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

Area of Science:

• Genetics
• Immunology
• Neuroscience

Background:

• Intrathecal synthesis of immunoglobulin G (IgG) is a hallmark of multiple sclerosis (MS) and a prognostic indicator.
• Previous research identified the major histocompatibility complex (MHC) and immunoglobulin heavy chain constant (IGHC) loci associated with IgG synthesis in MS.
• The precise genetic factors influencing intrathecal IgG synthesis in MS remain incompletely understood.

Purpose of the Study:

• To conduct a genome-wide association study (GWAS) to identify genetic variants associated with intrathecal IgG synthesis in MS.
• To investigate the relationship between genetic risk for MS and the extent of intrathecal IgG synthesis.
• To explore the impact of genetic factors on intrathecal immunoglobulin A and M synthesis.

Main Methods:

• A GWAS was performed on intrathecal IgG synthesis using the IgG index in a discovery cohort (n=3,934) and validated in a replication cohort (n=1,094).
• Logistic regression models adjusted for sex, age, and population structure were employed.
• Secondary analyses examined associations with IgG, IgA, and IgM synthesis, and imputed human leukocyte antigen (HLA) alleles. Polygenic risk scores were used to quantify MS genetic burden.

Main Results:

• A novel genome-wide significant association was found between the intronic variant rs844586 in the SAMD5 gene and intrathecal IgG synthesis (p=1.48 × 10⁻⁸).
• A potential causal variant, rs1407, was identified within the IGHC locus associated with the extent of intrathecal IgG synthesis (p=3.80 × 10⁻¹¹).
• Increased genetic burden for MS susceptibility, both within and outside the MHC region, was significantly associated with a higher likelihood and extent of intrathecal IgG synthesis.

Conclusions:

• This study identifies a novel association between a SAMD5 intronic variant and intrathecal IgG synthesis in MS.
• A potential causal variant in the IGHC locus influencing IgG synthesis extent was discovered.
• Evidence suggests that MS risk variants may influence disease severity by affecting the intrathecal humoral immune response, a key prognostic marker.