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

Gyda Bjornsdottir, Lilja Stefánsdóttir, 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 Styrkársdóttir, 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, 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 R. Ostrowski, Pär Ingemar Johansson, Daniel F. Gudbjartsson, Hreinn Stefansson, Unnur Þorsteinsdóttir, Margit Anita Hørup Larsen, Maria Didriksen, Susanne Sækmose, Eleftheria Zeggini, Konstantinos Hatzikotoulas, Lorraine Southam, Arthur Gilly, Andrei Barysenka, Joyce B. J. van Meurs, Cindy G. Boer, André G. Uitterlinden, Unnur Styrkársdóttir, Lilja Stefánsdóttir, 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, Jason Pui Yin Cheung, Pak Chung Sham, Peter Kraft, Jae Hee Kang, Kristian Hveem, John-Anker Zwart, Almut Luetge, 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, Soren Brunak, Sisse R. Ostrowski, Henrik Ullum, Unnur Thorsteinsdottir, Hreinn Stefansson, Daniel F. Gudbjartsson, Thorgeir E. Thorgeirsson, Kari Stefansson, DBDS Genetic Consortium, GO Consortium

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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 languageEnglish
Article number634
JournalNature Communications
Volume13
Issue number1
ISSN2041-1723
DOIs
Publication statusPublished - 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
  • Author Correction: Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

    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., Gudmundsson, L. J., & 25 othersPedersen, O. B., Hansen, T. F., Werge, T., Banasik, K., Troelsen, A., Skou, S. T., Thørner, L. W., Erikstrup, C., Nielsen, K. R., Mikkelsen, S., DBDS Genetic Consortium, Jonsdottir, I., Bjornsson, A., Olafsson, I. H., Ulfarsson, E., Blondal, J., Vikingsson, A., Brunak, S., Ostrowski, S. R., Ullum, H., Thorsteinsdottir, U., Stefansson, H., Gudbjartsson, D. F., Thorgeirsson, T. E. & Stefansson, K., Dec 2022, In: Nature Communications. 13, 1, 1 p., 2419.

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