Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disorder affecting more than 400,000 individuals in the United States. Epidemiological and genetic studies have produced overwhelming evidence for a genetic influence on the risk of MS. While the first confirmed MS genetic association (with the HLA-DRB1*1501 allele) was identified in the early 1970's, additional success was not forthcoming using the then available molecular and statistical tools. In 2007, and as a direct result of the current funding, we identified the first new genetic association in MS in over 30 years;we demonstrated that a common non-synonymous functional SNP in the IL7RA gene was associated with an increased risk of MS. Since making this discovery, we and others have identified and confirmed associations to several other genes, including IL2RA, CLEC16A, CD58, TYK2, TNFRSF1A, IRF8, CD6, and CD226. However, there are very significant genetic questions that remain unanswered in MS. First, these genes explain only a small fraction of the overall genetic influence on MS. Numerous additional genes of modest yet important effect remain to be found. Second, all this work has assumed the common-disease/common-variant hypothesis, which we contend is only part of the story. Detailed examination for rarer variants of stronger effect in both the nuclear and mitochondrial genomes has yet to be performed and may well explain a measurable proportion of the genetic influence on MS. We are in an excellent position to further examine the genetic role in both severity and type of progression of MS.
Our specific aims are to: 1). Confirm additional important genes in the IL7RA pathway;2). Confirm additional important genes identified in the top 5% of SNPs from the original MS GWAS analysis;3). Identify all variants in the confirmed non-MHC genes (currently IL7RA, IL2RA, CLEC16A, CD58, CD226) using high-throughput sequencing techniques. We will take advantage of our unique large multiplex family dataset to sequence MS cases most likely to carry rare variants of strong effect.

Public Health Relevance

Multiple sclerosis is a neurological autoimmune disorder that has a significant genetic component. To dissect this genetic architecture, we propose to extend our recent findings relative to IL7RA to test other genes in the IL7R pathway, and to test alternative and complementary hypotheses that rare variants and mitochondrial variation are important contributors to MS risk.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurological, Aging and Musculoskeletal Epidemiology (NAME)
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Utz, Ursula
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Vanderbilt University Medical Center
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Mosley, Jonathan D; Feng, QiPing; Wells, Quinn S et al. (2018) A study paradigm integrating prospective epidemiologic cohorts and electronic health records to identify disease biomarkers. Nat Commun 9:3522
Gamazon, Eric R; Segrè, Ayellet V; van de Bunt, Martijn et al. (2018) Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation. Nat Genet 50:956-967
Moutsianas, Loukas; Jostins, Luke; Beecham, Ashley H et al. (2015) Class II HLA interactions modulate genetic risk for multiple sclerosis. Nat Genet 47:1107-1113
Davis, Mary F; Haines, Jonathan L (2015) The intelligent use and clinical benefits of electronic medical records in multiple sclerosis. Expert Rev Clin Immunol 11:205-11
Bailey, Jessica N Cooke; Pericak-Vance, Margaret A; Haines, Jonathan L (2014) The impact of the human genome project on complex disease. Genes (Basel) 5:518-35
Bush, William S; Haines, Jonathan L (2014) Genotype Correlation Analysis Reveals Pathway-Based Functional Disequilibrium and Potential Epistasis in the Human Interactome. Appl Evol Comput (2014) 8602:890-901
International Multiple Sclerosis Genetics Consortium (IMSGC); Beecham, Ashley H; Patsopoulos, Nikolaos A et al. (2013) Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 45:1353-60
Zuvich, Rebecca L; Bush, William S; McCauley, Jacob L et al. (2011) Interrogating the complex role of chromosome 16p13.13 in multiple sclerosis susceptibility: independent genetic signals in the CIITA-CLEC16A-SOCS1 gene complex. Hum Mol Genet 20:3517-24
Yaspan, Brian L; Bush, William S; Torstenson, Eric S et al. (2011) Genetic analysis of biological pathway data through genomic randomization. Hum Genet 129:563-71
International Multiple Sclerosis Genetics Consortium (2011) Genome-wide association study of severity in multiple sclerosis. Genes Immun 12:615-25

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