Genetic Architecture of Intrathecal IgG Synthesis in Multiple Sclerosis: Integrating GWAS Signals, HLA Haplotypes, and Polygenic Risk
Intrathecal immunoglobulin G (IgG) synthesis is a defining immunopathologic feature of multiple sclerosis (MS) and is widely used as a prognostic indicator of subsequent disease course; importantly, it can be captured quantitatively by the IgG index, enabling genetic dissection of variability in the CNS-compartmentalized humoral response. In this multicenter study from the MultipleMS consortium, Pukaj and colleagues leverage the IgG index as an endophenotype to interrogate the genetic architecture of intrathecal IgG synthesis, motivated by prior evidence that the trait is relatively stable over time and therefore plausibly influenced by inherited factors.
The authors assembled a discovery cohort of 3,934 individuals with MS or clinically isolated syndrome from 17 European centers and defined “quantitative intrathecal IgG synthesis” using an IgG index threshold of ≥0.7 (vs < 0.7), followed by genome-wide association testing under logistic regression with adjustment for sex, age at lumbar puncture, year of lumbar puncture, and population structure (principal components), and fixed-effect meta-analysis across array/center strata. Secondary analyses addressed (i) the extent of intrathecal IgG synthesis using linear regression on transformed and clinically interpretable untransformed indices with robust standard errors, (ii) conditional analyses to identify independent signals, (iii) fine-mapping with Bayesian methods to prioritize candidate causal variants, and (iv) targeted HLA allele/haplotype association and polygenic risk score (PRS) analyses to connect MS susceptibility architecture to intrathecal humoral activity.
Heritability Indicates a Broad Polygenic Contribution Beyond Canonical Loci
A notable contribution of the work is the estimation of SNP-based heritability for the presence of intrathecal IgG synthesis, reported at approximately 40%, with minimal attenuation after excluding the major histocompatibility complex (MHC) and immunoglobulin heavy chain constant (IGHC) loci—suggesting that common variation outside these historically implicated regions accounts for substantial additional variance. While estimates for the extent of IgG synthesis were of similar magnitude, they did not reach statistical significance, underscoring either limited power for that quantitative model, phenotype heterogeneity across centers, or a more complex genetic architecture that may require larger sample sizes and/or improved locus coverage to resolve.
Two Chromosome 6 Signals: Replicating MHC Effects and Identifying a Novel SAMD5 Association
Consistent with prior literature, the most prominent association mapped to the MHC region on chromosome 6, with a lead variant (rs3135461) showing strong association with the presence of intrathecal IgG synthesis and with higher IgG indices, and exhibiting linkage disequilibrium with known tag variants for the high-impact MS risk haplotype involving HLA-DRB1*15:01. The central novelty is a second genome-wide significant signal outside the classical MHC interval: the low-frequency intronic variant rs844586 within SAMD5, where the minor allele was associated with a lower prevalence of intrathecal IgG synthesis; conditional modeling indicated independence from the MHC signal, replication showed consistent directionality, and joint meta-analysis retained genome-wide significance. Fine-mapping produced a credible set consistent with one or a small number of causal variants, and functional annotation highlighted the plausibility of regulatory mechanisms at this locus, positioning SAMD5 as a candidate modulator of CNS humoral immunobiology in MS.
Refining the IGHC Locus: A Candidate Causal Missense Variant Linked to the Extent of IgG Production
Because IGHC locus coverage can be uneven across genotyping arrays, the authors performed a targeted analysis in a subset (n = 1,413) with improved imputation performance at the locus, identifying rs1407 as a lead variant most strongly associated with the extent of intrathecal IgG synthesis and prioritizing it via fine-mapping with a high posterior inclusion probability. Biologically, rs1407 is a missense variant in IGHA1 (a conservative amino acid substitution) and is in high linkage disequilibrium with previously reported IGHC-region variants associated with IgG index, implying that earlier signals likely reflect the same underlying association. Importantly, the weaker association with the presence of synthesis versus the strong association with extent reinforces a recurring theme of the paper: partially distinct genetic determinants may govern whether intrathecal IgG synthesis occurs at all versus how pronounced the response becomes once established.
HLA Alleles, Extended Haplotypes, and a Link to Other Intrathecal Immunoglobulins
Moving beyond single-SNP signals, the investigators imputed classical 4-digit HLA alleles and identified independent associations consistent with an HLA-driven mechanism: HLA-DQB106:02 showed a strong association with intrathecal IgG synthesis, and conditional analysis supported an additional signal involving HLA-DQA101:03. Extended haplotype analyses suggested that the canonical MS risk haplotype (HLA-DRB115:01–DQA101:02–DQB106:02) exhibited particularly robust association with both the presence and extent of intrathecal IgG synthesis, with evidence that some haplotype effects persist even after conditioning on the lead MHC SNP, consistent with complex LD and potentially multiple functional layers within the region. Exploratory follow-up in a smaller single-center dataset suggested that the MHC lead variant and the DRB115:01-containing haplotype may also relate to higher intrathecal IgM indices, whereas the SAMD5 signal did not show clear associations with intrathecal IgA/IgM measures—findings that are directionally informative but appropriately framed as underpowered and hypothesis-generating.
Polygenic Risk for MS Susceptibility Tracks with Intrathecal IgG Synthesis and Suggests a Severity-Relevant Pathway
A particularly consequential inference is drawn from PRS analyses: higher genetic burden for MS susceptibility—computed both including and excluding MHC-region variants—was associated with increased likelihood of intrathecal IgG synthesis and with higher IgG indices, with replication in independent samples and supportive sensitivity analyses designed to mitigate bias from potential discovery overlap with the source MS-GWAS summary statistics. Conceptually, this indicates that the same distributed risk architecture that predisposes individuals to MS also biases the immune system toward a more prominent CNS-compartmentalized humoral response, thereby providing a plausible mechanistic bridge between susceptibility genetics and prognostic biomarkers linked to clinical outcomes. The study’s limitations—imperfect locus coverage in some regions (notably IGHC), heterogeneous clinical covariate availability across cohorts, and the need for functional validation of low-frequency and regulatory candidates—define an agenda for next steps: deeper sequencing and improved imputation panels for immunoglobulin loci, integrative eQTL/epigenomic analyses in relevant CNS and immune compartments, and experimental work to determine whether SAMD5-region variation causally modulates B-cell/plasma-cell biology, antibody production, or CNS tissue responses in 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:
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.
