Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology
Authors: Bjornsdottir Gyda , Stefansdottir Lilja , Thorleifsson Gudmar , Sulem Patrick , Norland Kristjan , Ferkingstad Egil , Oddsson Asmundur , Zink Florian , Lund Sigrun H. , Nawaz Muhammad S. , Bragi Walters G. , Skuladottir Astros Th. , Gudjonsson Sigurjon A. , Einarsson Gudmundur , Halldorsson Gisli H. , Bjarnadottir Valgerdur , Sveinbjornsson Gardar , Helgadottir Anna , Styrkarsdottir Unnur , Gudmundsson Larus J. , Pedersen Ole B. , Hansen Thomas Folkmann , Werge Thomas , Banasik Karina , Troelsen Anders , Skou Soren T. , Thørner Lise Wegner , Erikstrup Christian , Nielsen Kaspar Rene , Mikkelsen Susan ,   DBDS Genetic Consortium, Andersen Steffen , Brunak Søren , Burgdorf Kristoffer , Hjalgrim Henrik , Jemec Gregor , Jennum Poul , Johansson Per Ingemar , Nielsen Kasper Rene , Nyegaard Mette , Bruun Mie Topholm , Pedersen Ole Birger , Dinh Khoa Manh , Sørensen Erik , Ostrowski Sisse , Johansson Pär Ingemar , Gudbjartsson Daniel , Stefánsson Hreinn , Þorsteinsdóttir Unnur , Larsen Margit Anita Hørup , Didriksen Maria , Sækmose Susanne ,   GO Consortium, Zeggini Eleftheria , Hatzikotoulas Konstantinos , Southam Lorraine , Gilly Arthur , Barysenka Andrei , van Meurs Joyce B. J. , Boer Cindy G. , Uitterlinden André G. , Styrkársdóttir Unnur , Stefánsdóttir Lilja , Jonsson Helgi , Ingvarsson Thorvaldur , Esko Tõnu , Mägi Reedik , Teder-Laving Maris , Ikegawa Shiro , Terao Chikashi , Takuwa Hiroshi , Meulenbelt Ingrid , Coutinho de Almeida Rodrigo , Kloppenburg Margreet , Tuerlings Margo , Slagboom P. Eline , Nelissen Rob R. G. H. H. , Valdes Ana M. , Mangino Massimo , Tsezou Aspasia , Zengini Eleni , Alexiadis George , Babis George C. , Cheah Kathryn S. E. , Wu Tian T. , Samartzis Dino , Cheung Jason Pui Yin , Sham Pak Chung , Kraft Peter , Kang Jae Hee , Hveem Kristian , Zwart John-Anker , Luetge Almut , Skogholt Anne Heidi , Johnsen Marianne B. , Thomas Laurent F. , Winsvold Bendik , Gabrielsen Maiken E. , Lee Ming Ta Michael , Zhang Yanfei , Lietman Steven A. , Shivakumar Manu , Smith George Davey , Tobias Jonathan H. , Hartley April , Gaunt Tom R. , Zheng Jie , Wilkinson J. Mark , Steinberg Julia , Morris Andrew P. , Jonsdottir Ingileif , Bjornsson Aron , Olafsson Ingvar H. , Ulfarsson Elfar , Blondal Josep , Vikingsson Arnor , Brunak Soren , Ostrowski Sisse R. , Ullum Henrik , Thorsteinsdottir Unnur , Stefansson Hreinn , Gudbjartsson Daniel F. , Thorgeirsson Thorgeir E. , Stefansson Kari 
Published: February 2022

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.