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

Gyða Björnsdóttir ,Ingrid Meulenbelt ,Kristian Hveem ,Sigurjon A Gudjonsson ,Guðmar Þorleifsson ,Shiro Ikegawa ,Tom R Gaunt ,Ástrós Skúladóttir ,Laurent F Thomas ,Unnur Styrkársdóttir ,Margit Anita Hørup Larsen ,Gisli H Halldorsson ,Ásmundur Oddsson ,Lise Wegner Thørner ,Julia Steinberg ,Aspasia Tsezou ,Andrew P Morris ,George C Babis ,Jie Zheng ,Helgi Jónsson ,Jonathan H Tobias ,Karina Banasik ,Rodrigo Coutinho De Almeida ,Thomas Folkmann Hansen ,Almut Luetge ,Egil Ferkingstad ,Kasper Nielsen ,Maris Teder‐Laving ,Muhammad Sulaman Nawaz ,Larus J Gudmundsson ,Christian Erikstrup ,G Bragi Walters ,Garðar Sveinbjörnsson ,Yanfei Zhang ,Susanne Gjørup Sækmose ,Lorraine Southam ,Anna Helgadóttir ,Hiroshi Takuwa ,Patrick Sulem ,Eleftheria Zeggini ,P Eline Slagboom ,G Alexiadis ,Cindy G Boer ,Steffen Andersen ,Peter P Kraft ,Thorgeir E Thorgeirsson ,Bendik Slagsvold Winsvold ,Unnur Þorsteinsdóttir ,Elfar Úlfarsson ,George Davey Smith ,Joyce B J Van Meurs ,Søren Brunak ,Kristjan Norland ,Tõnu Esko ,Valgerður S Bjarnadóttir ,Maiken Elvestad Gabrielsen ,Tian Wu ,Ana M Valdes ,Sigrún H Lund ,Reedik Mägi ,Mette Nyegaard ,Arthur Gilly ,Konstantinos Hatzikotoulas ,Lilja Stefánsdóttir ,Susan Mikkelsen ,Ming Ta Michael Lee ,Anders Troelsen ,Henrik Hjalgrim ,Massimo Mangino ,Rob R.g.h.h Nelissen ,Daníel F Guðbjartsson ,Henrik Ullum ,Florian Zink ,Maria Didriksen ,Ingileif Jónsdóttir ,Khoa Manh Dinh ,Poul Jennum ,Chikashi Terao ,Ole Birger Pedersen ,Thomas Werge ,Margo Tuerlings ,Margreet Kloppenburg ,Þorvaldur Ingvarsson ,Arnór Víkingsson ,Guðmundur Einarsson ,Hreinn Stefánsson ,Gregor B.e Jemec ,Jason Pui Yin Cheung ,Manu Shivakumar ,J Mark Wilkinson ,Pak C Sham ,Marianne Bakke Johnsen ,Søren Thorgaard Skou ,Steven A Lietman ,John‐Anker Zwart ,Anne Heidi Skogholt ,Jae H Kang ,Mie Topholm Bruun ,Kristoffer Sølvsten Burgdorf ,Sisse Rye Ostrowski ,Kaspar René Nielsen ,April Hartley ,D Samartzis ,Erik Sørensen ,André G Uitterlinden ,Andrei Barysenka ,Aron Hjalti Björnsson ,Ingvar Hákon Ólafsson ,Kathryn S.e Cheah ,Eleni Zengini ,Josep Blondal ,Pär I Johansson ,Kári Stefánsson ,Kāri Stefánsson

doi: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.

Highlights

Back pain is a common and debilitating disorder with largely unknown underlying biology
In line with previous studies, we find that both back pain diagnoses show genetic correlations with their most commonly reported risk factors including osteoarthritis, body mass index (BMI), bone mineral density (BMD) of lumbar spine, depression and stress (Supplementary Data 2)
These phenotypes are highly genetically correlated, Mendelian randomization (MR) analyses show that while intervertebral disc disorder (IDD) variants consistently associate with dorsalgia, and variants associating with dorsalgia are enriched for IDD variants, the strength of their association with dorsalgia was not proportional to the association of these variants with IDD

Summary

Introduction

Back pain is a common and debilitating disorder with largely unknown underlying biology. 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). Genome-wide association studies (GWAS) have yielded three loci harboring variants associating with self-reported back pain[12,13] and severe lumbar IDD requiring surgery[14]. These are represented by variants in or near CHST3/SPOCK2 and SOX512,13, genes that are involved in regulation of chondrogenesis and the nervous system[15,16], and an intergenic signal between GSDMC and CCDC26 that associates with both self-reported back pain[12,13] and lumbar IDD requiring surgery[14]. We report 41 variants at 33 loci of which new associations with back pain are at 30 loci

Methods

Results

Conclusion