Discovery and Characterization of Genetic Risk Loci in Sjogren's Syndrome

The Sjögren's Genetics Network (SGENE) is an international collaboration focused on identifying and understanding the genetic variations that influence Sjögren's pathology. Collectively, SGENE collaborators from 26 different sites (5 in the United States; 21 in foreign countries) have recruited a large cohort of geographically diverse participants of European ancestry. Participants underwent extensive medical assessment for Sjögren's Disease (formerly Sjögren's Syndrome) using internationally accepted American-European Consensus Group (AECG) classification criteria or the American College of Rheumatology/European League Against Rheumatism classification criteria. Recruitment, sample collection, and genotyping were performed at unique SGENE sites in compliance with local institutional review board approval.

High-density SNP genotyping data were collated by the Oklahoma Medical Research Foundation (OMRF) and used to perform a GWAS of Sjögren's of European ancestry. Data quality control, GWAS imputation using the Haplotype Reference Consortium, panel version 1.1, and dbGaP preparation/posting were also performed at the OMRF. To facilitate research focused on understanding the genetics of Sjögren's Disease, the Genomic Summary Results from this GWAS are being made available herein (n=3232 Sjögren's cases; n=8962 healthy controls). To achieve adequate case-to-control ratios for the GWAS analyses, population-based control GWAS data were obtained from dbGaP (phs000428; phs000196; phs000187; phs000672. In accordance with IRB approval, subject consents, and data sharing restrictions, we have made available the individual-level genotyping data for a subset of Sjögren's cases (n=1,244) that were genotyped at the OMRF.

Bulk RNA-sequencing was also performed using total RNA extracted from peripheral whole blood samples from a subset of Sjögren's cases classified by status of Ro autoantibody (Ro-positive n=27; Ro-negative n=23) and healthy controls (n=27). In accordance with IRB approval, subject consents, and data sharing restrictions, we have made available the individual-level transcriptomic sequences as a subset of this cohort.

SmartSeq2 manual single cell RNA-sequencing (scRNA-seq) data was also generated from a subset of Sjögren's cases classified by status of Ro autoantibody (Ro positive n=9, Ro negative n=12) and from individuals with non-Sjögren's sicca syndrome (n=11). In accordance with IRB approval, subject consents, and data sharing restrictions, we have made available the individual-level transcriptomic sequences from a subset of this cohort.

• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 1244
• Subject Sample Telemetry Report (SSTR)

Inclusion Criteria:

1. All Sjögren's cases fulfilled internationally accepted American-European Consensus Group (AECG) classification criteria or the American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's disease according to clinical evaluations performed within the respective SGENE cohorts
2. European ancestry
3. Must be 18 years of age or older
4. Signed an IRB consent form agreeing to the terms of the study

Exclusion Criteria:

1. Less than 18 years of age
2. Belongs to a vulnerable population defined by the National Institutes of Health (NIH)
3. Non-European-derived ancestry

The International Sjögren's Genetics Network (SGENE) is a continually growing collaboration of 26 research groups from across the globe that are working together to uncover the genetic architecture of Sjögren's. In 2013, SGENE collaborators published the first large-scale genomic study of Sjögren's of European ancestry using ImmunoChip 1.0 array (Lessard, et al. Nature Genetics 2013. PMID: 24097067). This study identified six novel genome-wide significant regions of association, replicated several previously established associations, and identified several regions of suggestive association.

In 2022, SGENE collaborators published the largest-to-date genome-wide association study (GWAS) of Sjögren's of European ancestry, identifying 10 novel risk loci with functional implications in immune cells and the salivary gland (Khatri, et al. Nat Commun 2022. PMID 35896530).

In 2022, Lessard and colleagues also published a study that used bulk RNA-sequencing of whole blood to identify differentially expressed lncRNAs in Sjögren's. LINC01871 was identified and functionally characterized using CRISPR technologies (Joachims, et al. RMD Open 2022. PMID 36456101).

In 2025, Lessard and colleagues leveraged this GWAS data in a trans disease meta-analysis, fine-mapping, and bioinformatic interrogation of the DDX6-CXCR5 risk locus associated with Sjögren's and systemic lupus erythematosus (SLE). The study prioritized and functionally characterized five common SNPs spanning the two risk loci and identified shared genetic susceptibility that likely alters common mechanisms of autoimmunity including interferon signaling, autophagy, and lymphocytic infiltration of disease-target tissues (Wiley, et al. Ann Rheum Dis 2025. PMID 40447495).

• Primary Phenotype: Sjogren's Syndrome
• Xerostomia
• Keratoconjunctivitis Sicca

• CXCR5
• DDX6
• BLK
• FAM167A
• IL12A
• SYNGR1
• TYK2
• BAIAP2
• CHMP6
• RPTOR
• more ...

• Principal Investigator, Lead of SGENE: Contributed genotyping data (genomic summary results, individual-level genotyping data)
  • Christopher J. Lessard. Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
• SGENE Collaborator, Former lead of SGENE
  • Kathy L. Sivils. Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Current Affiliation: Translational Sciences, The Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, PA, USA.
• SGENE Collaborators: Contributed genotyping data (genomic summary results)
  • Gunnel Nordmark. Department of Medical Sciences, Rheumatology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Marie Wahren-Herlenius. Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
  • Xavier Mariette. 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.
  • Torsten Witte. Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany.
  • Maureen Rischmueller. Rheumatology Department, The Queen Elizabeth Hospital, Woodville, South Australia; University of Adelaide, Adelaide, South Australia, Australia.
  • Blake Warner. Salivary Disorder Unit, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA.
  • Lars Rönnblom. Department of Medical Sciences, Rheumatology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Roald Omdal. Department of Internal Medicine, Clinical Immunology Unit, Stavanger University Hospital, Stavanger, Norway.
  • Simon J. Bowman. Rheumatology Department, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK.
  • Per Eriksson. Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection, Linköping University, Linköping, Sweden.
  • Roland Jonsson. Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Rheumatology, Haukeland University Hospital, Bergen, Norway.
• SGENE Collaborator, UK Primary Sjögren's Syndrome Registry (genomic summary results)
  • Wan-Fai Ng. Translational and Clinical Research Institute, Newcastle University, UK; NIHR Newcastle Biomedical Centre and NIHR Newcastle Clinical Research Facility, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK.
• SGENE Collaborators, dbGaP SICCA Registry (genomic summary results)
  • Caroline H. Shiboski. Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA, USA.
  • Lindsey Criswell. Department of Medicine, Russell/Engleman Rheumatology Research Center, University of California San Francisco, San Francisco, CA, USA; Current affiliation: Genomics of Rheumatic Autoimmune Disease Section, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
• SGENE Collaborator, PRECISESADS Cohort (genomic summary results)
  • Marta E. Alarcon-Riquelme. Center for Genomics and Oncological Research, Pfizer, University of Granada, Andalusian Regional Government, Granada, Spain.
• SGENE Collaborator: Contributed samples and genotyping data (genomic summary results, individual-level genotyping data); assisted with transcriptomic sequencing analyses; principal investigator of the SmartSeq2 study
  • A. Darise Farris. Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
• Consortiums
  • PRECISESADS. Led by Marta E. Alarcon-Riquelme, Center for Genomics and Oncological Research, Pfizer, University of Granada, Andalusian Regional Government, Granada, Spain.
  • Sjögren's International Collaborative Clinical Alliance (SICCA). Led by Caroline H. Shiboski, Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA, USA.
  • UK Primary Sjögren's Syndrome Registry. Led by Wan-Fai Ng, Translational and Clinical Research Institute, Newcastle University, United Kingdom; NIHR Newcastle Biomedical Centre and NIHR Newcastle Clinical Research Facility, Newcastle upon Tyne Hospitals NHS Foundation Trust, United Kingdom.
• dbGaP Studies
  • Control data. phs000428.v2.p2: Health and Retirement Study.
  • Case data. phs000672.v1.p1: Sjögren's International Collaborative Clinical Alliance (SICCA).
  • Single cell transcriptomics data. phs002446.v1.p1: Single cell Omics Resolves Transcriptional Alterations in Sjogren’s Syndrome.
• Funding Sources
  • R01AR073855 (Lessard). National Institutes of Health, Bethesda, MD, USA.
  • R01AR065953 (Lessard). National Institutes of Health, Bethesda, MD, USA.
  • R01AR074310 (Farris). National Institutes of Health, Bethesda, MD, USA.
  • P50AR060804 (Sivils). National Institutes of Health, Bethesda, MD, USA.
  • N01DE32636 (SICCA). National Institutes of Health, Bethesda, MD, USA.
  • HHSN26S201300057C (SICCA). National Institutes of Health, Bethesda, MD, USA.
  • U01DE028891 (SICCA). National Institutes of Health, Bethesda, MD, USA.
  • U01HG004446 (SICCA-GWAS). National Institutes of Health, Bethesda, MD, USA.
  • P30AR070155 (SICCA-GWAS). National Institutes of Health, Bethesda, MD, USA.
  • R61AR076803 (Adrianto). National Institutes of Health, Bethesda, MD, USA.
  • R01AR050782 (Sivils). National Institutes of Health, Bethesda, MD, USA.
  • R01DE018209 (Sivils). National Institutes of Health, Bethesda, MD, USA.
  • R21AR079089 (Adrianto). National Institutes of Health, Bethesda, MD, USA.
  • Z01-DE000704 (Warner). Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
  • (Bowman). NIHR Birmingham Biomedical Research Centre, UK.
  • Projekt number 390874280 (Witte). Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC 2155, Germany.
  • Grant 316120 (Wahren-Herlenius). Research Council of Norway, Oslo, Norway.
  • 240421 (Reksten). Research Council of Norway, Oslo, Norway.
  • 911807 (Omdal). Western Norway Regional Health Authority (Helse Vest), Stavanger, Norway.
  • 912043 (Omdal). Western Norway Regional Health Authority (Helse Vest), Stavanger, Norway.
  • (Rönnblom, Nordmark, Wahren-Herlenius). King Gustav V’s 80-year Foundation, Sweden.
  • (Nordmark). Swedish Cancer Society, Sweden.
  • (Wahren-Herlenius). The Stockholm County Council, Sweden.
  • 2017-000641 (Swedish Twin Registry). Swedish Research Council, Sweden.
  • PHRC 2006 P060228 (Mariette). Assistance Publique-Hôpitaux de Paris (Ministry of Health), Paris, France.
  • (Mariette). French Society of Rheumatology, France.
  • (Sivils). Sjögren's Syndrome Foundation, Bethesda, MD, USA.
  • (Lessard). Presbyterian Health Foundation.
  • R33AR076803 (Adrianto). National Institutes of Health.
• Collaborators
  • Astrid Rasmussen. Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
  • Indra Adrianto. Center for Bioinformatics, Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA.
• Funding Source
  • (Lessard). Sjogren's Foundation.
  • (Wahren-Herlenius; Jonsson). FOREUM Foundation of Research in Rheumatology.
  • (Sivils). Phileona Foundation.
  • (Rönnblom, Nordmark, Wahren-Herlenius). Swedish Research Council for Medicine and Health.