Systematic genetic analysis of the MHC region reveals mechanistic underpinnings of HLA type associations with disease

eLife

Hiroko Matsui¹  Margaret KR Donovan²  Naoki Nariai³  Joaquin Reyna⁴  Oliver Stegle⁵  Marc-Jan Bonder⁶  David Jakubosky⁷  Agnieszka D'Antonio-Chronowska⁸  Kelly A Frazer⁹  Matteo D'Antonio⁹ 

[1] Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, San Diego, United States;Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, United States;Department of Biomedical Informatics, 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;Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, San Diego, United States;Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, United States;Department of Pediatrics, Rady Children’s Hospital, University of California, San Diego, San Diego, United States;European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridge, United Kingdom;Institute for Genomic Medicine, University of California, San Diego, San Diego, United States;

关键词: major histocompatibility complex;    eQTLs;    gene expression;    HLA types;   

DOI  :  10.7554/eLife.48476

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown