Multi-Level Analyses of Genome-Wide Association Study to Reveal Significant Risk Genes and Pathways in Neuromyelitis Optica Spectrum Disorder

Abstract

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system and it is understandable that environmental and genetic factors underlie the etiology of NMOSD. However, the susceptibility genes and associated pathways of NMOSD patients who are AQP4-Ab positive and negative have not been elucidated.MethodsSecondary analysis from a NMOSD Genome-wide association study (GWAS) dataset originally published in 2018 (215 NMOSD cases and 1244 controls) was conducted to identify potential susceptibility genes and associated pathways in AQP4-positive and negative NMOSD patients, respectively (132 AQP4-positive and 83 AQP4-negative).ResultsIn AQP4-positive NMOSD cases, five shared risk genes were obtained at chromosome 6 in AQP4-positive NMOSD cases by using more stringent p-Values in both methods (p < 0.05/16,532), comprising CFB, EHMT2, HLA-DQA1, MSH5, and SLC44A4. Fifty potential susceptibility gene sets were determined and 12 significant KEGG pathways were identified. Sixty-seven biological process pathways, 32 cellular-component pathways, and 29 molecular-function pathways with a p-Value of <0.05 were obtained from the GO annotations of the 128 pathways identified. In the AQP4 negative NMOSD group, no significant genes were obtained by using more stringent p-Values in both methods (p < 0.05/16,485). The 22 potential susceptibility gene sets were determined. There were no shared potential susceptibility genes between the AQP4-positive and negative groups, furthermore, four significant KEGG pathways were also identified. Of the GO annotations of the 165 pathways identified, 99 biological process pathways, 37 cellular-component pathways, and 29 molecular-function pathways with a p-Value of <0.05 were obtained.ConclusionThe potential molecular mechanism underlying NMOSD may be related to proteins encoded by these novel genes in complements, antigen presentation, and immune regulation. The new results may represent an improved comprehension of the genetic and molecular mechanisms underlying NMOSD.

Rare variants and HLA haplotypes associated in patients with neuromyelitis optica spectrum disorders

“…None of the variants we identified overlapped with the variants detected in the re-analysis of the Estrada et al. data ( 47 , 48 ), or of a separate association study on a group of Japanese patients ( 49 ). However, the latter study identified a variant in the gene encoding a voltage gated potassium channel, KCNMA1, as increasing susceptibility to NMOSD ( 49 ).…”

“…The identification of variants in complement genes, including pathogenic mutations, in the NMOSD patient population supports a role for the complement cascade in the pathogenesis of this disease. None of the variants we identified overlapped with the variants detected in the re-analysis of the Estrada et al data (47,48), or of a separate association study on a group of Japanese patients (49). However, the latter study identified a variant in the gene encoding a voltage gated potassium channel, KCNMA1, as increasing susceptibility to NMOSD (49).…”

“…Genetic associations of NMOSD with alleles outside the HLA region are only starting to be explored. Genome wide association studies (GWAS) of NMOSD (43)(44)(45)(46) have shown an association with single nucleotide polymorphisms (SNPs) located near genes encoding complement proteins and several candidate genes involved in NMOSD, including a potassium channel gene, KCMA1 (47)(48)(49).…”

Neuromyelitis Optica Spectrum Disorder: From Basic Research to Clinical Perspectives

“…In summary, the potential molecular mechanisms underlying AQP4-seropositive NMOSD may be related to proteins encoded by the novel genes involved in complement activation, antigen presentation, antibody-dependent cytotoxicity, and immune regulation [ 103 ].…”

Genetics behind Cerebral Disease with Ocular Comorbidity: Finding Parallels between the Brain and Eye Molecular Pathology

“…Subsequent astrocyte cytotoxicity caused by inflammatory events, such as granulocyte infiltration or macrophage infiltration [ 436 ], leads to the loss of AQP4 and the astrocyte marker glial fibrillary acidic protein (GFAP) as well as the disruption of the blood–brain barrier (BBB), followed by oligodendrocyte and neuronal cell death. Therefore, SNPs in AQP4 [ 156 ] or T cell marker genes (such as CD58 [ 159 , 162 , 163 , 164 ], CD127 [ 165 ], CD226 [ 166 ], and NECL2 [ 155 ]) and susceptible loci related to complement system (such as CFB [ 149 ] and C4B [ 175 ]) or NK cell markers (such as PRF1 [ 151 ]) can be associated with susceptibility to NMOSD.…”