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

Gyda Bjornsdottir*, Lilja Stefansdottir, DBDS Genetic Consortium, GO Consortium, 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 HelgadottirUnnur Styrkarsdottir, Larus J. Gudmundsson, Ole Birger 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 Ostrowski, Thorgeir E. Thorgeirsson, Kari Stefansson

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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
Early online date2 Feb 2022
DOIs
Publication statusPublished - 1 Dec 2022

Bibliographical note

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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