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. 2016 Nov 18;11(11):e0166923.
doi: 10.1371/journal.pone.0166923. eCollection 2016.

Identifying Causal Genes at the Multiple Sclerosis Associated Region 6q23 Using Capture Hi-C

Paul Martin  1 , Amanda McGovern  1 , Jonathan Massey  1 , Stefan Schoenfelder  2 , Kate Duffus  1 , Annie Yarwood  1 , Anne Barton  1   3 , Jane Worthington  1   3 , Peter Fraser  2 , Stephen Eyre  1 , Gisela Orozco  1
Affiliations

Identifying Causal Genes at the Multiple Sclerosis Associated Region 6q23 Using Capture Hi-C

Paul Martin et al. PLoS One. .

Abstract

Background: The chromosomal region 6q23 has been found to be associated with multiple sclerosis (MS) predisposition through genome wide association studies (GWAS). There are four independent single nucleotide polymorphisms (SNPs) associated with MS in this region, which spans around 2.5 Mb. Most GWAS variants associated with complex traits, including these four MS associated SNPs, are non-coding and their function is currently unknown. However, GWAS variants have been found to be enriched in enhancers and there is evidence that they may be involved in transcriptional regulation of their distant target genes through long range chromatin looping.

Aim: The aim of this work is to identify causal disease genes in the 6q23 locus by studying long range chromatin interactions, using the recently developed Capture Hi-C method in human T and B-cell lines. Interactions involving four independent associations unique to MS, tagged by rs11154801, rs17066096, rs7769192 and rs67297943 were analysed using Capture Hi-C Analysis of Genomic Organisation (CHiCAGO).

Results: We found that the pattern of chromatin looping interactions in the MS 6q23 associated region is complex. Interactions cluster in two regions, the first involving the rs11154801 region and a second containing the rs17066096, rs7769192 and rs67297943 SNPs. Firstly, SNPs located within the AHI1 gene, tagged by rs11154801, are correlated with expression of AHI1 and interact with its promoter. These SNPs also interact with other potential candidate genes such as SGK1 and BCLAF1. Secondly, the rs17066096, rs7769192 and rs67297943 SNPs interact with each other and with immune-related genes such as IL20RA, IL22RA2, IFNGR1 and TNFAIP3. Finally, the above-mentioned regions interact with each other and therefore, may co-regulate these target genes.

Conclusion: These results suggest that the four 6q23 variants, independently associated with MS, are involved in the regulation of several genes, including immune genes. These findings could help understand mechanisms of disease and suggest potential novel therapeutic targets.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Overview of MS 6q23 Immunochip associated regions.
Tracks are labelled as follows: A–HindIII restriction fragments; B–LD regions targeted in ‘region’ Capture Hi-C; C–HindIII restriction fragments targeted in ‘region’ Capture Hi-C; D–Gene regions targeted in ‘promoter’ Capture Hi-C; E–HindIII restriction fragments targeted in ‘promoter’ Capture Hi-C; F–RefSeq genes (packed for clarity); G–MS index SNPs; H–Density of MS LD SNPs (r2 ≥ 0.8) and I–MS LD regions. The genomic region chr6:136,238,000–137,360,000 has been omitted for clarity. All co-ordinates are based on GRCh37. Generated using the WashU EpiGenome Browser (http://epigenomegateway.wustl.edu/browser/).
Fig 2
Fig 2. Overview of MS 6q23 interactions.
Tracks are labelled as follows: A–LD regions targeted in ‘region’ Capture Hi-C; B–Gene regions targeted in ‘promoter’ Capture Hi-C; C–RefSeq genes (packed for clarity); D–MS index SNPs; E–MS LD regions; F–Interactions observed in the GM12878 B-cell line and G–Interactions observed in the Jurkat T-cell line. Promoter and region Capture Hi-C experiments have been merged for clarity. The genomic region chr6:136,650,000–137,280,000 has been omitted for clarity. All co-ordinates are based on GRCh37. Generated using the WashU EpiGenome Browser (http://epigenomegateway.wustl.edu/browser/).
Fig 3
Fig 3. Increased expression of IL20RA in primary CD8+ T-cells from 21 healthy individuals carrying the G risk allele of rs17066096, P = 0.01.
The three different genotypes for the SNPs are displayed on the X axis and gene expression levels on the Y axis. Error bars indicate standard deviation.
See this image and copyright information in PMC

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