Institute for Genomic Medicine, University of California, San Diego, San Diego, United States.
Department of Pediatrics, Rady Children's Hospital, University of California, San Diego, San Diego, United States.
Elife. 2019 Nov 20;8:e48476. doi: 10.7554/eLife.48476.
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 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.
MHC 区域与自身免疫性和传染病高度相关。在这里，我们深入研究了遗传变异、基因表达与疾病之间的关联。我们利用 419 个人的 WGS 数据创建了 MHC 区域调控变异的综合图谱，以调用八位 HLA 类型和匹配的 iPSC 的 RNA-seq 数据。基于这个调控图谱，我们探索了 4083 个特征的 GWAS 信号，检测到 180 个疾病位点与 eQTL 的共定位。我们表明，与仅使用单变体相比，考虑 HLA 类型单倍型的 eQTL 分析具有更大的功效。我们研究了 8.1 个祖先单倍型与囊性纤维化中延迟定植之间的关联，推测表达下调是可能的因果机制。我们的研究提供了对 MHC 区域遗传结构的深入了解，并确定了由于 HLA 基因和非 HLA 基因表达差异而导致的疾病关联。
