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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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).
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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.
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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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DOI: https://doi.org/10.1038/s41588-024-01732-8