Abstract
Introduction: Neuromyelitis Optica Spectrum Disorder (NMOSD) is a severe autoimmune demyelinating disease of the optic nerves and spinal cord affecting 0.4-4/100,000 individuals worldwide. Recently, an international consensus was reached to harmonize diagnosis criteria of neuroinflammatory diseases. The majority of patients with NMOSD are positive for a specific auto-antibody against the astrocytic aquaporin-4 (AQP4) water channel. A separate entity named MOGAD (MOG antibody-associated disease) groups patients with antibodies directed against the myelin oligodendrocyte glycoprotein (MOG). Two studies explored the genomic signature of NMOSD to date: 215 patients vs. 1244 controls from the USA and 203 patients vs. 1782 controls from Japan. They both found SNPs associated with NMOSD (AQP4) risk around HLA-DRB1 gene. However, only a few MOGAD patients were included in these GWASs, consequently, there is no formal GWAS about MOGAD to date.Objectives/Aims: To identify new genetic associations with NMOSD and MOGAD patients.Methods: DNA from 663 NMOSD and MOGAD patients (French NOMADMUS registry) was extracted and genotyped on the PMRA Affymetrix® Axiom chip (900k SNPs). After careful quality controls, we selected 656 patients with high-confidence genotypes.Results: We analyzed the genetic structure using a principal component analysis (PCA) to determine the ancestry of our patients. We could determine that a majority of our samples were of European ancestry (70%). We restricted our study to this population as other ancestries did not bear enough samples to perform a sufficiently powered analysis. We performed a GWAS comparing these patients to 1544 controls from France. We identified a SNP within the HLA class II genomic region to be significantly associated with NMOSD (AQP4) patients (P=1.1x10-9, OR 3.3) which is in line with previous studies. In addition, we found a novel SNP close to the MAP3K7 gene in chromosome 6 showing a suggestive association with MOGAD patients (P=3.9x10-7, OR 3.1).Conclusion: These preliminary results are very promising; however, additional analyses are needed to better describe these associations. We need to perform SNPs imputation to fine-map the genetic associations. We also need to impute the HLA to pinpoint associated HLA alleles, especially in NMOSD AQP4+ patients. This study is of great importance to better understand the genetic interplay between these neuroinflammatory diseases and find clues about their underlying pathophysiological mechanisms.