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A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica.

Nat Commun. 2018 May 16;9(1):1929. doi: 10.1038/s41467-018-04332-3.

Estrada K1, Whelan CW2,3,4, Zhao F5, Bronson P1, Handsaker RE2,3,4, Sun C1, Carulli JP1, Harris T1,6, Ransohoff RM7,8, McCarroll SA2,3,4, Day-Williams AG1,9, Greenberg BM10, MacArthur DG11,12.


Neuromyelitis optica (NMO) is a rare autoimmune disease that affects the optic nerve and spinal cord. Most NMO patients ( > 70%) are seropositive for circulating autoantibodies against aquaporin 4 (NMO-IgG+). Here, we meta-analyze whole-genome sequences from 86 NMO cases and 460 controls with genome-wide SNP array from 129 NMO cases and 784 controls to test for association with SNPs and copy number variation (total N = 215 NMO cases, 1244 controls). We identify two independent signals in the major histocompatibility complex (MHC) region associated with NMO-IgG+, one of which may be explained by structural variation in the complement component 4 genes. Mendelian Randomization analysis reveals a significant causal effect of known systemic lupus erythematosus (SLE), but not multiple sclerosis (MS), risk variants in NMO-IgG+. Our results suggest that genetic variants in the MHC region contribute to the etiology of NMO-IgG+ and that NMO-IgG+ is genetically more similar to SLE than MS.

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