Prioritizing TBKBP1 Gene in Multiple Sclerosis Susceptibility

Multiple Sclerosis (MS) is a complex autoimmune disease characterized by the destruction of myelin in the central nervous system. Despite extensive research, understanding the full genetic underpinnings of MS remains elusive. A recent study published in the Journal of Neurology (2022) by Melissa Sorosina et al. sheds new light on this issue by prioritizing the TBKBP1 gene as relevant for MS susceptibility through a multi-step genomic approach.

Background and Objective
Over 200 genetic loci have been associated with MS, explaining approximately 50% of its heritability. This suggests that additional genetic factors and mechanisms contribute to the disease's "missing heritability." The study aimed to analyze a large cohort of Italian individuals to identify markers associated with MS and assess their potential functional impact.

Study Design and Methods
The study included 2571 MS patients and 3234 healthy controls of continental Italian origin. The research team employed a multi-step approach:

Discovery Phase: A genome-wide association study (GWAS) was conducted using the Italian cohort, followed by a meta-analysis with a European ancestry cohort to increase statistical power.
Replication Phase: Top associated loci were tested in two additional Italian cohorts using array-based genotyping and pool-based target sequencing.
Functional Prioritization: Conditional expression quantitative trait loci (eQTL) and methylation quantitative trait loci (mQTL) analyses were performed to prioritize markers with potential functional roles.

Key Findings
The study confirmed that top associated signals overlapped with already known MS loci on chromosomes 3 and 17. Three single nucleotide polymorphisms (SNPs) — rs4267364, rs8070463, and rs67919208 — were identified as involved in the regulation of the TBKBP1 gene, highlighting its relevance in MS susceptibility.

Chromosome 3 Locus: The identified locus is an intergenic region with no clear functional annotation. Despite this, its potential regulatory effect on the upstream gene EOMES in T cells aligns with previous studies suggesting a role in MS.

Chromosome 17 Locus: This region includes several genes, with TBKBP1 emerging as a key candidate. The study's eQTL and mQTL analyses showed that the MS-associated alleles of the prioritized SNPs (rs4267364, rs8070463, and rs67919208) were linked to higher expression and methylation of TBKBP1 in immune cells.

Implications and Future Directions
The study's results underscore the importance of TBKBP1 in MS pathogenesis. TBKBP1 encodes the TBK1 binding protein 1, an adaptor involved in the TNFα/NFκB pathway. Given TBK1's role in T-cell homeostasis and migration to the CNS in MS, TBKBP1 might influence similar processes, suggesting its potential as a therapeutic target.

Further research is needed to elucidate the exact mechanisms by which TBKBP1 contributes to MS and to explore its potential in clinical applications. This study demonstrates the power of combining GWAS, replication, and functional analyses to uncover novel insights into complex diseases like MS.

Conclusion
The study by Sorosina et al. provides compelling evidence that TBKBP1 is a significant player in MS susceptibility. By leveraging a large Italian cohort and employing a rigorous multi-step approach, the researchers have advanced our understanding of MS genetics and opened new avenues for research and potential therapies.

References
Sorosina, M., Barizzone, N., Clarelli, F., Anand, S., Lupoli, S., Salvi, E., ... & Martinelli Boneschi, F. (2022). A multi-step genomic approach prioritized TBKBP1 gene as relevant for multiple sclerosis susceptibility. Journal of neurology, 269(8), 4510-4522.