Genetic mapping across autoimmune diseases reveals shared associations and mechanisms

International Multiple Sclerosis Genetics Consortium; Matthew R Lincoln; Noah Connally; Pierre-Paul Axisa; Christiane Gasperi; Mitja Mitrovic; David van Heel; Cisca Wijmenga; Sebo Withoff; Iris H Jonkers; Leonid Padyukov; 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

International Multiple Sclerosis Genetics Consortium, Matthew R Lincoln, Noah Connally, Pierre-Paul Axisa, Christiane Gasperi, Mitja Mitrovic, David van Heel, Cisca Wijmenga, Sebo Withoff, Iris H Jonkers, Leonid Padyukov, 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^*

^*Corresponding author for this work

Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Research output: Contribution to journal › Article › Academic › peer-review

4 Citations (Scopus)

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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	13-May-2024
DOIs	https://doi.org/10.1038/s41588-024-01732-8
Publication status	Published - May-2024

Keywords

Humans
Autoimmune Diseases/genetics
Quantitative Trait Loci
Chromosome Mapping
Genetic Predisposition to Disease
Alleles
Polymorphism, Single Nucleotide
Genome-Wide Association Study
Case-Control Studies
Multifactorial Inheritance/genetics

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International Multiple Sclerosis Genetics Consortium, Lincoln, M. R., Connally, N., Axisa, P.-P., Gasperi, C., Mitrovic, M., van Heel, D., Wijmenga, C., Withoff, S., Jonkers, I. H., Padyukov, L., Rich, S. S., Graham, R. R., Gaffney, P. M., Langefeld, C. D., Vyse, T. J., Hafler, D. A., Chun, S., Sunyaev, S. R., & 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

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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.",

keywords = "Humans, Autoimmune Diseases/genetics, Quantitative Trait Loci, Chromosome Mapping, Genetic Predisposition to Disease, Alleles, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Case-Control Studies, Multifactorial Inheritance/genetics",

author = "{International Multiple Sclerosis Genetics Consortium} and 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 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 = "{\textcopyright} 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2024",

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

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International Multiple Sclerosis Genetics Consortium, Lincoln, MR, Connally, N, Axisa, P-P, Gasperi, C, Mitrovic, M, van Heel, D, Wijmenga, C , Withoff, S , Jonkers, IH, Padyukov, L, 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

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

AU - International Multiple Sclerosis Genetics Consortium

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 - 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.

KW - Humans

KW - Autoimmune Diseases/genetics

KW - Quantitative Trait Loci

KW - Chromosome Mapping

KW - Genetic Predisposition to Disease

KW - Alleles

KW - Polymorphism, Single Nucleotide

KW - Genome-Wide Association Study

KW - Case-Control Studies

KW - Multifactorial Inheritance/genetics

U2 - 10.1038/s41588-024-01732-8

DO - 10.1038/s41588-024-01732-8

M3 - Article

C2 - 38741015

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

Abstract

Keywords

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