Thorleifsson, Patrick Sulem, Kristjan Norland, Egil Ferkingstad, Asmundur Oddsson, Florian Zink, Sigrun H. Lund, Muhammad S. Nawaz, Walters G. Bragi, Astros Th. Skuladottir, Larus J. Gudmundsson, Ole B. Pedersen, Thomas Folkmann Hansen, Thomas Werge, Karina Banasik, Anders Troelsen, Søren T. Skou, Lise Wegner ThørnerChristian Erikstrup, Kaspar René Nielsen, Susan Mikkelsen, Steffen Andersen, Søren Brunak, Kristoffer Sølvsten Burgdorf, Henrik Hjalgrim, Gregot Jemec, Poul Jennum, Per Ingemar Johansson, Rene Kasper Nielsen, Mette Nyegaard, Mie Topholm Bruun, Khoa Manh Dinh, Erik Sørensen, Sisse Rye Ostrowski, Pär Ingemar Johansson, Daniel F. Gudbjartsson, Hreinn Stefansson, Unnur Thorsteinsdottir, Margit Anita Hørup Larsen, Maria Didriksen, Susanne Sækmose, Eleftheria Zeggini, Konstantinos Hatzikotoulas, Lorraine Southam, Arthur Gilly, Joyce B. J. van Meurs, Cindy G. Boer, André G. Uitterlinden, Helgi Jonsson, Thorvaldur Ingvarsson, Tõnu Esko, Reedik Mägi, Maris Teder-Laving, Shiro Ikegawa, Chikashi Terao, Hiroshi Takuwa, Ingrid Meulenbelt, Rodrigo Coutinho de Almeida, Margreet Kloppenburg, Margo Tuerlings, P. Eline Slagboom, Rob R. G. H. H. Nelissen, Ana M. Valdes, Massimo Mangino, Aspasia Tsezou, Eleni Zengini, George Alexiadis, George C. Babis, Kathryn S. E. Cheah, Tian T. Wu, Dino Samartzis, Pak Chung Sham, Peter Kraft, Jae Hee Kang, Kristian Hveem, John-Anker Zwart, Almut Lütge, Anne Heidi Skogholt, Marianne B. Johnsen, Laurent F. Thomas, Bendik Winsvold, Maiken E. Gabrielsen, Ming Ta Michael Lee, Yanfei Zhang, Steven A. Lietman, Manu Shivakumar, George Davey Smith, Jonathan H. Tobias, April Hartley, Tom R. Gaunt, Jie Zheng, J. Mark Wilkinson, Julia Steinberg, Andrew P. Morris, Ingileif Jonsdottir, Aron Bjornsson, Ingvar H. Olafsson, Elfar Ulfarsson, Josep Blondal, Arnor Vikingsson, Sisse Rye Ostrowski, Henrik Ullum, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Thorgeir E. Thorgeirsson^*, Kari Stefansson^*, DBDS Genetic Consortium, GO Consortium

^*Corresponding author for this work

Department of Finance

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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 (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

Original language	English
Article number	634
Journal	Nature Communications
Volume	13
Issue number	1
Number of pages	13
DOIs	https://doi.org/10.1038/s41467-022-28167-1
Publication status	Published - 1 Dec 2022

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Bjornsdottir, G., Stefansdottir, L., Thorleifsson, G., Sulem, P., Norland, K., Ferkingstad, E., Oddsson, A., Zink, F., Lund, S. H., Nawaz, M. S., Bragi, W. G., Skuladottir, A. T., Gudmundsson, L. J., Pedersen, O. B., Folkmann Hansen, T., Werge, T., Banasik, K., Troelsen, A., Skou, S. T., ... GO Consortium (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 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 Gudmundsson, {Larus J.} and Pedersen, {Ole B.} and {Folkmann Hansen}, Thomas and Thomas Werge and Karina Banasik and Anders Troelsen and Skou, {S{\o}ren T.} and Th{\o}rner, {Lise Wegner} and Christian Erikstrup and Nielsen, {Kaspar Ren{\'e}} and Susan Mikkelsen and Steffen Andersen and S{\o}ren Brunak and Burgdorf, {Kristoffer S{\o}lvsten} and Henrik Hjalgrim and Gregot Jemec and Poul Jennum and Johansson, {Per Ingemar} and Nielsen, {Rene Kasper} and Mette Nyegaard and Bruun, {Mie Topholm} and Dinh, {Khoa Manh} and Erik S{\o}rensen and Ostrowski, {Sisse Rye} and Johansson, {P{\"a}r Ingemar} and Gudbjartsson, {Daniel F.} and Hreinn Stefansson and Unnur Thorsteinsdottir and {H{\o}rup Larsen}, {Margit Anita} and Maria Didriksen and Susanne S{\ae}kmose and Eleftheria Zeggini and Konstantinos Hatzikotoulas and Lorraine Southam and Arthur Gilly and {van Meurs}, {Joyce B. J.} and Boer, {Cindy G.} and Uitterlinden, {Andr{\'e} G.} and Helgi Jonsson and Thorvaldur Ingvarsson and T{\~o}nu Esko and Reedik M{\"a}gi and Maris Teder-Laving and Shiro Ikegawa and Chikashi Terao and Hiroshi Takuwa and Ingrid Meulenbelt and {Coutinho de Almeida}, Rodrigo and Margreet Kloppenburg and Margo Tuerlings and Slagboom, {P. Eline} and Nelissen, {Rob R. G. H. H.} and Valdes, {Ana M.} and Massimo Mangino and Aspasia Tsezou and Eleni Zengini and George Alexiadis and Babis, {George C.} and Cheah, {Kathryn S. E.} and Wu, {Tian T.} and Dino Samartzis and Sham, {Pak Chung} and Peter Kraft and Kang, {Jae Hee} and Kristian Hveem and John-Anker Zwart and Almut L{\"u}tge and Skogholt, {Anne Heidi} and Johnsen, {Marianne B.} and Thomas, {Laurent F.} and Bendik Winsvold and Gabrielsen, {Maiken E.} and Lee, {Ming Ta Michael} and Yanfei Zhang and Lietman, {Steven A.} and Manu Shivakumar and Smith, {George Davey} and Tobias, {Jonathan H.} and April Hartley and Gaunt, {Tom R.} and Jie Zheng and Wilkinson, {J. Mark} and Julia Steinberg and Morris, {Andrew P.} and Ingileif Jonsdottir and Aron Bjornsson and Olafsson, {Ingvar H.} and Elfar Ulfarsson and Josep Blondal and Arnor Vikingsson and Ostrowski, {Sisse Rye} and Henrik Ullum and Unnur Thorsteinsdottir and Gudbjartsson, {Daniel F.} and Thorgeirsson, {Thorgeir E.} and Kari Stefansson and {DBDS Genetic Consortium} and {GO Consortium}",

year = "2022",

month = dec,

day = "1",

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

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Springer Nature",

number = "1",

}

Bjornsdottir, G, Stefansdottir, L, Thorleifsson, G, Sulem, P, Norland, K, Ferkingstad, E, Oddsson, A, Zink, F, Lund, SH, Nawaz, MS, Bragi, WG, Skuladottir, AT, Gudmundsson, LJ, Pedersen, OB, Folkmann Hansen, T, Werge, T, Banasik, K, Troelsen, A, Skou, ST, Thørner, LW, Erikstrup, C, Nielsen, KR, Mikkelsen, S, Andersen, S, Brunak, S, Burgdorf, KS, Hjalgrim, H, Jemec, G, Jennum, P, Johansson, PI, Nielsen, RK, Nyegaard, M, Bruun, MT, Dinh, KM, Sørensen, E, Ostrowski, SR, Johansson, PI, Gudbjartsson, DF, Stefansson, H, Thorsteinsdottir, U, Hørup Larsen, MA, Didriksen, M, Sækmose, S, Zeggini, E, Hatzikotoulas, K, Southam, L, Gilly, A, van Meurs, JBJ, Boer, CG, Uitterlinden, AG, Jonsson, H, Ingvarsson, T, Esko, T, Mägi, R, Teder-Laving, M, Ikegawa, S, Terao, C, Takuwa, H, Meulenbelt, I, Coutinho de Almeida, R, Kloppenburg, M, Tuerlings, M, Slagboom, PE, Nelissen, RRGHH, Valdes, AM, Mangino, M, Tsezou, A, Zengini, E, Alexiadis, G, Babis, GC, Cheah, KSE, Wu, TT, Samartzis, D, Sham, PC, Kraft, P, Kang, JH, Hveem, K, Zwart, J-A, Lütge, A, Skogholt, AH, Johnsen, MB, Thomas, LF, Winsvold, B, Gabrielsen, ME, Lee, MTM, Zhang, Y, Lietman, SA, Shivakumar, M, Smith, GD, Tobias, JH, Hartley, A, Gaunt, TR, Zheng, J, Wilkinson, JM, Steinberg, J, Morris, AP, Jonsdottir, I, Bjornsson, A, Olafsson, IH, Ulfarsson, E, Blondal, J, Vikingsson, A, Ostrowski, SR, Ullum, H, Thorsteinsdottir, U, Gudbjartsson, DF, Thorgeirsson, TE, Stefansson, K, DBDS Genetic Consortium & GO Consortium 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 - 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 - Gudmundsson, Larus J.

AU - Pedersen, Ole B.

AU - Folkmann Hansen, Thomas

AU - Werge, Thomas

AU - Banasik, Karina

AU - Troelsen, Anders

AU - Skou, Søren T.

AU - Thørner, Lise Wegner

AU - Erikstrup, Christian

AU - Nielsen, Kaspar René

AU - Mikkelsen, Susan

AU - Andersen, Steffen

AU - Brunak, Søren

AU - Burgdorf, Kristoffer Sølvsten

AU - Hjalgrim, Henrik

AU - Jemec, Gregot

AU - Jennum, Poul

AU - Johansson, Per Ingemar

AU - Nielsen, Rene Kasper

AU - Nyegaard, Mette

AU - Bruun, Mie Topholm

AU - Dinh, Khoa Manh

AU - Sørensen, Erik

AU - Ostrowski, Sisse Rye

AU - Johansson, Pär Ingemar

AU - Gudbjartsson, Daniel F.

AU - Stefansson, Hreinn

AU - Thorsteinsdottir, Unnur

AU - Hørup Larsen, Margit Anita

AU - Didriksen, Maria

AU - Sækmose, Susanne

AU - Zeggini, Eleftheria

AU - Hatzikotoulas, Konstantinos

AU - Southam, Lorraine

AU - Gilly, Arthur

AU - van Meurs, Joyce B. J.

AU - Boer, Cindy G.

AU - Uitterlinden, André G.

AU - Jonsson, Helgi

AU - Ingvarsson, Thorvaldur

AU - Esko, Tõnu

AU - Mägi, Reedik

AU - Teder-Laving, Maris

AU - Ikegawa, Shiro

AU - Terao, Chikashi

AU - Takuwa, Hiroshi

AU - Meulenbelt, Ingrid

AU - Coutinho de Almeida, Rodrigo

AU - Kloppenburg, Margreet

AU - Tuerlings, Margo

AU - Slagboom, P. Eline

AU - Nelissen, Rob R. G. H. H.

AU - Valdes, Ana M.

AU - Mangino, Massimo

AU - Tsezou, Aspasia

AU - Zengini, Eleni

AU - Alexiadis, George

AU - Babis, George C.

AU - Cheah, Kathryn S. E.

AU - Wu, Tian T.

AU - Samartzis, Dino

AU - Sham, Pak Chung

AU - Kraft, Peter

AU - Kang, Jae Hee

AU - Hveem, Kristian

AU - Zwart, John-Anker

AU - Lütge, Almut

AU - Skogholt, Anne Heidi

AU - Johnsen, Marianne B.

AU - Thomas, Laurent F.

AU - Winsvold, Bendik

AU - Gabrielsen, Maiken E.

AU - Lee, Ming Ta Michael

AU - Zhang, Yanfei

AU - Lietman, Steven A.

AU - Shivakumar, Manu

AU - Smith, George Davey

AU - Tobias, Jonathan H.

AU - Hartley, April

AU - Gaunt, Tom R.

AU - Zheng, Jie

AU - Wilkinson, J. Mark

AU - Steinberg, Julia

AU - Morris, Andrew P.

AU - Jonsdottir, Ingileif

AU - Bjornsson, Aron

AU - Olafsson, Ingvar H.

AU - Ulfarsson, Elfar

AU - Blondal, Josep

AU - Vikingsson, Arnor

AU - Ostrowski, Sisse Rye

AU - Ullum, Henrik

AU - Thorsteinsdottir, Unnur

AU - Gudbjartsson, Daniel F.

AU - Thorgeirsson, Thorgeir E.

AU - Stefansson, Kari

AU - DBDS Genetic Consortium

AU - GO Consortium

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

U2 - 10.1038/s41467-022-28167-1

DO - 10.1038/s41467-022-28167-1

M3 - Journal article

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 634

ER -