Systematic genetic analysis of the MHC region reveals mechanistic underpinnings of HLA type associations with disease
- University of California, San Diego, United States
- European Molecular Biology Laboratory, European Bioinformatics Institute, United Kingdom
Abstract
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 4,083 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.
Data availability
Whole-genome sequencing data of 273 individuals in the iPSCORE cohort (Panopoulos et al., 2017) is publicly available through dbGaP: phs001325. RNA-seq data of 215 iPSCs in the iPSCORE cohort (DeBoever et al., 2017) is publicly available through dbGaP:phs000924. Whole-genome sequencing data of 377 individuals in the HipSci cohort is publicly available through EGA: PRJEB15299. RNA-seq data of 231 iPSCs in the HipSci cohort is publicly available through ENA: PRJEB7388. eQTL and HLA-type eQTL summary statistics are available at Figshare (https://figshare.com/s/c8533530204e1822c6f4 and https://figshare.com/s/eab712af0e4baeb99251).
Article and author information
Author details
Funding
California Institute for Regenerative Medicine (GC1R-06673)
- Kelly A Frazer
National Institutes of Health (HG008118)
- Kelly A Frazer
National Institutes of Health (HL107442)
- Kelly A Frazer
National Institutes of Health (DK105541)
- Kelly A Frazer
National Institutes of Health (DK112155)
- Kelly A Frazer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, D'Antonio et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Systematic genetic analysis of the MHC region reveals mechanistic underpinnings of HLA type associations with disease
eLife 8:e48476.
https://doi.org/10.7554/eLife.48476
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