Copy number variations in multiple sclerosis and neuromyelitis optica

Area of Science:

• Genetics
• Immunology
• Neurology

Background:

• Multiple sclerosis (MS) and neuromyelitis optica (NMO) are debilitating neurological autoimmune diseases.
• The genetic underpinnings of MS and NMO, particularly in Asian populations, require further elucidation.
• Copy number variations (CNVs) are increasingly recognized as significant contributors to complex diseases.

Purpose of the Study:

• To investigate the association between CNVs and the susceptibility to MS and NMO in a Japanese cohort.
• To identify specific CNV regions implicated in the pathogenesis of these neurological disorders.

Main Methods:

• Genome-wide association analyses were conducted on discovery and replication cohorts comprising MS patients, NMO/NMOSD patients, and healthy controls.
• High-density single nucleotide polymorphism microarrays were utilized to detect CNVs.
• Peripheral blood T-cell subsets were analyzed to assess the somatic acquisition of identified CNVs.

Main Results:

• Deletion-type CNVs were identified primarily in T cell receptor (TCR) gamma and alpha loci.
• A TCR gamma locus deletion was significantly associated with MS (OR=52.6).
• TCR alpha locus deletions showed strong associations with both MS (OR=13.0) and NMO/NMOSD (OR=54.6).
• These CNVs were predominantly found in T-cell subsets, suggesting somatic acquisition.
• NMO/NMOSD patients with CNVs were more likely to be seronegative for anti-aquaporin-4 antibodies or have lower titers.

Conclusions:

• Deletion-type CNVs at specific TCR loci regions are significant risk factors for developing MS and NMO.
• These findings highlight the role of somatic CNVs in autoimmune neurological diseases.
• The identified CNVs may serve as potential biomarkers for disease susceptibility and clinical subtypes.