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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 publication

DOI

10.1038/s41588-024-01732-8

Type

Journal article

Journal

Nature genetics

Publication Date

05/2024

Volume

56

Pages

838 - 845

Addresses

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

Keywords

International Multiple Sclerosis Genetics Consortium, Humans, Autoimmune Diseases, Genetic Predisposition to Disease, Case-Control Studies, Chromosome Mapping, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Alleles, Quantitative Trait Loci, Genome-Wide Association Study