Genetic mapping across autoimmune diseases reveals shared associations and mechanisms

Matthew R. Lincoln; Noah Connally; Pierre-Paul Axisa; Christiane Gasperi; Mitja Mitrovic; David Van heel; Cisca Wijmenga; Sebo Withoff; Iris h. Jonkers; Leonid Padyukov; 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 A. Hafler; Stephen L. Hauser; Alastair Compston; Gil Mcvean; Philip De jager; Stephen j. Sawcer; Jakob l. Mccauley; Stephen S. Rich; Robert R. Graham; Patrick M. Gaffney; Carl D. Langefeld; Timothy J. Vyse; David a. Hafler; Sung Chun; Shamil r. Sunyaev; Chris Cotsapas

doi:10.1038/s41588-024-01732-8

Genetic mapping across autoimmune diseases reveals shared associations and mechanisms

Matthew R. Lincoln, Noah Connally, Pierre-Paul Axisa, Christiane Gasperi, Mitja Mitrovic, David Van heel, Cisca Wijmenga, Sebo Withoff, Iris h. Jonkers, Leonid Padyukov, Ashley h. Beecham, Nikolaos a. Patsopoulos, Chris Cotsapas, David Booth, An Goris, Annette Oturai, Janna Saarela, Betrand Fontaine, Bertrand Hemmer, Martin ClaesFrauke 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 A. Hafler, Stephen L. Hauser, Alastair Compston, Gil Mcvean, Philip De jager, Stephen j. Sawcer, Jakob l. Mccauley, Stephen S. Rich, Robert R. Graham, Patrick M. Gaffney, Carl D. Langefeld, Timothy J. Vyse, David a. Hafler, Sung Chun, Shamil r. Sunyaev, Chris Cotsapas

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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.

Original language	English
Pages (from-to)	838-845
Number of pages	8
Journal	Nature Genetics
Volume	56
Issue number	5
Early online date	14 May 2024
DOIs	https://doi.org/10.1038/s41588-024-01732-8
Publication status	Published - May 2024

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Lincoln, M. R., Connally, N., Axisa, P.-P., Gasperi, C., Mitrovic, M., Van heel, D., Wijmenga, C., Withoff, S., Jonkers, I. H., Padyukov, L., Beecham, A. H., Patsopoulos, N. A., Cotsapas, C., Booth, D., Goris, A., Oturai, A., Saarela, J., Fontaine, B., Hemmer, B., ... Cotsapas, C. (2024). Genetic mapping across autoimmune diseases reveals shared associations and mechanisms. Nature Genetics, 56(5), 838-845. https://doi.org/10.1038/s41588-024-01732-8

@article{2a2bc49164c443c9a44999d4a73ccebd,

title = "Genetic mapping across autoimmune diseases reveals shared associations and mechanisms",

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.",

author = "Lincoln, {Matthew R.} and Noah Connally and Pierre-Paul Axisa and Christiane Gasperi and Mitja Mitrovic and {Van heel}, David and Cisca Wijmenga and Sebo Withoff and Jonkers, {Iris h.} and Leonid Padyukov and Beecham, {Ashley h.} and Patsopoulos, {Nikolaos a.} and Chris Cotsapas and David Booth and An Goris and Annette Oturai and Janna Saarela and Betrand Fontaine and Bertrand Hemmer and Martin Claes and Frauke Zipp and Sandra D{\textquoteright}alfonso and Filippo Martinelli-Boneschi and Bruce Taylor and Harbo, {Hanne f.} and Ingrid Kockum and Jan Hillert and Tomas Olsson and Oksenberg, {Jorge R.} and Rogier Hintzen and Barcellos, {Lisa f.} and Lars Alfredsson and Federica Esposito and Roland Martin and Haines, {Jonathan l.} and Pericak-Vance, {Margaret a.} and Ivinson, {Adrian j.} and Graeme Stewart and Hafler, {David A.} and Hauser, {Stephen L.} and Alastair Compston and Gil Mcvean and {De jager}, Philip and Sawcer, {Stephen j.} and Mccauley, {Jakob l.} and Rich, {Stephen S.} and Graham, {Robert R.} and Gaffney, {Patrick M.} and Langefeld, {Carl D.} and Vyse, {Timothy J.} and Hafler, {David a.} and Sung Chun and Sunyaev, {Shamil r.} and Chris Cotsapas",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.",

year = "2024",

month = may,

doi = "10.1038/s41588-024-01732-8",

language = "English",

volume = "56",

pages = "838--845",

journal = "Nature Genetics",

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Lincoln, MR, Connally, N, Axisa, P-P, Gasperi, C, Mitrovic, M, Van heel, D, Wijmenga, C, Withoff, S, Jonkers, IH, Padyukov, L, Beecham, AH, Patsopoulos, NA, Cotsapas, C, Booth, D, Goris, A, Oturai, A, Saarela, J, Fontaine, B, Hemmer, B, Claes, M, Zipp, F, D’alfonso, S, Martinelli-Boneschi, F, Taylor, B, Harbo, HF, Kockum, I, Hillert, J, Olsson, T, Oksenberg, JR, Hintzen, R, Barcellos, LF, Alfredsson, L, Esposito, F, Martin, R, Haines, JL, Pericak-Vance, MA, Ivinson, AJ, Stewart, G, Hafler, DA, Hauser, SL, Compston, A, Mcvean, G, De jager, P, Sawcer, SJ, Mccauley, JL, Rich, SS, Graham, RR, Gaffney, PM, Langefeld, CD, Vyse, TJ, Hafler, DA, Chun, S, Sunyaev, SR & Cotsapas, C 2024, 'Genetic mapping across autoimmune diseases reveals shared associations and mechanisms', Nature Genetics, vol. 56, no. 5, pp. 838-845. https://doi.org/10.1038/s41588-024-01732-8

TY - JOUR

T1 - Genetic mapping across autoimmune diseases reveals shared associations and mechanisms

AU - Lincoln, Matthew R.

AU - Connally, Noah

AU - Axisa, Pierre-Paul

AU - Gasperi, Christiane

AU - Mitrovic, Mitja

AU - Van heel, David

AU - Wijmenga, Cisca

AU - Withoff, Sebo

AU - Jonkers, Iris h.

AU - Padyukov, Leonid

AU - Beecham, Ashley h.

AU - Patsopoulos, Nikolaos a.

AU - Cotsapas, Chris

AU - Booth, David

AU - Goris, An

AU - Oturai, Annette

AU - Saarela, Janna

AU - Fontaine, Betrand

AU - Hemmer, Bertrand

AU - Claes, Martin

AU - Zipp, Frauke

AU - D’alfonso, Sandra

AU - Martinelli-Boneschi, Filippo

AU - Taylor, Bruce

AU - Harbo, Hanne f.

AU - Kockum, Ingrid

AU - Hillert, Jan

AU - Olsson, Tomas

AU - Oksenberg, Jorge R.

AU - Hintzen, Rogier

AU - Barcellos, Lisa f.

AU - Alfredsson, Lars

AU - Esposito, Federica

AU - Martin, Roland

AU - Haines, Jonathan l.

AU - Pericak-Vance, Margaret a.

AU - Ivinson, Adrian j.

AU - Stewart, Graeme

AU - Hafler, David A.

AU - Hauser, Stephen L.

AU - Compston, Alastair

AU - Mcvean, Gil

AU - De jager, Philip

AU - Sawcer, Stephen j.

AU - Mccauley, Jakob l.

AU - Rich, Stephen S.

AU - Graham, Robert R.

AU - Gaffney, Patrick M.

AU - Langefeld, Carl D.

AU - Vyse, Timothy J.

AU - Hafler, David a.

AU - Chun, Sung

AU - Sunyaev, Shamil r.

AU - Cotsapas, Chris

PY - 2024/5

Y1 - 2024/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85192804752&partnerID=8YFLogxK

U2 - 10.1038/s41588-024-01732-8

DO - 10.1038/s41588-024-01732-8

M3 - Article

SN - 1061-4036

VL - 56

SP - 838

EP - 845

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

Genetic mapping across autoimmune diseases reveals shared associations and mechanisms

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