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

• Published in: Nature communications 2018-05, Vol.9 (1), p.1929-10, Article 1929
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: 45; 45/23; 631/208/205/2138; 631/250/371; 692/699/249/1313; 692/699/375/1411; Adult; Aquaporin 4; Aquaporin 4 - immunology; Autoantibodies; Autoimmune diseases; Chronic conditions; Copy number; DNA Copy Number Variations; Etiology; Female; Gene sequencing; Genetic diversity; Genetic Predisposition to Disease - genetics; Genetic variance; Genomes; Haplotypes; Humanities and Social Sciences; Humans; Immunoglobulin G; Immunoglobulin G - immunology; Major histocompatibility complex; Major Histocompatibility Complex - genetics; Male; Middle Aged; multidisciplinary; Multiple sclerosis; Neuromyelitis; Neuromyelitis Optica - genetics; Neuromyelitis Optica - immunology; Nucleotide sequence; Optic nerve; Polymorphism, Single Nucleotide; Risk analysis; Risk Factors; Science; Science (multidisciplinary); Single-nucleotide polymorphism; Spinal cord; Systemic lupus erythematosus; Whole Genome Sequencing - methods
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04332-3

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. Neuromyelitis optica (NMO) is a rare autoimmune condition characterized by inflammation and demyelination of the optic nerve and the spinal cord. Here, Estrada et al. identify NMO susceptibility variants in the MHC region and find that autoantibody-positive NMO genetically overlaps with lupus.