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 () and Kari Stefansson ()
Additional contact information
Gyda Bjornsdottir: deCODE Genetics/Amgen, Inc.
Lilja Stefansdottir: deCODE Genetics/Amgen, Inc.
Gudmar Thorleifsson: deCODE Genetics/Amgen, Inc.
Patrick Sulem: deCODE Genetics/Amgen, Inc.
Kristjan Norland: deCODE Genetics/Amgen, Inc.
Egil Ferkingstad: deCODE Genetics/Amgen, Inc.
Asmundur Oddsson: deCODE Genetics/Amgen, Inc.
Florian Zink: deCODE Genetics/Amgen, Inc.
Sigrun H. Lund: deCODE Genetics/Amgen, Inc.
Muhammad S. Nawaz: deCODE Genetics/Amgen, Inc.
G. Bragi Walters: deCODE Genetics/Amgen, Inc.
Astros Th. Skuladottir: deCODE Genetics/Amgen, Inc.
Sigurjon A. Gudjonsson: deCODE Genetics/Amgen, Inc.
Gudmundur Einarsson: deCODE Genetics/Amgen, Inc.
Gisli H. Halldorsson: deCODE Genetics/Amgen, Inc.
Valgerdur Bjarnadottir: Landspitali University Hospital
Gardar Sveinbjornsson: deCODE Genetics/Amgen, Inc.
Anna Helgadottir: deCODE Genetics/Amgen, Inc.
Unnur Styrkarsdottir: deCODE Genetics/Amgen, Inc.
Larus J. Gudmundsson: deCODE Genetics/Amgen, Inc.
Ole B. Pedersen: Zealand University Hospital
Thomas Folkmann Hansen: Rigshospitalet-Glostrup
Thomas Werge: University of Copenhagen
Karina Banasik: University of Copenhagen
Anders Troelsen: University of Copenhagen
Soren T. Skou: University of Southern Denmark
Lise Wegner Thørner: Copenhagen University Hospital
Christian Erikstrup: Aarhus University Hospital
Kaspar Rene Nielsen: Aalborg University Hospital
Susan Mikkelsen: Aarhus University Hospital
Ingileif Jonsdottir: deCODE Genetics/Amgen, Inc.
Aron Bjornsson: Landspitali University Hospital
Ingvar H. Olafsson: Landspitali University Hospital
Elfar Ulfarsson: Landspitali University Hospital
Josep Blondal: Health Care Institution of West Iceland
Arnor Vikingsson: Landspitali University Hospital
Soren Brunak: University of Copenhagen
Sisse R. Ostrowski: University of Copenhagen
Henrik Ullum: Statens Serum Institut, Copenhagen
Unnur Thorsteinsdottir: deCODE Genetics/Amgen, Inc.
Hreinn Stefansson: deCODE Genetics/Amgen, Inc.
Daniel F. Gudbjartsson: deCODE Genetics/Amgen, Inc.
Thorgeir E. Thorgeirsson: deCODE Genetics/Amgen, Inc.
Kari Stefansson: deCODE Genetics/Amgen, Inc.

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28167-1

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