美国耶鲁大学医学院Chris Cotsapas研究组，利用自身免疫性疾病的遗传图谱揭示出共享的关联和致病机制。这一研究成果发表在2024年5月13日出版的国际学术期刊《自然—遗传学》上。

研究人员利用与6种疾病有关的129058个病例和对照集合，证明约40%的重叠关联是由相同等位基因引起的。研究通过将患者和对照结合在一起，将共享等位基因的精细图谱分辨率提高了两倍，使人们能够确定由共享等位基因诱导的多表达性状位点。

这些模式表明存在共享的致病机制，但并非是单一的自身免疫机制。该研究方法可应用于任何一组性状，在样本收集日益困难的情况下尤其凸显了其价值。

研究人员表示，自身免疫性疾病和炎症性疾病是免疫系统多基因疾病。许多基因组位点都蕴藏着多种疾病的风险等位基因，但由于基因图谱的分辨率有限，无法确定是否是同一等位基因导致了这些疾病，也无法确定是否存在共同的致病机制。

附：英文原文

Title: Genetic mapping across autoimmune diseases reveals shared associations and mechanisms

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

Issue&Volume: 2024-05-13

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.

DOI: 10.1038/s41588-024-01732-8

Source: https://www.nature.com/articles/s41588-024-01732-8