Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
Division of Neurology at the Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Nat Genet. 2024 May;56(5):838-845. doi: 10.1038/s41588-024-01732-8. Epub 2024 May 13.
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.
自身免疫和炎症性疾病是免疫系统的多基因疾病。许多基因组位点都携带有多种疾病的风险等位基因，但遗传图谱的分辨率有限，无法确定是否由相同的等位基因负责，这表明存在共同的潜在机制。在这里，我们使用了 6 种疾病的 129058 例病例和对照的集合，结果表明，约 40%的重叠关联是由相同的等位基因引起的。我们通过跨疾病合并病例和对照，将共享等位基因的精细映射分辨率提高了两倍，从而使我们能够识别更多由共享等位基因驱动的表达数量性状基因座。这些模式表明存在广泛的致病机制共享，但不存在单一的全球自身免疫机制。我们的方法可以应用于任何一组特征，并且在样本集合变得枯竭时特别有价值。
