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

Author

Listed:
  • Karol Estrada

    (Translational Genome Sciences, Biogen)

  • Christopher W. Whelan

    (Broad Institute of Harvard and MIT
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Fengmei Zhao

    (Massachusetts General Hospital)

  • Paola Bronson

    (Translational Genome Sciences, Biogen)

  • Robert E. Handsaker

    (Broad Institute of Harvard and MIT
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Chao Sun

    (Translational Genome Sciences, Biogen)

  • John P. Carulli

    (Translational Genome Sciences, Biogen)

  • Tim Harris

    (Translational Genome Sciences, Biogen
    Bioverativ)

  • Richard M. Ransohoff

    (Acute Neurology and Pain, Biogen
    Third Rock Ventures)

  • Steven A. McCarroll

    (Broad Institute of Harvard and MIT
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Aaron G. Day-Williams

    (Translational Genome Sciences, Biogen
    Genetics and Pharmacogenomics, Merck)

  • Benjamin M. Greenberg

    (University of Texas Southwestern Medical Center)

  • Daniel G. MacArthur

    (Broad Institute of Harvard and MIT
    Massachusetts General Hospital)

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.

Suggested Citation

  • Karol Estrada & Christopher W. Whelan & Fengmei Zhao & Paola Bronson & Robert E. Handsaker & Chao Sun & John P. Carulli & Tim Harris & Richard M. Ransohoff & Steven A. McCarroll & Aaron G. Day-William, 2018. "A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04332-3
    DOI: 10.1038/s41467-018-04332-3
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