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

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

Author information

1
Translational Genome Sciences, Biogen, Cambridge, MA, 02142, USA.
2
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
3
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
4
Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
5
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA.
6
Bioverativ, Waltham, MA, 02451, USA.
7
Neuroimmunology, Acute Neurology and Pain, Biogen, Cambridge, MA, 02142, USA.
8
Third Rock Ventures, Boston, MA, 02116, USA.
9
Genetics and Pharmacogenomics, Merck, Boston, MA, 02115, USA.
10
Department of Neurology and Neurotherapeutics, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. Benjamin.greenberg@utsouthwestern.edu.
11
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. danmac@broadinstitute.org.
12
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA. danmac@broadinstitute.org.

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.

PMID:
29769526
PMCID:
PMC5955905
DOI:
10.1038/s41467-018-04332-3
[Indexed for MEDLINE]
Free PMC Article

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