Journal Article

Genetic mapping across autoimmune diseases reveals shared associations and mechanisms

Wijmenga, Cisca, Gasperi, Christiane, Withoff, Sebo, Jonkers, Iris H., Lincoln, Matthew R., Axisa, Pierre-Paul, Cotsapas, Chris, Padyukov, Leonid, van Heel, David, Langefeld, Carl D., Gaffney, Patrick M., Chun, Sung, Graham, Robert R., Rich, Stephen S., Sunyaev, Shamil R., Connally, Noah, Mitrovic, Mitja, Vyse, Timothy J., Hafler, David A.

2024

Overview

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. Joint likelihood mapping across six autoimmune diseases identifies shared and distinct association signals and improves fine-mapping resolution at loci with shared effects, yielding insights into the underlying biological mechanisms.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/205/2138 / 631/250/249/1313 / Agriculture / Alleles / Animal Genetics and Genomics / Autoimmune diseases / Autoimmune Diseases - genetics / Biomedical and Life Sciences / Biomedicine / Cancer Research / Case-Control Studies / Celiac disease / Chromosome Mapping / Comorbidity / Gene Function / Gene loci / Gene mapping / Genetic Predisposition to Disease / Genome-Wide Association Study / Genomes / Haplotypes / Health risk assessment / Human Genetics / Humans / Immune system / Inflammatory bowel disease / Inflammatory diseases / Multifactorial Inheritance - genetics / Polygenic inheritance / Polymorphism, Single Nucleotide / Quality control / Quantitative Trait Loci / Sample size