TY - JOUR
T1 - A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica
AU - Estrada, Karol
AU - Whelan, Christopher W.
AU - Zhao, Fengmei
AU - Bronson, Paola
AU - Handsaker, Robert E.
AU - Sun, Chao
AU - Carulli, John P.
AU - Harris, Tim
AU - Ransohoff, Richard M.
AU - McCarroll, Steven A.
AU - Day-Williams, Aaron G.
AU - Greenberg, Benjamin M.
AU - MacArthur, Daniel G.
N1 - Funding Information:
We thank Nolan Kamitaki and Giulio Genovese for relevant discussion and ideas for this manuscript. Sequencing and genotyping was sponsored by Biogen, Inc. Funding to support specimen collection was provided by The University of Texas Southwestern CONQUER Project, The Accelerated Cure Project and The Guthy Jackson Charitable Foundation for NMO. Work on C4 by C.W.W. and R.E.H. in S.A.M.’s lab was supported by the National Human Genome Research Institute (R01 HG006855, to S.A.M.).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-018-04332-3
DO - 10.1038/s41467-018-04332-3
M3 - Article
C2 - 29769526
AN - SCOPUS:85047086528
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1929
ER -