Systematic genetic analysis of the MHC region reveals mechanistic underpinnings of HLA type associations with disease
Systematic genetic analysis of the MHC region reveals mechanistic underpinnings of HLA type associations with disease
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DOI：
10.7554/elife.48476
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发表时间：
2019-11-20
期刊：
影响因子：
7.7
通讯作者：
Frazer, Kelly A.
中科院分区：
文献类型：
--
作者：
D'Antonio, Matteo;Reyna, Joaquin;Frazer, Kelly A.
MHC区域与自身免疫性疾病和感染性疾病高度相关。在这里，我们对遗传变异、基因表达和疾病之间的关联进行了深入的探讨。我们使用来自419个个体的WGS创建了MHC区域中调控变异的综合地图，以调用来自匹配的iPSC的八位数HLA类型和RNA-seq数据。在此基础上，我们探索了4083个性状的GWAS信号，检测了180个疾病位点与eQTL的共定位。我们表明，eQTL分析考虑HLA型单倍型有显着更大的权力相比，只使用单一的变异。我们研究了8.1祖先单倍型和囊性纤维化中延迟定植之间的关联，假设RNF 5表达的下调是可能的因果机制。我们的研究提供了深入了解MHC区域的遗传结构，并指出了由于HLA基因和非HLA基因的差异表达而导致的疾病关联。
The MHC region is highly associated with autoimmune and infectious diseases. Here we conduct an in-depth interrogation of associations between genetic variation, gene expression and disease. We create a comprehensive map of regulatory variation in the MHC region using WGS from 419 individuals to call eight-digit HLA types and RNA-seq data from matched iPSCs. Building on this regulatory map, we explored GWAS signals for 4083 traits, detecting colocalization for 180 disease loci with eQTLs. We show that eQTL analyses taking HLA type haplotypes into account have substantially greater power compared with only using single variants. We examined the association between the 8.1 ancestral haplotype and delayed colonization in Cystic Fibrosis, postulating that downregulation of RNF5 expression is the likely causal mechanism. Our study provides insights into the genetic architecture of the MHC region and pinpoints disease associations that are due to differential expression of HLA genes and non-HLA genes.