Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology
Gyða Björnsdóttir, Lilja Stefánsdóttir, Guðmar Þorleifsson, Patrick Sulem, Kristján Norland, Egil Ferkingstad, Ásmundur Oddsson, Florian Zink, Sigrún H. Lund, Muhammad Sulaman Nawaz, G. Bragi Walters, Ástrós Skúladóttir, Sigurjón A. Guðjónsson, Guðmundur Einarsson, Gísli H. Halldórsson, Valgerður S. Bjarnadóttir, Garðar Sveinbjörnsson, Anna Helgadóttir, Unnur Styrkársdóttir, Lárus J. Gudmundsson, Ole Birger Pedersen, Thomas Folkmann Hansen, Thomas Werge, Karina Banasik, Anders Troelsen, Søren Thorgaard Skou, Lise Wegner Thørner, Christian Erikstrup, Kaspar René Nielsen, Susan Mikkelsen, Steffen Andersen, Søren Brunak, Kristoffer Sølvsten Burgdorf, Henrik Hjalgrim, Gregor B. E. Jemec, Poul Jennum, Per Ingemar Johansson, Kasper Nielsen, Mette Nyegaard, Mie Topholm Bruun, Ole Birger Pedersen, Khoa Manh Dinh, Erik Sørensen, Sisse Rye Ostrowski, Pär I. Johansson, Daníel F. Guðbjartsson, Hreinn Stefánsson, Unnur Þorsteinsdóttir, Margit Anita Hørup Larsen, Maria Didriksen, Susanne Gjørup Sækmose, Eleftheria Zeggini, Konstantinos Hatzikotoulas, Lorraine Southam, Arthur Gilly, Andrei Barysenka, Joyce B. J. van Meurs, Cindy G. Boer, André G. Uitterlinden, Unnur Styrkársdóttir, Lilja Stefánsdóttir, Helgi Jónsson, Þorvaldur Ingvarsson, Tõnu Esko, Reedik Mägi, Maris Teder‐Laving, Shiro Ikegawa, Chikashi Terao, Hiroshi Takuwa, Ingrid Meulenbelt, Rodrigo Coutinho de Almeida, M. Kloppenburg, Margo Tuerlings, P. Eline Slagboom, Rob G. H. H. Nelissen, Ana M. Valdes, Massimo Mangino, Aspasia Tsezou, Eleni Zengini, George Alexiadis, George C. Babis, Kathryn S.E. Cheah, Tian Wu, Dino Samartzis, Jason Pui Yin Cheung, Pak C. Sham, Peter Kraft, Jae H. Kang, Kristian Hveem, John‐Anker Zwart, Almut Luetge, Anne Heidi Skogholt, Marianne Bakke Johnsen, Laurent F. Thomas, Bendik S. Winsvold, Maiken E. Gabrielsen, Ming Ta Michael Lee, Yanfei Zhang, Steven A. Lietman, Manu Shivakumar
Abstract
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 (OR IDD = 0.92, P = 1.6 × 10 −39 ; OR dorsalgia = 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.