Genetic Risk Variants for Multiple Sclerosis and Other Loci Linked to Intrathecal Immunoglobulin G Synthesis

Abstract

Background and objectives: Intrathecal synthesis of immunoglobulin G (IgG) is a key feature of multiple sclerosis (MS) and a prognostic marker for the disease course. Although previous studies identified 2 genetic regions-the major histocompatibility complex (MHC) region on chromosome 6 and the immunoglobulin heavy chain constant (IGHC) locus on chromosome 14-associated with intrathecal IgG synthesis in MS, the genetic underpinnings remain insufficiently understood.

Methods: We conducted a genome-wide association study on intrathecal IgG synthesis using the IgG index to identify individuals with (≥0.7) or without (<0.7) quantitative intrathecal synthesis. We used logistic regression models adjusting for sex, age, and population structure. We performed secondary analyses to examine associations between identified loci and the extent of intrathecal IgG synthesis and the presence and extent of intrathecal immunoglobulin A and M synthesis. We further conducted association analyses for imputed human leukocyte antigen alleles and analyzed whether a higher genetic burden for MS risk-quantified through polygenic risk scores-is associated with intrathecal IgG synthesis.

Results: In the discovery cohort (n = 3,934), we identified a novel genome-wide significant association of the intronic variant rs844586 (p = 1.48 × 10^-8) in the sterile alpha motif domain containing 5 (SAMD5) gene on chromosome 6, with intrathecal IgG synthesis. We could confirm this association in a replication cohort (n = 1,094) and demonstrated that it is independent of a previously described association signal at the MHC region. In a subset (n = 1,413), we further identified rs1407 as a potential causal variant (p = 3.80 × 10^-11, posterior inclusion probability = 0.92) for the previously reported association signal at the IGHC locus with the extent of intrathecal IgG synthesis. In addition, we demonstrated that a higher genetic burden for MS susceptibility, both within and outside of the MHC region, is associated with a higher likelihood of and a more pronounced intrathecal IgG synthesis.

Discussion: Our study revealed a previously unknown association between an intronic variant in SAMD5 with intrathecal IgG synthesis and identified a potential causal variant within the IGHC locus. It further provides evidence for possible effects of known MS risk variants on disease severity through their effect on the intrathecal humoral immune response, a prognostic marker for the disease course.

Figure 1. Two Loci on Chromosome 6 Are Associated With Intrathecal IgG Synthesis

(A) Manhattan plot depicting the results of the GWAS on the presence of intrathecal IgG synthesis. The x-axis shows chromosomal base positions, while the y-axis represents -log10 p-values (y-axis) for all analyzed variants. The dashed line indicates the genome-wide significance (p < 5 × 10⁻⁰⁸) threshold. Note that the IGHC locus was not adequately covered in this dataset. (B) Association plot for the SAMD5 locus on chromosome 6 containing a genome-wide significant association signal. Color-coding represents LD r² values with the lead variant rs844586 as reference. GWAS = genome-wide association study; IGHC = immunoglobulin heavy chain constant.

Figure 2. The IGHC Locus on Chromosome 14 Is Associated With the Extent of Intrathecal IgG

(A) Association plot showing the results of logistic regression models on a subset of samples (n = 1,413) for a genetic locus on chromosome 14. The dashed lines indicate the genome-wide significance (p < 5 × 10⁻⁰⁸) threshold. Color-coding reflects the linkage disequilibrium (LD) with the lead variant rs1407. (B) Association plot showing the results of linear regression models on the same genetic locus. IgG = immunoglobulin G; IGHC = immunoglobulin heavy chain constant.

Figure 3. Higher Genetic Risk for MS Susceptibility Is Associated With Intrathecal IgG Synthesis

Forest plots showing the summary statistics of logistic regression models on the presence of intrathecal IgG synthesis (A and B) and the linear regression models on the IgG indices (C and D) demonstrating that PRS for MS susceptibility calculated with (A and C) and without variants at the MHC region on chromosome 6 (B and D) are positively associated with the presence of intrathecal IgG synthesis and the extent of intrathecally produced IgG. IgG = immunoglobulin G; MHC = major histocompatibility complex; MS = multiple sclerosis; PRS = polygenic risk score.