The 6q23 Puzzle: How 3D Genome Mapping Reveals New Clues to Multiple Sclerosis

Multiple sclerosis (MS) is one of the most genetically complex immune-mediated diseases. Beyond the well-known risk contributed by the HLA region, more than 100 non-HLA genetic loci contribute small but meaningful increments to MS susceptibility. One such region—chromosome 6q23—has puzzled researchers for years.

A study, Identifying Causal Genes at the Multiple Sclerosis Associated Region 6q23 Using Capture Hi-C, takes a fresh look at 6q23 using an advanced chromatin-mapping technique called Capture Hi-C. The results reveal a tangled, 3-dimensional regulatory landscape where MS-associated variants engage in long-range chromatin looping to influence distant immune and neurological genes. These insights could eventually point to new therapeutic opportunities.

Why 6q23? A Region of Many Questions
Genome-wide association studies (GWAS) identified four independent MS susceptibility variants packed into a relatively small 2.5-Mb stretch at 6q23. Importantly, these variants are:

rs11154801

rs17066096

rs7769192

rs67297943

And intriguingly, unlike many autoimmune loci that are shared among diseases like rheumatoid arthritis or lupus, these specific variants appear unique to MS.

The challenge is that all four SNPs lie outside coding regions. That means they likely exert their influence through gene regulation, potentially by altering enhancer activity or long-range chromatin interactions. Classic GWAS approaches can’t tell us which genes these SNPs actually regulate.

Enter Capture Hi-C, a high-resolution method to map physical DNA–DNA contacts.

The Power of Capture Hi-C: Seeing the Genome in 3D
The authors used Capture Hi-C in T cells (Jurkat) and B cells (GM12878) to zoom in on thousands of potential chromatin interactions across the 6q23 region. This method enriches for interactions involving specific genomic regions of interest, thereby increasing resolution to the level of single HindIII restriction fragments (~4 kb).

In total, the team identified 827 unique chromatin interactions involving MS-associated regions, with strong validation from publicly available Hi-C datasets.

Two major interaction hubs emerged:

The rs11154801 hub within the AHI1 locus

The rs17066096/rs7769192/rs67297943 hub, which clusters around key immune genes including IL20RA, IL22RA2, IFNGR1, and TNFAIP3

Despite being separated by over 2.3 Mb, these hubs even interact with each other in T cells, hinting at coordinated regulation in MS .

Hub #1: The AHI1 Region — A Neurological Connection With a Twist

The SNP rs11154801, sitting within an intron of AHI1, shows strong evidence of regulating the gene:

It physically interacts with the AHI1 promoter in both T and B cells

It is associated with AHI1 expression in multiple tissues, including brain and blood

This reinforces AHI1 as a plausible MS risk gene, especially given AHI1’s role in brain development and its link to Joubert syndrome

Capture Hi-C showed that the rs11154801 region also forms long-range loops—some >1 Mb—to other genes:

SGK1, a salt-sensing kinase known to promote pathogenic Th17 differentiation in EAE, the mouse model of MS

BCLAF1, involved in lymphocyte survival and apoptosis, both relevant to MS immunopathology

Regions near MYC and PDE7B, offering further regulatory connections

This suggests that rs11154801 is part of a broader regulatory network that touches both neurological and immune pathways—matching MS’s dual nature as a neuroimmune disorder.

Hub #2: Immune Genes Under 3D Control

The second hub comprises three MS-associated SNPs:

rs17066096

rs7769192

rs67297943

These variants physically interact not only with each other but also with several key immune genes, all of which sit far away in linear genomic distance:

IL22RA2 & IL20RA

These encode receptors for IL-22 and IL-20 family cytokines, both involved in epithelial defense and inflammatory signaling.

The authors highlight:

Anti-IL-20 therapies are already showing clinical benefit in psoriasis and rheumatoid arthritis

The chromatin interactions observed here raise the provocative possibility that such therapies could be repurposed for MS

IFNGR1

A receptor for IFN-γ, a cytokine long implicated in autoimmunity.

TNFAIP3 (A20)

A master negative regulator of NF-κB signaling, and one of the most important autoimmunity genes across diseases.

The fact that MS-specific variants in 6q23 physically loop to these inflammatory genes suggests a compelling mechanism: 3D genome architecture may coordinate the regulation of inflammatory pathways relevant to MS.

Even better, one SNP (rs17066096) showed an eQTL effect on IL20RA in primary CD8 T cells—a rare and valuable link between genetic variation, chromatin looping, and gene expression.

A Cross-Hub Interaction: Where Neuro and Immune Pathways Meet
One of the most fascinating findings is that the two major hubs—AHI1/SGK1/BCLAF1 and IL20RA/IL22RA2/IFNGR1/TNFAIP3—physically interact in T cells.

This offers a possible mechanistic explanation for why MS uniquely affects the immune system and the central nervous system:

Neurological genes and immune genes may be co-regulated through shared chromatin loops, forming what some researchers call “transcription factories”.

Such convergence could help explain why the MS-specific SNPs at 6q23 differ from the broader autoimmune SNPs that affect other diseases.

Prioritizing Causal Variants: Narrowing the Field
Using regulatory annotations (HaploReg, RegulomeDB) combined with Capture Hi-C, the authors effectively pruned:

19 candidate SNPs near rs11154801 → 6 high-priority candidates 7 SNPs near rs17066096 → 3 candidates 72 SNPs near rs7769192 → 4 candidates These refined SNP lists offer testable targets for CRISPR validation, reporter assays, and functional studies.

What This Means for MS Research
This study makes several important contributions:

1. It identifies strong candidate genes for MS

AHI1, SGK1, BCLAF1, IL20RA, IL22RA2, IFNGR1, TNFAIP3

2. It highlights the 3D genome as a key player in MS genetics

Linear genome distance is irrelevant when chromatin loops bring regions together for co-regulation.

3. It suggests new therapeutic avenues

If IL-20 family receptors are genetically and physically connected to MS risk variants, anti-IL-20 therapies may be worth exploring for MS.

4. It provides a roadmap for functional follow-up

Refined SNP lists + chromatin maps = actionable starting points for modeling MS genetic mechanisms.

Final Thoughts: These Loops Matter
MS is a disease where the immune system and nervous system collide. This paper provides a powerful example of how 3D genome architecture helps bridge that divide.

By placing MS-associated variants into a spatial context, the authors uncover a network of long-range interactions linking genes involved in neurodevelopment, immune signaling, apoptosis, and cytokine responses. The picture that emerges is not of isolated genetic hits, but of an interconnected regulatory ecosystem.

And as the field moves toward treatments personalized by genetics, understanding these chromatin networks will be essential.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Martin, P., McGovern, A., Massey, J., Schoenfelder, S., Duffus, K., Yarwood, A., ... & Orozco, G. (2016). Identifying causal genes at the multiple sclerosis associated region 6q23 using capture Hi-C. PLoS One, 11(11), e0166923.