The Hunt for MS Genes: How an Italian Study Zeroed In on TBKBP1
If you follow health science, you've probably heard of the "missing heritability" problem. It’s a major puzzle in genetics. For many common diseases, like multiple sclerosis (MS), we’ve identified hundreds of genetic "hotspots" (or loci) linked to the illness. But when we add up all their effects, they only explain about half of the genetic risk. So, where is the other half hiding?
That’s the question at the heart of a fascinating 2022 study in the Journal of Neurology. A team of researchers wondered if some of these missing genetic clues might be specific to certain populations. Genetic signals that are common in one group might be rare in another, getting lost in large, mixed studies.
To test this, they focused on a large group of people from continental Italy. Their goal? To find new genetic markers for MS and, more importantly, to figure out what those markers actually do.
A Four-Step Genomic Investigation
This study wasn't just a simple scan. It was a sophisticated, multi-step investigation involving thousands of people—2,571 Italian MS patients and 3,234 healthy controls. Here’s how their "genomic detective" work unfolded:
The Wide Search (Discovery): First, they performed a genome-wide association study (GWAS), which is like scanning the entire "map" of the human genome for statistical hotspots linked to MS. They tried this two ways:
The "Local" Approach: Just looking for signals within their Italian-only cohort (ITA GWAS).
The "Global" Approach: Boosting their statistical power by combining their Italian data with a huge dataset of other Europeans (the "NonIT-EUR" cohort).
The Cross-Check (Replication): Science demands proof. The researchers took their top "hits" from the discovery phase and checked them in a completely separate group of Italian patients and controls (ITA OA). If a hotspot showed up again, they knew it was likely a real signal and not just a statistical fluke.
The Magnifying Glass (Fine-Mapping): Once a region was confirmed, they zoomed in. They used high-resolution "target sequencing" on a new group (ITA NGS) to map the exact genetic variants in that region, moving from a satellite view of a neighborhood down to a specific street address.
The "So What?" (Prioritization): This is the most crucial part. A genetic variant is just a string of letters. What does it do? The team "prioritized" the variants by checking if they had a functional job, such as:
eQTL analysis: Does the variant act like a "dimmer switch," changing how much a nearby gene is expressed (turned on)?
mQTL analysis: Does the variant affect DNA methylation—the little chemical "tags" that tell a gene when to be active or silent?
What the Detectives Found
The first, "Local" approach—the hunt for a uniquely Italian MS gene—came up empty. While they found some initial candidates, none of them could be confirmed in the replication step. This is a finding in itself: it suggests there probably isn't a strong MS gene hiding in the continental Italian population that we haven't seen elsewhere.
But the "Global" approach was a success.
This more powerful meta-analysis confirmed two well-known MS hotspots on chromosomes 3 and 17. And when the team aimed their "magnifying glass" and "prioritization" tools at the complex region on chromosome 17, one gene stood out from all the others: TBKBP1.
Why TBKBP1 Matters: A "Smoking Gun"
The chromosome 17 region is a busy place, genetically speaking, with at least eight genes. But the analysis kept pointing to TBKBP1. The researchers identified three specific genetic typos (SNPs) that were not only associated with MS, but also seemed to be directly involved in regulating this gene.
Here’s the "smoking gun" they found:
One SNP (rs4267364) sits in a genetic "control panel" known as an enhancer. They found that the MS-risk version of this SNP is linked to higher expression (more activity) of the TBKBP1 gene in blood cells.
Two other SNPs (rs8070463 and rs67919208) were linked to changes in the gene's methylation "tags". The ultimate effect appears to be the same: an upregulation, or boost, in TBKBP1 activity.
So, what is TBKBP1? It’s an adaptor protein, meaning it acts like a key connector in the immune system's communication network. It's involved in the TNFα/NFkB pathway, a critical process for launching an immune response.
Tellingly, the researchers noted that TBKBP1 is most highly expressed in the very cells that are prime suspects in the MS autoimmune attack: activated T-cells and Natural Killer (NK) cells.
The Takeaway
This study suggests a compelling hypothesis: people with these specific genetic risk variants may over-produce the TBKBP1 protein in their immune cells. This could put their immune system on high alert, making it more likely to launch the self-destructive attack on the central nervous system that causes MS.
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:
Sorosina, M., Barizzone, N., Clarelli, F. et al. A multi-step genomic approach prioritized TBKBP1 gene as relevant for multiple sclerosis susceptibility. J Neurol 269, 4510–4522 (2022). https://doi.org/10.1007/s00415-022-11109-8
