Genetic mapping across autoimmune diseases reveals shared associations and mechanisms

doi:10.1038/s41588-024-01732-8

. 2024 May;56(5):838-845.

doi: 10.1038/s41588-024-01732-8. Epub 2024 May 13.

Genetic mapping across autoimmune diseases reveals shared associations and mechanisms

Matthew R Lincoln^{1

2

3}, Noah Connally¹, Pierre-Paul Axisa¹, Christiane Gasperi¹, Mitja Mitrovic^{1

4}, David van Heel⁵, Cisca Wijmenga⁶, Sebo Withoff⁶, Iris H Jonkers⁶, Leonid Padyukov⁷; International Multiple Sclerosis Genetics Consortium; Stephen S Rich^{8

9}, Robert R Graham^{10

11}, Patrick M Gaffney¹², Carl D Langefeld^{13

14}, Timothy J Vyse¹⁵, David A Hafler¹, Sung Chun^{16

17}, Shamil R Sunyaev^{16

17}, Chris Cotsapas^{18

19

20}

Collaborators, Affiliations

Collaborators

Affiliations

¹ Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
² Division of Neurology at the Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
³ Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
⁴ Faculty of Chemistry and Chemical Engineering, University of Maribor, Maribor, Slovenia.
⁵ Blizard Institute, Queen Mary University of London, London, UK.
⁶ Department of Genetics at the University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁷ Division of Rheumatology at the Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
⁸ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁹ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
¹⁰ Maze Therapeutics, South San Francisco, CA, USA.
¹¹ Genentech, South San Francisco, CA, USA.
¹² Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
¹³ Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹⁴ Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹⁵ Department of Medical and Molecular Genetics, Kings College London, London, UK.
¹⁶ Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA.
¹⁷ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
¹⁸ Department of Neurology, Yale School of Medicine, New Haven, CT, USA. cotsapas@gmail.com.
¹⁹ Department of Genetics, Yale School of Medicine, New Haven, CT, USA. cotsapas@gmail.com.
²⁰ Vesalius Therapeutics, Cambridge, MA, USA. cotsapas@gmail.com.

PMID: 38741015
DOI: 10.1038/s41588-024-01732-8

Genetic mapping across autoimmune diseases reveals shared associations and mechanisms

Matthew R Lincoln et al. Nat Genet. 2024 May.

. 2024 May;56(5):838-845.

doi: 10.1038/s41588-024-01732-8. Epub 2024 May 13.

Authors

Collaborators

Affiliations

¹ Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
² Division of Neurology at the Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
³ Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
⁴ Faculty of Chemistry and Chemical Engineering, University of Maribor, Maribor, Slovenia.
⁵ Blizard Institute, Queen Mary University of London, London, UK.
⁶ Department of Genetics at the University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁷ Division of Rheumatology at the Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
⁸ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁹ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
¹⁰ Maze Therapeutics, South San Francisco, CA, USA.
¹¹ Genentech, South San Francisco, CA, USA.
¹² Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
¹³ Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹⁴ Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹⁵ Department of Medical and Molecular Genetics, Kings College London, London, UK.
¹⁶ Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA.
¹⁷ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
¹⁸ Department of Neurology, Yale School of Medicine, New Haven, CT, USA. cotsapas@gmail.com.
¹⁹ Department of Genetics, Yale School of Medicine, New Haven, CT, USA. cotsapas@gmail.com.
²⁰ Vesalius Therapeutics, Cambridge, MA, USA. cotsapas@gmail.com.

PMID: 38741015
DOI: 10.1038/s41588-024-01732-8

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.

PubMed Disclaimer

References

1. Rosenblum, M. D., Remedios, K. A. & Abbas, A. K. Mechanisms of human autoimmunity. J. Clin. Invest. 125, 2228–2233 (2015). - PubMed - PMC - DOI
1. International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 365, eaav7188 (2019).
1. de Lange, K. M. et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat. Genet. 49, 256–261 (2017). - PubMed - PMC - DOI
1. Maurano, M. T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012). - PubMed - PMC - DOI
1. Gusev, A. et al. Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. Am. J. Hum. Genet. 95, 535–552 (2014). - PubMed - PMC - DOI

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
- Nature Publishing Group
Medical
- MedlinePlus Health Information

[1] Rosenblum, M. D., Remedios, K. A. & Abbas, A. K. Mechanisms of human autoimmunity. J. Clin. Invest. 125, 2228–2233 (2015). - PubMed - PMC - DOI

[2] Rosenblum, M. D., Remedios, K. A. & Abbas, A. K. Mechanisms of human autoimmunity. J. Clin. Invest. 125, 2228–2233 (2015). - PubMed - PMC - DOI

[3] International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 365, eaav7188 (2019).

[4] International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 365, eaav7188 (2019).

[5] de Lange, K. M. et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat. Genet. 49, 256–261 (2017). - PubMed - PMC - DOI

[6] de Lange, K. M. et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat. Genet. 49, 256–261 (2017). - PubMed - PMC - DOI

[7] Maurano, M. T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012). - PubMed - PMC - DOI

[8] Maurano, M. T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012). - PubMed - PMC - DOI

[9] Gusev, A. et al. Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. Am. J. Hum. Genet. 95, 535–552 (2014). - PubMed - PMC - DOI

[10] Gusev, A. et al. Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. Am. J. Hum. Genet. 95, 535–552 (2014). - PubMed - PMC - DOI

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Genetic mapping across autoimmune diseases reveals shared associations and mechanisms

Collaborators

Affiliations

Genetic mapping across autoimmune diseases reveals shared associations and mechanisms

Authors

Collaborators

Affiliations

Abstract

Similar articles

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Abstract

Similar articles

References

MeSH terms

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Medical