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

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-Williams; Benjamin M Greenberg; Daniel G MacArthur

doi:10.1038/s41467-018-04332-3

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.

Authors

Karol Estrada¹, Christopher W Whelan^{2

3

4}, Fengmei Zhao⁵, Paola Bronson¹, Robert E Handsaker^{2

3

4}, Chao Sun¹, John P Carulli¹, Tim Harris^{1

6}, Richard M Ransohoff^{7

8}, Steven A McCarroll^{2

3

4}, Aaron G Day-Williams^{1

9}, Benjamin M Greenberg¹⁰, Daniel G MacArthur^{11

12}

Affiliations

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. [email protected].
¹¹ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. [email protected].
¹² Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aquaporin 4 / immunology
DNA Copy Number Variations
Female
Genetic Predisposition to Disease / genetics*
Haplotypes
Humans
Immunoglobulin G / immunology
Major Histocompatibility Complex / genetics
Male
Middle Aged
Neuromyelitis Optica / genetics*
Neuromyelitis Optica / immunology
Polymorphism, Single Nucleotide*
Risk Factors
Whole Genome Sequencing / methods*

Substances

Aquaporin 4
Immunoglobulin G

Grants and funding

R01 HG006855/HG/NHGRI NIH HHS/United States