Whole Exome sequencing reveals the major genetic contributors to Chinese patients with NMOSD seropositive for AQP4-IgG

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease. Previous evidence implied that genetic factors are involved in its pathogenesis, which is still limited. Methods: Whole exome sequencing (WES) was performed in 228 Chinese NMOSD patients who are seropositive for aquaporine 4 (AQP4)-IgG in the Guangzhou city, South China and a total of 1,400 normal individuals collected in South China. In this cohort, human leukocyte antigen (HLA) subtype of 101 AQP4-IgG positive NMOSD patients and 571 controls was further analysed by HLA sequencing. Results: It indicated a significant associated region on chromosome 6, which is the loci of HLA system, with DQB1, DQA2 and DQA1 displaying intensively significant variation. HLA sequencing confirmed that the most significant genes include DQB1, DRB1, DQA1 and DPA1, and the most significant allele was HLA-DQB1*05:02.Gene based burden analysis using all identified variants demonstrated that the NOP16 gene (FDR 2 ) were significantly related with the disease. IgG1-G390R was also a significantly associated genetic site related to NMOSD. In functional enrichment analyses, identified genes that likely associated with NMOSD were enriched in the nervous and immune related metabolic pathways. Conclusions: In addition to HLA genes, non-HLA genes, such as NOP16 and IgG1-G390R, could also increase disease susceptibility of Chinese patients with NMOSD seropostive for AQP4-IgG