Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology
Gyða Björnsdóttir(deCODE Genetics (Iceland)), Lilja Stefánsdóttir(deCODE Genetics (Iceland)), Guðmar Þorleifsson(deCODE Genetics (Iceland)), Patrick Sulem(deCODE Genetics (Iceland)), Kristján Norland(deCODE Genetics (Iceland)), Egil Ferkingstad(deCODE Genetics (Iceland)), Ásmundur Oddsson(deCODE Genetics (Iceland)), Florian Zink(deCODE Genetics (Iceland)), Sigrún H. Lund(deCODE Genetics (Iceland)), Muhammad Sulaman Nawaz(deCODE Genetics (Iceland)), G. Bragi Walters(deCODE Genetics (Iceland)), Ástrós Skúladóttir(deCODE Genetics (Iceland)), Sigurjón A. Guðjónsson(deCODE Genetics (Iceland)), Guðmundur Einarsson(deCODE Genetics (Iceland)), Gísli H. Halldórsson(Reykjavík University), Valgerður S. Bjarnadóttir(Reykjavík University), Garðar Sveinbjörnsson(deCODE Genetics (Iceland)), Anna Helgadóttir(deCODE Genetics (Iceland)), Unnur Styrkársdóttir(deCODE Genetics (Iceland)), Lárus J. Gudmundsson(deCODE Genetics (Iceland)), Ole Birger Pedersen(University of Copenhagen), Thomas Folkmann Hansen(University of Copenhagen), Thomas Werge(University of Copenhagen), Karina Banasik(University of Copenhagen), Anders Troelsen(University of Copenhagen), Søren Thorgaard Skou(University of Southern Denmark), Lise Wegner Thørner(Aalborg University Hospital), Christian Erikstrup(Aarhus University Hospital), Kaspar René Nielsen(Copenhagen Business School), Susan Mikkelsen(Aarhus University Hospital), Steffen Andersen(Statens Serum Institut), Søren Brunak(University of Copenhagen), Kristoffer Sølvsten Burgdorf(University of Copenhagen), Henrik Hjalgrim(Aalborg University Hospital), Gregor B. E. Jemec(Aarhus University), Poul Jennum(Odense University Hospital), Per Ingemar Johansson(University of Copenhagen), Kasper Nielsen(Aalborg University Hospital), Mette Nyegaard(Copenhagen University Hospital), Mie Topholm Bruun(Copenhagen University Hospital), Ole Birger Pedersen(University of Copenhagen), Khoa Manh Dinh(Copenhagen University Hospital), Erik Sørensen(Zealand University Hospital Køge), Sisse Rye Ostrowski(University of Copenhagen), Pär I. Johansson(Helmholtz Zentrum München), Daníel F. Guðbjartsson(deCODE Genetics (Iceland)), Hreinn Stefánsson(deCODE Genetics (Iceland)), Unnur Þorsteinsdóttir(Helmholtz Zentrum München), Margit Anita Hørup Larsen(Erasmus MC), Maria Didriksen(Erasmus MC), Susanne Gjørup Sækmose(Erasmus MC), Eleftheria Zeggini(deCODE Genetics (Iceland)), Konstantinos Hatzikotoulas(deCODE Genetics (Iceland)), Lorraine Southam(Reykjavík University), Arthur Gilly(Akureyri Hospital), Andrei Barysenka(University of Tartu), Joyce B. J. van Meurs(University of Tartu), Cindy G. Boer(University of Tartu), André G. Uitterlinden(RIKEN Center for Integrative Medical Sciences), Unnur Styrkársdóttir(deCODE Genetics (Iceland)), Lilja Stefánsdóttir(deCODE Genetics (Iceland)), Helgi Jónsson(Leiden University Medical Center), Þorvaldur Ingvarsson(Leiden University Medical Center), Tõnu Esko(Leiden University Medical Center), Reedik Mägi(Leiden University Medical Center), Maris Teder‐Laving(Leiden University Medical Center), Shiro Ikegawa(Leiden University Medical Center), Chikashi Terao(University of Nottingham), Hiroshi Takuwa(King's College London), Ingrid Meulenbelt(University of Thessaly), Rodrigo Coutinho de Almeida(KAT General Hospital of Attica), M. Kloppenburg(KAT General Hospital of Attica), Margo Tuerlings(National and Kapodistrian University of Athens), P. Eline Slagboom(University of Hong Kong), Rob G. H. H. Nelissen(University of Hong Kong), Ana M. Valdes(University of Hong Kong), Massimo Mangino(University of Hong Kong), Aspasia Tsezou(University of Hong Kong), Eleni Zengini(Harvard University), George Alexiadis(Brigham and Women's Hospital), George C. Babis(Norwegian University of Science and Technology), Kathryn S.E. Cheah(Norwegian University of Science and Technology), Tian Wu(Norwegian University of Science and Technology), Dino Samartzis(Norwegian University of Science and Technology), Jason Pui Yin Cheung(Norwegian University of Science and Technology), Pak C. Sham(Norwegian University of Science and Technology), Peter Kraft(Norwegian University of Science and Technology), Jae H. Kang(Norwegian University of Science and Technology), Kristian Hveem(Geisinger Health System), John‐Anker Zwart(Geisinger Health System), Almut Luetge(Geisinger Health System), Anne Heidi Skogholt(University of Pennsylvania), Marianne Bakke Johnsen(University of Bristol), Laurent F. Thomas(Southmead Hospital), Bendik S. Winsvold(University of Bristol), Maiken E. Gabrielsen(University of Bristol), Ming Ta Michael Lee(University of Bristol), Yanfei Zhang(University of Sheffield), Steven A. Lietman(Helmholtz Zentrum München), Manu Shivakumar(University of Manchester), George Davey Smith(deCODE Genetics (Iceland)), Jonathan H. Tobias(Reykjavík University), April Hartley(Reykjavík University), Tom R. Gaunt(Reykjavík University), Jie Zheng, J. Mark Wilkinson(Reykjavík University), Julia Steinberg(University of Copenhagen), Andrew P. Morris(University of Copenhagen), Ingileif Jónsdóttir(Statens Serum Institut), Aron Hjalti Björnsson(Reykjavík University), Ingvar Hákon Ólafsson(Reykjavík University), Elfar Úlfarsson(Reykjavík University), Josep Blondal(deCODE Genetics (Iceland)), Arnór Víkingsson(Reykjavík University), Søren Brunak(University of Copenhagen), Sisse Rye Ostrowski(University of Copenhagen), Henrik Ullum(Statens Serum Institut), Unnur Þorsteinsdóttir(deCODE Genetics (Iceland)), Hreinn Stefánsson(deCODE Genetics (Iceland)), Daníel F. Guðbjartsson(deCODE Genetics (Iceland)), Thorgeir E. Thorgeirsson(deCODE Genetics (Iceland)), Kāri Stefánsson(deCODE Genetics (Iceland))
Cited by 57Open Access
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.
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