Yuan Shuai, Chen Jie, Geng Jiawei, Zhao Sizheng Steven, Yarmolinsky James, Arkema Elizabeth V, Abramowitz Sarah, Levin Michael G, Tsilidis Kostas K, Burgess Stephen, Damrauer Scott M, Larsson Susanna C
Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Nat Commun. 2025 Mar 12;16(1):2481. doi: 10.1038/s41467-025-57829-z.
Sarcoidosis is a complex inflammatory disease with a strong genetic component. Here, we perform a genome-wide association study in 9755 sarcoidosis cases to identify risk loci and map associated genes. We then use transcriptome-wide association studies and enrichment analyses to explore pathways involved in sarcoidosis and use Mendelian randomization to examine associations with modifiable factors and circulating biomarkers. We identify 28 genomic loci associated with sarcoidosis, with the C1orf141-IL23R locus showing the largest effect size. We observe gene expression patterns related to sarcoidosis in the spleen, whole blood, and lung, and highlight 75 tissue-specific genes through transcriptome-wide association studies. Furthermore, we use enrichment analysis to establish key roles for T cell activation, leukocyte adhesion, and cytokine production in sarcoidosis. Additionally, we find associations between sarcoidosis and genetically predicted body mass index, interleukin-23 receptor, and eight circulating proteins.
结节病是一种具有强大遗传成分的复杂炎症性疾病。在此,我们对9755例结节病患者进行了全基因组关联研究,以确定风险位点并绘制相关基因图谱。然后,我们使用全转录组关联研究和富集分析来探索结节病所涉及的通路,并使用孟德尔随机化来研究与可改变因素和循环生物标志物的关联。我们确定了28个与结节病相关的基因组位点,其中C1orf141-IL23R位点的效应大小最大。我们在脾脏、全血和肺中观察到与结节病相关的基因表达模式,并通过全转录组关联研究突出了75个组织特异性基因。此外,我们使用富集分析确定了T细胞活化、白细胞粘附和细胞因子产生在结节病中的关键作用。此外,我们发现结节病与遗传预测的体重指数、白细胞介素-23受体和八种循环蛋白之间存在关联。
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