Genome-wide association study identifies Sjögren's risk loci with functional implications in immune and glandular cells

Bhuwan Khatri; Kandice L Tessneer; Astrid Rasmussen; Farhang Aghakhanian; Tove Ragna Reksten; Adam Adler; Ilias Alevizos; Juan-Manuel Anaya; Lara A Aqrawi; Eva Baecklund; Johan G Brun; Sara Magnusson Bucher; Maija-Leena Eloranta; Fiona Engelke; Helena Forsblad-d'Elia; Stuart B Glenn; Daniel Hammenfors; Juliana Imgenberg-Kreuz; Janicke Liaaen Jensen; Svein Joar Auglænd Johnsen; Malin V Jonsson; Marika Kvarnström; Jennifer A Kelly; He Li; Thomas Mandl; Javier Martín; Gaétane Nocturne; Katrine Brække Norheim; Øyvind Palm; Kathrine Skarstein; Anna M Stolarczyk; Kimberly E Taylor; Maria Teruel; Elke Theander; Swamy Venuturupalli; Daniel J Wallace; Kiely M Grundahl; Kimberly S Hefner; Lida Radfar; David M Lewis; Donald U Stone; C Erick Kaufman; Michael T Brennan; Joel M Guthridge; Judith A James; R Hal Scofield; Patrick M Gaffney; Lindsey A Criswell; Roland Jonsson; Per Eriksson; Simon J Bowman; Roald Omdal; Lars Rönnblom; Blake Warner; Maureen Rischmueller; Torsten Witte; A Darise Farris; Xavier Mariette; Marta E Alarcon-Riquelme; PRECISESADS Clinical Consortium; Caroline H Shiboski; Sjögren’s International Collaborative Clinical Alliance (SICCA); Marie Wahren-Herlenius; Wan-Fai Ng; UK Primary Sjögren’s Syndrome Registry; Kathy L Sivils; Indra Adrianto; Gunnel Nordmark; Christopher J Lessard

doi:10.1038/s41467-022-30773-y

Genome-wide association study identifies Sjögren's risk loci with functional implications in immune and glandular cells

Nat Commun. 2022 Jul 27;13(1):4287. doi: 10.1038/s41467-022-30773-y.

Authors

Bhuwan Khatri¹, Kandice L Tessneer¹, Astrid Rasmussen¹, Farhang Aghakhanian¹, Tove Ragna Reksten^{2

3}, Adam Adler⁴, Ilias Alevizos⁵, Juan-Manuel Anaya⁶, Lara A Aqrawi^{7

8}, Eva Baecklund⁹, Johan G Brun³, Sara Magnusson Bucher¹⁰, Maija-Leena Eloranta⁹, Fiona Engelke¹¹, Helena Forsblad-d'Elia¹², Stuart B Glenn¹, Daniel Hammenfors¹³, Juliana Imgenberg-Kreuz⁹, Janicke Liaaen Jensen⁷, Svein Joar Auglænd Johnsen¹⁴, Malin V Jonsson^{3

15}, Marika Kvarnström^{16

17}, Jennifer A Kelly¹, He Li^{2

18}, Thomas Mandl¹⁹, Javier Martín²⁰, Gaétane Nocturne²¹, Katrine Brække Norheim^{3

22}, Øyvind Palm²³, Kathrine Skarstein^{3

24}, Anna M Stolarczyk¹, Kimberly E Taylor²⁵, Maria Teruel²⁶, Elke Theander^{27

28}, Swamy Venuturupalli^{29

30}, Daniel J Wallace^{29

30}, Kiely M Grundahl¹, Kimberly S Hefner³¹, Lida Radfar³², David M Lewis³³, Donald U Stone³⁴, C Erick Kaufman³⁵, Michael T Brennan^{36

37}, Joel M Guthridge^{2

38}, Judith A James^{2

35}, R Hal Scofield^{2

35

39}, Patrick M Gaffney¹, Lindsey A Criswell^{25

40

41}, Roland Jonsson^{3

13}, Per Eriksson⁴², Simon J Bowman^{43

44

45}, Roald Omdal^{3

14}, Lars Rönnblom⁹, Blake Warner⁵, Maureen Rischmueller^{46

47}, Torsten Witte¹¹, A Darise Farris², Xavier Mariette²¹, Marta E Alarcon-Riquelme²⁶; PRECISESADS Clinical Consortium; Caroline H Shiboski⁴⁸; Sjögren’s International Collaborative Clinical Alliance (SICCA); Marie Wahren-Herlenius^{3

16}, Wan-Fai Ng^{49

50}; UK Primary Sjögren’s Syndrome Registry; Kathy L Sivils^{2

18}, Indra Adrianto⁵¹, Gunnel Nordmark⁹, Christopher J Lessard^{52

53}

Affiliations

¹ Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
² Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
³ Department of Clinical Science, University of Bergen, Bergen, Norway.
⁴ NGS Core Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
⁵ Salivary Disorder Unit, National Institute of Dental and Craniofacial Research, Bethesda, MD, USA.
⁶ Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogotá, Colombia.
⁷ Department of Oral Surgery and Oral Medicine, Faculty of Dentistry, University of Oslo, Oslo, Norway.
⁸ Department of Health Sciences, Kristiania University College, Oslo, Norway.
⁹ Department of Medical Sciences, Rheumatology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
¹⁰ Department of Rheumatology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
¹¹ Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany.
¹² Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
¹³ Department of Rheumatology, Haukeland University Hospital, Bergen, Norway.
¹⁴ Department of Internal Medicine, Clinical Immunology Unit, Stavanger University Hospital, Stavanger, Norway.
¹⁵ Section for Oral and Maxillofacial Radiology, Department of Clinical Dentistry, Medical Faculty, University of Bergen, Bergen, Norway.
¹⁶ Rheumatology Unity, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
¹⁷ Academic Specialist Center, Center for Rheumatology and Studieenheten, Stockholm Health Services, Region Stockholm, Sweden.
¹⁸ Translational Sciences, The Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, PA, USA.
¹⁹ Rheumatology, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
²⁰ Instituto de Biomedicina y Parasitología López-Neyra, Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain.
²¹ Université Paris-Saclay, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bicêtre, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1184, Le Kremlin Bicêtre, France.
²² Department of Rheumatology, Stavanger University Hospital, Stavanger, Norway.
²³ Department of Rheumatology, University of Oslo, Oslo, Norway.
²⁴ Department of Pathology, Haukeland University Hospital, Bergen, Norway.
²⁵ Department of Medicine, Russell/Engleman Rheumatology Research Center, University of California San Francisco, San Francisco, California, USA.
²⁶ Genyo, Center for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain.
²⁷ Department of Rheumatology, Skåne University Hospital, Malmö, Sweden.
²⁸ Medical Affairs, Jannsen-Cilag EMEA (Europe/Middle East/Africa), Beerse, Belgium.
²⁹ Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³⁰ David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
³¹ Hefner Eye Care and Optical Center, Oklahoma City, OK, USA.
³² Oral Diagnosis and Radiology Department, University of Oklahoma College of Dentistry, Oklahoma City, OK, USA.
³³ Department of Oral and Maxillofacial Pathology, University of Oklahoma College of Dentistry, Oklahoma City, OK, USA.
³⁴ Department of Ophthalmology, Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
³⁵ Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
³⁶ Department of Oral Medicine/Oral & Maxillofacial Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC, USA.
³⁷ Department of Otolaryngology/Head and Neck Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
³⁸ Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
³⁹ US Department of Veterans Affairs Medical Center, Oklahoma City, OK, USA.
⁴⁰ Institute of Human Genetics (IHG), University of California San Francisco, San Francisco, CA, USA.
⁴¹ Genomics of Autoimmune Rheumatic Disease Section, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
⁴² Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection, Linköping University, Linköping, Sweden.
⁴³ Rheumatology Department, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK.
⁴⁴ Rheumatology Research Group, Institute of Inflammation & Ageing, University of Birmingham, Birmingham, UK.
⁴⁵ Rheumatology Department, Milton Keynes University Hospital, Milton Keynes, UK.
⁴⁶ Rheumatology Department, The Queen Elizabeth Hospital, Woodville, South Australia.
⁴⁷ University of Adelaide, Adelaide, South Australia.
⁴⁸ Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA, USA.
⁴⁹ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
⁵⁰ NIHR Newcastle Biomedical Centre and NIHR Newcastle Clinical Research Facility, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
⁵¹ Center for Bioinformatics, Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA.
⁵² Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA. chris-lessard@omrf.org.
⁵³ Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. chris-lessard@omrf.org.

Abstract

Sjögren's disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren's cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural

MeSH terms

Genetic Predisposition to Disease
Genome-Wide Association Study*
Humans
Polymorphism, Single Nucleotide
Sjogren's Syndrome* / genetics

Abstract

Publication types

MeSH terms

Grants and funding