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Genetic mapping across autoimmune diseases reveals shared associations and mechanisms

Nature Genetics volume 56, pages 838–845 (2024)Cite this article

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Abstract

Autoimmune and inflammatory diseases are polygenic disorders of the immune system. Many genomic loci harbor risk alleles for several diseases, but the limited resolution of genetic mapping prevents determining whether the same allele is responsible, indicating a shared underlying mechanism. Here, using a collection of 129,058 cases and controls across 6 diseases, we show that ~40% of overlapping associations are due to the same allele. We improve fine-mapping resolution for shared alleles twofold by combining cases and controls across diseases, allowing us to identify more expression quantitative trait loci driven by the shared alleles. The patterns indicate widespread sharing of pathogenic mechanisms but not a single global autoimmune mechanism. Our approach can be applied to any set of traits and is particularly valuable as sample collections become depleted.

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Fig. 1: Joint analysis of shared autoimmune disease risk alleles improves fine-mapping twofold.
Fig. 2: A shared effect on chromosome 1 can be fine-mapped to eight variants across celiac disease, IBD and MS.
Fig. 3: The increased resolution of fine-mapping shared associations across diseases allows identification of more disease–eQTL overlaps.
Fig. 4: Jointly analyzing an association shared between MS and CeD improves fine-mapping resolution and identifies a shared eQTL for RGS1.

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Data availability

This paper analyzes existing, publicly available data. The accession numbers for these datasets are listed in Supplementary Table 2.

Code availability

Code used in this analysis is available on GitHub at https://github.com/cotsapaslab/CrossDiseaseImmunochip (ref. 80) and archived on Zenodo at https://doi.org/10.5281/zenodo.8371032 (ref. 81).

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Acknowledgements

We thank the EAGLE eczema consortium for providing GWAS summary statistics. This research utilizes resources provided by the T1DGC, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development and JDRF and supported by U01 DK062418. We thank the RACI consortium for access to RA data and the International IBD Genetics Consortium for access to IBD data. Deidentified data were provided from a total of 4,617 samples (2,563 SLE cases and 2,054 population controls) in the Lupus Family Registry and Repository collection at the Oklahoma Medical Research Foundation. The SLE Genentech samples were originally genotyped and analyzed as part of a large SLEGEN Consortium ImmunoChip study. The Alliance for Lupus Research (now Lupus Research Alliance) provided funds for the SLE ImmunoChip study. M.R.L. is supported by a Career Transition Fellowship from the Consortium of MS Centers and the National MS Society (TA-2206-39622) and an Early Career Award in MS from the Waugh Family Foundation. C.G. received a research fellowship from the Deutsche Forschungsgemeinschaft (German Research Foundation) for this project. She further received funding from the Hans und Klementia Langmatz-Stifung and the Hertie Network of Excellence in Clinical Neuroscience, not related to this study. C.W. was supported by an ERC advanced grant (FP/2007-2013/ERC grant 2012-322698), the Spinoza prize grant (NWO SPI 92-266), a grant from Stiftelsen K. G. Jebsen and the Netherlands Organ-on-Chip Initiative—an NWO Gravitation project (024.003.001) funded by the Ministry of Education, Culture and Science of the government of the Netherlands. S.W. was supported by the Netherlands Organ-on-Chip Initiative, an NWO Gravitation project (024.003.001) funded by the Ministry of Education, Culture and Science of the government of the Netherlands. I.H.J. is supported by a Rosalind Franklin Fellowship from the University of Groningen and an NWO VIDI grant (no. 016.171.047).

Author information

Author notes

  1. Mitja Mitrovic

    Present address: Faculty of Chemistry and Chemical Engineering, University of Maribor, Maribor, Slovenia

  2. Chris Cotsapas

    Present address: Vesalius Therapeutics, Cambridge, MA, USA

  3. Deceased: Rogier Hintzen.

Authors and Affiliations

  1. Department of Neurology, Yale School of Medicine, New Haven, CT, USA

    Matthew R. Lincoln, Noah Connally, Pierre-Paul Axisa, Christiane Gasperi, Mitja Mitrovic, Chris Cotsapas, David Hafler, David A. Hafler & Chris Cotsapas

  2. Division of Neurology at the Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    Matthew R. Lincoln

  3. Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, Ontario, Canada

    Matthew R. Lincoln

  4. Blizard Institute, Queen Mary University of London, London, UK

    David van Heel

  5. Department of Genetics at the University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

    Cisca Wijmenga, Sebo Withoff & Iris H. Jonkers

  6. Division of Rheumatology at the Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden

    Leonid Padyukov

  7. Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA

    Stephen S. Rich

  8. Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA

    Stephen S. Rich

  9. Maze Therapeutics, South San Francisco, CA, USA

    Robert R. Graham

  10. Genentech, South San Francisco, CA, USA

    Robert R. Graham

  11. Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    Patrick M. Gaffney

  12. Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Carl D. Langefeld

  13. Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Carl D. Langefeld

  14. Department of Medical and Molecular Genetics, Kings College London, London, UK

    Timothy J. Vyse

  15. Division of Genetics, Brigham and Women’s Hospital, Boston, MA, USA

    Nikolaos A. Patsopoulos, Sung Chun & Shamil R. Sunyaev

  16. Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA

    Sung Chun & Shamil R. Sunyaev

  17. Department of Genetics, Yale School of Medicine, New Haven, CT, USA

    Chris Cotsapas & Chris Cotsapas

  18. John P. Hussman Institute for Human Genomics at the Miller School of Medicine, University of Miami, Miami, FL, USA

    Ashley H. Beecham, Margaret A. Pericak-Vance & Jakob L. McCauley

  19. Systems Biology and Computer Science Program at the Ann Romney Center for Neurological Diseases, Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA

    Nikolaos A. Patsopoulos

  20. Westmead Institute for Medical Research, Sydney, New South Wales, Australia

    David Booth & Graeme Stewart

  21. Laboratory for Neuroimmunology at the Section of Experimental Neurology, KU Leuven, Leuven, Belgium

    An Goris

  22. Danish Multiple Sclerosis Center at the Department of Neurology, Section 2082, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Annette Oturai

  23. Institute for Molecular Medicine Finland at the Helsinki Institute for Life Sciences, University of Helsinki, Helsinki, Finland

    Janna Saarela

  24. Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway

    Janna Saarela

  25. INSERM, UPMC, Département de Neurologie Pitié-Salpêtrière, Paris, France

    Betrand Fontaine

  26. Department of Neurology at Klinikum rechts der Isar, Technische Universität München, Munich, Germany

    Bertrand Hemmer

  27. Department of Clinical Sciences at Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden

    Martin Claes

  28. Focus Program Translational Neuroscience and Immunotherapy, Department of Neurology at the University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany

    Frauke Zipp

  29. Department of Health Sciences and Center on Auto-immune and Allergic Diseases, University of Eastern Piedmont, Novara, Italy

    Sandra D’Alfonso

  30. Dino Ferrari Center at the Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

    Filippo Martinelli-Boneschi

  31. Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia

    Bruce Taylor

  32. Department of Neurology, Oslo University Hospital, Oslo, Norway

    Hanne F. Harbo

  33. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Ingrid Kockum, Jan Hillert, Tomas Olsson & Lars Alfredsson

  34. UCSF Weill Institute for Neurosciences at the Department of Neurology, University of California, San Francisco, San Francisco, CA, USA

    Jorge R. Oksenberg, Roland Martin & Stephen L. Hauser

  35. MS Center ErasMS, Department of Neurology, Erasmus MC, Rotterdam, the Netherlands

    Rogier Hintzen

  36. Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA

    Lisa F. Barcellos

  37. Neurology Unit and Laboratory of Human Genetics of Neurological Disorders, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Federica Esposito

  38. Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA

    Jonathan L. Haines

  39. Harvard NeuroDiscovery Center, Harvard Medical School, Boston, MA, USA

    Adrian J. Ivinson

  40. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK

    Alastair Compston & Stephen J. Sawcer

  41. The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    Gil McVean

  42. Center For Translational and Computational Neuroimmunology and the Multiple Sclerosis Center at the Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA

    Philip De Jager

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  1. Matthew R. Lincoln
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  2. Noah Connally
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Consortia

International Multiple Sclerosis Genetics Consortium

  • Ashley H. Beecham
  • , Nikolaos A. Patsopoulos
  • , Chris Cotsapas
  • , David Booth
  • , An Goris
  • , Annette Oturai
  • , Janna Saarela
  • , Betrand Fontaine
  • , Bertrand Hemmer
  • , Martin Claes
  • , Frauke Zipp
  • , Sandra D’Alfonso
  • , Filippo Martinelli-Boneschi
  • , Bruce Taylor
  • , Hanne F. Harbo
  • , Ingrid Kockum
  • , Jan Hillert
  • , Tomas Olsson
  • , Jorge R. Oksenberg
  • , Rogier Hintzen
  • , Lisa F. Barcellos
  • , Lars Alfredsson
  • , Federica Esposito
  • , Roland Martin
  • , Jonathan L. Haines
  • , Margaret A. Pericak-Vance
  • , Adrian J. Ivinson
  • , Graeme Stewart
  • , David Hafler
  • , Stephen L. Hauser
  • , Alastair Compston
  • , Gil McVean
  • , Philip De Jager
  • , Stephen J. Sawcer
  •  & Jakob L. McCauley

Contributions

M.R.L., N.C., P.-P.A., C.G. and M.M. curated and analyzed data. D.v.H., C.W., S.W., I.H.J., L.P., International Multiple Sclerosis Genetics Consortium, S.S.R., R.R.G., P.M.G., C.D.L., T.J.V. and D.A.H. provided data. M.R.L. and C.C. wrote and edited the paper, with input from all co-authors. S.C. and S.R.S. designed and implemented analytical methods. C.C. conceptualized and oversaw the project.

Corresponding author

Correspondence to Chris Cotsapas.

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The authors declare no competing interests.

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Nature Genetics thanks Carl Anderson, Anne Barton and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–18 and Note.

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Supplementary Table

Supplementary Tables 1–4.

Supplementary Data 1

Accounting of study participants.

Supplementary Data 2

Accounting of SNPs.

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Lincoln, M.R., Connally, N., Axisa, PP. et al. Genetic mapping across autoimmune diseases reveals shared associations and mechanisms. Nat Genet 56, 838–845 (2024). https://doi.org/10.1038/s41588-024-01732-8

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