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

  • Author(s): Estrada, Karol;
  • Whelan, Christopher W;
  • Zhao, Fengmei;
  • Bronson, Paola;
  • Handsaker, Robert E;
  • Sun, Chao;
  • Carulli, John P;
  • Harris, Tim;
  • Ransohoff, Richard M;
  • McCarroll, Steven A;
  • Day-Williams, Aaron G;
  • Greenberg, Benjamin M;
  • MacArthur, Daniel G
  • et al.
Abstract

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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