New Genetic Clues Reveal Why Some People with Multiple Sclerosis Produce More Brain Antibodies
Multiple sclerosis (MS) is one of the most studied autoimmune diseases of the central nervous system (CNS), yet the genetic mechanisms driving its complex immune landscape are still being uncovered. A new large-scale genome-wide association study (GWAS) by Albert Pukaj and colleagues, published in Neurology: Neuroimmunology & Neuroinflammation, sheds new light on how our genes influence a key feature of MS—the intrathecal (central nervous system) production of immunoglobulin G (IgG).
Why IgG Matters in MS
Intrathecal IgG synthesis—the production of antibodies within the CNS—is a hallmark of MS. It’s routinely measured through the IgG index, a biomarker derived from cerebrospinal fluid (CSF) and serum levels. Elevated IgG index values indicate heightened immune activity behind the blood–brain barrier and often correlate with a more aggressive disease course.
Interestingly, while IgG levels remain stable over time in MS patients, they vary widely between individuals—suggesting a strong genetic component. But until now, only two regions of the genome were clearly linked to this process:
The major histocompatibility complex (MHC) on chromosome 6, and
The immunoglobulin heavy chain constant region (IGHC) on chromosome 14.
A Deeper Dive Into the Genetics of Intrathecal Immunity
To identify new genetic contributors, the researchers analyzed data from 3,934 MS patients across 17 European centers as part of the MultipleMS Consortium. They compared individuals with and without intrathecal IgG synthesis, using rigorous quality control and logistic regression models that accounted for age, sex, and population structure. Findings were then replicated in an independent cohort of 1,094 patients.
A New Player: SAMD5 on Chromosome 6
The study revealed a previously unknown association between intrathecal IgG synthesis and an intronic variant (rs844586) in the SAMD5 gene on chromosome 6. Individuals carrying the minor allele (T) had lower odds of exhibiting intrathecal IgG synthesis.
This variant remained significant even after adjusting for the well-known MHC effect—making SAMD5 an independent genetic factor. SAMD5 encodes a protein that interacts with various signaling molecules, including ephrin receptors, which are involved in neurogenesis and immune regulation. The team also noted that the variant influences SAMD5 expression in thyroid and brain tissue, hinting at broader immune-neural interactions.
Confirming an Old Suspect: The IGHC Locus
The study also confirmed and refined the previously reported association at the IGHC locus on chromosome 14. Here, the team pinpointed rs1407, a missense variant in the IGHA1 gene, as the most likely causal variant affecting IgG levels. Each copy of the rs1407*G allele corresponded to higher IgG indices, reflecting enhanced antibody synthesis within the CNS.
Interestingly, rs1407 alters a single amino acid (glutamic to aspartic acid) and has been linked to differential expression of other immunoglobulin genes (e.g., IGHG2, IGHG3), suggesting a fine-tuned genetic control over antibody diversity and abundance.
HLA and the MHC: Still Central to MS Immunity
As expected, the HLA-DRB115:01–DQA101:02–DQB1*06:02 haplotype—the strongest known genetic risk factor for MS—was again associated with higher IgG synthesis. This supports the notion that MS susceptibility genes not only influence disease risk but also shape the immune activity within the CNS. Another HLA haplotype, DQA101:03–DQB106:03–DRB113:01*, showed weaker, non-independent effects.
Polygenic Risk and the Humoral Response
To explore the broader genetic landscape, the authors calculated polygenic risk scores (PRS) for MS. They found that individuals with a higher genetic burden of MS risk variants—both inside and outside the MHC region—were significantly more likely to have intrathecal IgG synthesis and higher IgG indices overall.
This suggests a shared genetic architecture between MS susceptibility and the intensity of the immune response within the CNS. In simple terms, the same genes that make someone prone to developing MS may also make their immune system more active once the disease is established.
What This Means for MS Research
This study provides a nuanced view of MS genetics, highlighting three major takeaways:
A new locus (SAMD5) contributes independently to CNS antibody production.
A likely causal IGHC variant (rs1407) clarifies previous findings and deepens our understanding of antibody-related genetics.
Polygenic risk for MS influences not just disease onset, but also disease biology—specifically, the strength of humoral immune activation in the CNS.
Together, these findings point toward genetically driven differences in immune regulation that could affect how MS progresses and responds to therapy.
The Bigger Picture
While the study doesn’t claim to explain all the genetic determinants of IgG synthesis—heritability estimates near 40% indicate much remains undiscovered—it marks a critical step forward. Future research may combine GWAS data with single-cell transcriptomics, epigenetic mapping, or multi-omics integration to unravel the mechanisms linking these variants to immune function.
As we move toward precision medicine in MS, such insights will be invaluable for identifying patients at higher risk of severe disease, tailoring treatments, and understanding the fundamental biology of neuroinflammation.
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:
Pukaj, A., Harroud, A., Shchetynsky, K., Wirsching, L., Peters, L., Andlauer, T. F., ... & MultipleMS consortium. (2025). Genetic Risk Variants for Multiple Sclerosis and Other Loci Linked to Intrathecal Immunoglobulin G Synthesis. Neurology: Neuroimmunology & Neuroinflammation, 12(6), e200499.
