Integrating Autoimmune Risk Loci with Gene-Expression Data Identifies Specific Pathogenic Immune Cell Subsets
Integrating Autoimmune Risk Loci with Gene-Expression Data Identifies Specific Pathogenic Immune Cell Subsets
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DOI：
10.1016/j.ajhg.2011.09.002
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发表时间：
2011-10-07
影响因子：
9.8
通讯作者：
Raychaudhuri, Soumya
中科院分区：
文献类型：
--
作者：
Hu, Xinli;Kim, Hyun;Raychaudhuri, Soumya
尽管全基因组关联研究表明许多个体基因座与复杂疾病有关，但确定确切的因果等位基因及其作用的细胞类型仍然具有极大的挑战性。为了最终了解疾病的发病机制，研究人员必须仔细构思相关致病细胞类型的功能研究，以证明与疾病相关的基因变异对细胞的影响。这一挑战在自身免疫性疾病中尤为突出，如类风湿性关节炎，在这些疾病中，各种免疫细胞类型中的任何一种都可能受到基因变异的影响而致病。为此，我们开发了一种统计方法，通过使用来自免疫基因组联盟的223个小鼠分类免疫细胞的基因表达数据集来识别自身免疫性疾病中的潜在致病细胞类型。我们在系统性红斑狼疮中发现了移行B细胞基因的丰富(p=5.9×10(-6))，在克罗恩病中发现了上皮相关刺激的树突状细胞基因(p=1.6×10(-5))。最后，我们证明了在类风湿性关节炎基因座(p<；10(-6))中存在丰富的CD4+效应记忆T细胞基因。为了进一步验证CD_4+效应记忆T细胞在类风湿性关节炎中的作用，我们在最近的全基因组关联研究荟萃分析(PG is<；0.001)中确定了436个尚不知道与疾病相关但具有统计学意义的相关基因。即使在这些假定的基因座中，我们也注意到在CD4+效应记忆T细胞中特异性表达的基因显著丰富(p=1.25x10(-4))。这些细胞类型是未来功能研究的主要候选者，以揭示风险等位基因在自身免疫中的作用。我们的方法也适用于自身免疫以外的其他表型，在这些表型中，已经发现了许多基因座，并且可以获得高质量的细胞类型特异性基因表达。
Although genome-wide association studies have implicated many individual loci in complex diseases, identifying the exact causal alleles and the cell types within which they act remains greatly challenging. To ultimately understand disease mechanism, researchers must carefully conceive functional studies in relevant pathogenic cell types to demonstrate the cellular impact of disease-associated genetic variants. This challenge is highlighted in autoimmune diseases, such as rheumatoid arthritis, where any of a broad range of immunological cell types might potentially be impacted by genetic variation to cause disease. To this end, we developed a statistical approach to identify potentially pathogenic cell types in autoimmune diseases by using a gene-expression data set of 223 murine-sorted immune cells from the Immunological Genome Consortium. We found enrichment of transitional B cell genes in systemic lupus erythematosus (p = 5.9 x 10(-6)) and epithelial-associated stimulated dendritic cell genes in Crohn disease (p = 1.6 x 10(-5)). Finally, we demonstrated enrichment of CD4+ effector memory T cell genes within rheumatoid arthritis loci (p < 10(-6)). To further validate the role of CD4+ effector memory T cells within rheumatoid arthritis, we identified 436 loci that were not yet known to be associated with the disease but that had a statistically suggestive association in a recent genome-wide association study (GWAS) meta-analysis (PG WAS < 0.001). Even among these putative loci, we noted a significant enrichment for genes specifically expressed in CD4+ effector memory T cells (p = 1.25 x 10(-4)). These cell types are primary candidates for future functional studies to reveal the role of risk alleles in autoimmunity. Our approach has application in other phenotypes, outside of autoimmunity, where many loci have been discovered and high-quality cell-type-specific gene expression is available.