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; 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 B Pedersen; Thomas Folkmann Hansen; Thomas Werge; Karina Banasik; Anders Troelsen; Soren T Skou; Lise Wegner Thørner; Christian Erikstrup; Kaspar Rene Nielsen; Susan Mikkelsen; Ingileif Jonsdottir; Aron Bjornsson; Ingvar H Olafsson; Elfar Ulfarsson; Josep Blondal; Arnor Vikingsson; Soren Brunak; Sisse R Ostrowski; Henrik Ullum; Unnur Thorsteinsdottir; Hreinn Stefansson; Daniel F Gudbjartsson; Thorgeir E Thorgeirsson; Kari Stefansson; DBDS Genetic 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, G Bragi Walters, Astros Th Skuladottir, Sigurjon A Gudjonsson, Gudmundur Einarsson, Gisli H Halldorsson, Valgerdur Bjarnadottir, Gardar Sveinbjornsson, Anna Helgadottir, Unnur Styrkarsdottir, Larus J GudmundssonOle B Pedersen, Thomas Folkmann Hansen, Thomas Werge, Karina Banasik, Anders Troelsen, Soren T Skou, Lise Wegner Thørner, Christian Erikstrup, Kaspar Rene Nielsen, Susan Mikkelsen, Ingileif Jonsdottir, Aron Bjornsson, Ingvar H Olafsson, Elfar Ulfarsson, Josep Blondal, Arnor Vikingsson, Soren Brunak, Sisse R Ostrowski, Henrik Ullum, Unnur Thorsteinsdottir, Hreinn Stefansson, Daniel F Gudbjartsson, Thorgeir E Thorgeirsson, Kari Stefansson, DBDS Genetic Consortium

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
Pages (from-to)	1-13
Number of pages	13
ISSN	2041-1722
DOIs	https://doi.org/10.1038/s41467-022-28167-1
Publication status	Published - 2 Feb 2022

Keywords

3' Untranslated Regions
Bone and Bones/metabolism
Genome-Wide Association Study
Humans
Intervertebral Disc Degeneration/genetics
Intervertebral Disc Displacement/genetics
Intervertebral Disc/metabolism
Sodium Sulfate Cotransporter/genetics
Sulfates/metabolism
Symporters/genetics

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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 Walters, G., Skuladottir, A. T., Gudjonsson, S. A., Einarsson, G., Halldorsson, G. H., Bjarnadottir, V., Sveinbjornsson, G., Helgadottir, A., Styrkarsdottir, U., ... DBDS Genetic Consortium (2022). Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology. Nature Communications, 13(1), 1-13. [634]. https://doi.org/10.1038/s41467-022-28167-1

Bjornsdottir, G, Stefansdottir, L, 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, Jonsdottir, I, Bjornsson, A, Olafsson, IH, Ulfarsson, E, Blondal, J, Vikingsson, A, Brunak, S, Ostrowski, SR, Ullum, H, Thorsteinsdottir, U, Stefansson, H, Gudbjartsson, DF, Thorgeirsson, TE, Stefansson, K & DBDS Genetic Consortium 2022, 'Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology', Nature Communications, vol. 13, no. 1, 634, pp. 1-13. https://doi.org/10.1038/s41467-022-28167-1

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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.",

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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 - 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 B

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 - Jonsdottir, Ingileif

AU - Bjornsson, Aron

AU - Olafsson, Ingvar H

AU - Ulfarsson, Elfar

AU - Blondal, Josep

AU - Vikingsson, Arnor

AU - Brunak, Soren

AU - Ostrowski, Sisse R

AU - Ullum, Henrik

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Hreinn

AU - Gudbjartsson, Daniel F

AU - Thorgeirsson, Thorgeir E

AU - Stefansson, Kari

AU - DBDS Genetic Consortium

PY - 2022/2/2

Y1 - 2022/2/2

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.

KW - 3' Untranslated Regions

KW - Bone and Bones/metabolism

KW - Genome-Wide Association Study

KW - Humans

KW - Intervertebral Disc Degeneration/genetics

KW - Intervertebral Disc Displacement/genetics

KW - Intervertebral Disc/metabolism

KW - Sodium Sulfate Cotransporter/genetics

KW - Sulfates/metabolism

KW - Symporters/genetics

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U2 - 10.1038/s41467-022-28167-1

DO - 10.1038/s41467-022-28167-1

M3 - Journal article

C2 - 35110524

VL - 13

SP - 1

EP - 13

JO - Nature Communications

JF - Nature Communications

SN - 2041-1722

IS - 1

M1 - 634

ER -

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

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Keywords

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