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’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.

Metadata

Item Type:	Article
Authors/Creators:	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 Andersen, S Brunak, S Burgdorf, K Hjalgrim, H Jemec, G Jennum, P Johansson, PI Nielsen, KR Nyegaard, M Bruun, MT Pedersen, OB Dinh, KM Sørensen, E Ostrowski, S Johansson, PI Gudbjartsson, D Stefánsson, H Þorsteinsdóttir, U Larsen, MAH Didriksen, M Sækmose, S Zeggini, E Hatzikotoulas, K Southam, L Gilly, A Barysenka, A van Meurs, JBJ Boer, CG Uitterlinden, AG Styrkársdóttir, U Stefánsdóttir, L 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 Cheung, JPY Sham, PC Kraft, P Kang, JH Hveem, K Zwart, J-A Luetge, 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 Brunak, S Ostrowski, SR Ullum, H Thorsteinsdottir, U Stefansson, H Gudbjartsson, DF Thorgeirsson, TE Stefansson, K
Copyright, Publisher and Additional Information:	© The Author(s) 2022. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	3' Untranslated Regions; Bone and Bones; Genome-Wide Association Study; Humans; Intervertebral Disc; Intervertebral Disc Degeneration; Intervertebral Disc Displacement; Sodium Sulfate Cotransporter; Sulfates; Symporters
Dates:	Published: 2 February 2022 Published (online): 2 February 2022 Accepted: 12 January 2022
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Human Metabolism (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Oncology (Sheffield)
Depositing User:	Symplectic Sheffield
Date Deposited:	23 Feb 2022 12:09
Last Modified:	01 Feb 2023 01:53
Status:	Published
Publisher:	Nature Research (part of Springer Nature)
Refereed:	Yes
Identification Number:	10.1038/s41467-022-28167-1
Related URLs:	PubMed URL Erratum/Corrigendum
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:183955

CORE (COnnecting REpositories)

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

Abstract

Metadata

Download

Published Version

Export

Statistics