The Largest Genomics Study of NMO in History: Whole Genome Sequencing of 150 Patients with Neuromyelitis Optica (P4.007)

Objective: The objective of this study was to analyze a large number of NMO patients and controls with whole genome sequencing and determine if there was any evidence of a mendelian inheritance pattern. Background: Neuromyelitis optica is an autoimmune disorder commonly characterized by autoantibodies directed against aquaporin 4. A few studies have identified HLA associations, but these genetic studies have been limited to SNP analyses. Design/Methods: 150 DNA samples from NMO patients and 10 samples from the parents of 5 NMO patients were submitted for whole genome sequencing. Genomes were sequenced to at least 30X coverage using Illumina short read technology. Read data were aligned and variants called using the CASAVA1.8.2 pipeline. For gene definition we used ENSEMBL (Release 68) gene models. Variants were annotated for novelty and frequency relative to HapMap3, and missense mutations were analyzed for functional impact using the combined SIFT/PolyPhen2 module of Condel. HLA types were determined from genome sequences using Omixon software (http://www.omixon.com/hla). Results: Data from the whole genome sequencing confirmed prior studies examining the association with certain HLA types. Specifically, 38% of seropositive NMO patients had DQB*03:01 alleles. 32 of seronegative patients had DRB1*03:01 alleles. No specific mutations were identified in AQP4 genes. Conclusions: NMO patients have different HLA restrictions based on serostatus. There were no specific mutations in AQP4 genes. This is the largest genetic study of NMO in history. Study Supported by Biogen Idec. Samples were provided by the Accelerated Cure Project with some costs of sample acquisition provided by the Guthy Jackson Foundation Disclosure: Dr. Greenberg has received personal compensation for activities with Chugai, GlaxoSmithKline, Inc., Sanofi-Aventis, Diogenix, Biogen Idec, Amplimmune, Acorda, and MSAA. Dr. Greenberg has received personal compensation in an editorial capacity for JAMA Neurology. Dr. Greenberg holds stock and/or stock options in DioGenix, Inc, which sponsored research in which Dr. Greenberg was involved as an investigator. Dr. Greenberg has received research support from Guthy-Jackson Charitable Foundation, Accelerated Cure Project, and Biogen Idec. Dr. Kerr has received personal compensation for activities with Biogen Idec as an employee. Dr. Kerr holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Kerr was involved as an investigator. Dr. Harris has nothing to disclose. Dr. Day-Williams has nothing to disclose. Dr. Carulli has received personal compensation for activities with Biogen Idec as an employee.