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

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

Title: Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology
Author: Nielsen, K.R.
Pedersen, O.B.
Sørensen, E.
Ostrowski, S.
Johansson, P.I.
Gudbjartsson, D.
Stefansson, H.
Larsen, M.A.H.
Didriksen, M.
Sækmose, S.
... 67 more authors Show all authors
Date: 2022-02-02
Language: English
Scope: 2337466
University/Institute: Agricultural University of Iceland
Landspitali - The National University Hospital of Iceland
University of Akureyri
School: Health Sciences
Department: Office of Division of Diagnostic and Support Services
Faculty of Physical Sciences
Faculty of Medicine
Women's and Childrens's Services
Faculty of Industrial Engineering, Mechanical Engineering and Computer Science
Department of Engineering
Internal Medicine and Emergency Services
Faculty of Food Science and Nutrition
Other departments
Series: Nature Communications; 13(1)
ISSN: 2041-1723
DOI: 10.1038/s41467-022-28167-1
Subject: Heila- og taugaskurðlæknisfræði; Gigtarlæknisfræði; Náttúrufræðingar; Intervertebral Disc Degeneration; Intervertebral Disc Displacement; Back Pain; Genome-Wide Association Study; Bone and Bones/metabolism; Intervertebral Disc/metabolism; Humans; Symporters/genetics; Sodium Sulfate Cotransporter/genetics; Sulfates/metabolism; Intervertebral Disc Degeneration/genetics; Intervertebral Disc Displacement/genetics; 3' Untranslated Regions; General Physics and Astronomy; General Chemistry; General Biochemistry,Genetics and Molecular Biology
URI: https://hdl.handle.net/20.500.11815/3898

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Citation:

Nielsen, K R, Pedersen, O B, Sørensen, E, Ostrowski, S, Johansson, P I, Gudbjartsson, D, Stefansson, H, Larsen, M A H, Didriksen, M, Sækmose, S, Zeggini, E, Hatzikotoulas, K, Southam, L, Gilly, A, Barysenka, A, van Meurs, J B J, Boer, C G, Uitterlinden, A G, Styrkársdóttir, U, Stefánsdóttir, L, Esko, T, Mägi, R, Teder-Laving, M, Ikegawa, S, Terao, C, Takuwa, H, Meulenbelt, I, Coutinho de Almeida, R, Kloppenburg, M, Tuerlings, M, Slagboom, P E, Nelissen, R R G H H, Valdes, A M, Mangino, M, Tsezou, A, Zengini, E, Alexiadis, G, Babis, G C, Cheah, K S E, Wu, T T, Samartzis, D, Cheung, J P Y, Sham, P C, Kraft, P, Kang, J H, Hveem, K, Zwart, J-A, Luetge, A, Skogholt, A H, Johnsen, M B, Thomas, L F, Winsvold, B, Gabrielsen, M E, Lee, M T M, Zhang, Y, Lietman, S A, Shivakumar, M, Smith, G D, Tobias, J H, Hartley, A, Gaunt, T R, Zheng, J, Wilkinson, J M, Steinberg, J, Morris, A P, Ulfarsson, E, Blondal, J, Brunak, S, Ostrowski, S R, Ullum, H, Þorsteinsdóttir, U, Stefansson, H, Gudbjartsson, D F, Thorgeirsson, T E, 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, pp. 634. https://doi.org/10.1038/s41467-022-28167-1

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.

Description:

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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