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

Matteo D'Antonio,Naoki Nariai,David Jakubosky,Marc-Jan Bonder,Margaret Kr Donovan,Hiroko Matsui,Oliver Stegle,Kelly A Frazer,Agnieszka D'Antonio-Chronowska,Joaquin Reyna

doi:10.7554/elife.48476

Matteo D'Antonio, Naoki Nariai + Show 8 more

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https://doi.org/10.7554/elife.48476

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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 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.

Highlights

The 4 Mb major histocompatibility (MHC) region on chromosome 6p21.3, which encodes the human leucocyte antigen (HLA) gene complex, is highly polymorphic, gene dense, and has strong linkage disequilibrium (LD) (Dendrou et al, 2018; Fehrmann et al, 2011)
Regulatory variants in the MHC region play important roles in complex traits To characterize the associations between genetic variation in the MHC region, gene expression and disease, we investigated if eGenes and complex traits shared the same causal variants using a colocalization approach (Giambartolomei et al, 2014)
The human MHC region on 6p21.3 has been associated with many autoimmune and infectious diseases, it is typically excluded from eQTL studies due to its high single nucleotide polymorphisms (SNPs) frequency and complex LD structure (Lam et al, 2017)

Summary

Introduction

The 4 Mb major histocompatibility (MHC) region on chromosome 6p21.3, which encodes the human leucocyte antigen (HLA) gene complex, is highly polymorphic, gene dense, and has strong linkage disequilibrium (LD) (Dendrou et al, 2018; Fehrmann et al, 2011). Several studies have suggested that the mechanistic underpinnings underlying associations with some autoimmune diseases may be due to certain HLA types being more likely than other HLA types to atypically present self-antigens (Klein et al, 2014; Oldstone, 1998; Yin et al, 2013). Expression differences between different HLA types of the same HLA gene could contribute to disease associations. Some of the genetic associations with specific HLA types could be due to causal variants on the same haplotype, that affect the expression or function of non-HLA genes in the MHC region (Holoshitz, 2013). There are complex interactions between genetic variation, gene expression and function of both HLA and non-HLA genes, and disease, rendering the MHC region an important but difficult interval to genetically interrogate

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