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Immunoglobulin gene polymorphisms shape the naïve B-cell receptor repertoire; relevance to celiac disease

Genes & Immunity (2026)Cite this article

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Abstract

Genetic variation in the loci encoding immunoglobulin genes (IGH, IGK and IGL) affects the repertoire of B-cell receptors (BCRs). Such effects were previously demonstrated for total peripheral blood B cells, but so far have not been investigated at scale for isolated naïve B cells. As B cells are implicated in the pathogenesis of autoimmune diseases, genetically encoded features of the naïve BCR repertoire may affect disease risk, for instance in celiac disease (CeD) which is hallmarked by stereotyped disease-specific antibodies that recognize antigen in their germline configuration. Here we have characterized the BCR repertoire of naïve B cells in 102 individuals with CeD and 102 control subjects by undertaking gene usage quantitative trait loci analyses based on repertoire sequencing and single nucleotide polymorphism genotyping. Variants within each of the loci had significant effects on the naïve BCR repertoires, with the usage of 80% of IGH genes, 54% of IGK genes and 84% of IGL genes being significantly affected by gene polymorphisms. Effects of genetic polymorphisms on BCR usage were observed for genes implicated in stereotypic responses previously associated with CeD, yet no strong evidence for CeD predisposing effects of polymorphisms within the IGH, IGK and IGL loci was uncovered.

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Fig. 1: Associations between SNPs and usage frequencies of V, D and J genes of the IG loci.
Fig. 2: Per-gene guQTL significance in the IG loci.
Fig. 3: LD within the IGH locus and large gene networks with shared guQTLs.
Fig. 4: Differences in genotype distributions between CeD and control subjects and relation to gene usage.
Fig. 5: Usage frequencies of CeD-relevant IG genes.

Data availability

Both raw and processed AIRR-seq data and genotyping data for the IGH, IGK and IGL regions and necessary metadata will be deposited at the European Genome-Phenome Archive (EGA) under controlled access due to data protection. Data access is regulated through a data access agreement, and data usage will be limited to studies aiming to investigate immunological mechanisms related to autoimmune diseases. Corresponding authors can be contacted with any inquiries related to data access. Data requests must be made through the EGA website and will be evaluated by the Data Access Committee (made up of LMS, IL, and EN-J) within two weeks. Data analysis scripts can be made available by the authors upon reasonable request.

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Acknowledgements

We would like to thank all participants of the HUNT4 study for donation of blood samples to this project, and the personnel at HUNT Research Center and Levanger Hospital for assistance with collecting the sample material of the study subjects. The Trøndelag Health Study (HUNT) is a collaboration between HUNT Research Center (Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology [NTNU]), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. We thank Marie Kongshaug Johannessen, Marte Viken, and Lisa Brynjulfsen for assistance with experimental procedures. The Norwegian Sequencing Center and the Flow Cytometry Core Facility (both at Oslo University Hospital) provided analytical service. Sigma2 provided computational resources. Data analysis was performed on the TSD (Tjenester for Sensitive Data) facilities, owned by the University of Oslo. This study was funded by means from the South-Eastern Norway Regional Health Authority (project 2022040), the Research Council of Norway (project 283274), and the University of Oslo (to LMS), from the Norwegian Coeliac Society (to LMS and EN-J), and from NTNU’s Outstanding Academic Fellows Program (to EN-J).

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Author notes

  1. These authors contributed equally: Ida Lindeman, Ludvig M. Sollid.

Authors and Affiliations

  1. Norwegian Coeliac Disease Research Centre, University of Oslo, Oslo, Norway

    Aengus Officer, Louise F. Risnes, Knut E. A. Lundin, Ida Lindeman & Ludvig M. Sollid

  2. Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Aengus Officer, Shiva Dahal-Koirala, Knut E. A. Lundin & Ludvig M. Sollid

  3. Department of Biochemistry and Molecular Genetics, School of Medicine, University of Louisville, Louisville, KY, USA

    Corey T. Watson & Eric Engelbrecht

  4. Department of Immunology, Oslo University Hospital—Rikshospitalet, Oslo, Norway

    Shiva Dahal-Koirala, Ida Lindeman & Ludvig M. Sollid

  5. Department of Gastroenterology, Oslo University Hospital—Rikshospitalet, Oslo, Norway

    Louise F. Risnes & Knut E. A. Lundin

  6. HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway

    Eivind Ness-Jensen

  7. Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway

    Eivind Ness-Jensen

  8. Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden

    Eivind Ness-Jensen

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Contributions

LMS conceived and designed the study. IL, SD-K, and AO contributed to the study design. AO, IL, and SD-K performed experiments. AO and IL performed the formal data analysis and created the figures. AO, IL, LMS, EE, and CTW interpreted the data and provided input to data analysis. EN-J and KEAL provided biological samples and ethical approvals. SD-K and LFR contributed to sample collection. LMS and EN-J provided funding. LMS, IL, and CTW supervised the study. AO drafted the original manuscript. AO, IL, LMS, and CTW revised the manuscript. All authors approved the revised manuscript.

Corresponding authors

Correspondence to Aengus Officer or Ludvig M. Sollid.

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CTW is a founder and shareholder of Clareo Biosciences, Inc. and serves as Chief Scientific Officer. The remaining authors declare no competing interests.

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Officer, A., Watson, C.T., Engelbrecht, E. et al. Immunoglobulin gene polymorphisms shape the naïve B-cell receptor repertoire; relevance to celiac disease. Genes Immun (2026). https://doi.org/10.1038/s41435-026-00384-4

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