Multiple sclerosis (MS) is a common and severe disorder of the central nervous system characterized by chronic inflammation, myelin loss, gliosis, varying degrees of axonal and oligodendrocyte pathology, and progressive neurological dysfunction. MS pathogenesis includes a complex genetic component. In spite of intensive long-standing efforts, the knowledge of MS genetics remains incomplete. Our overall objective is to characterize the repertoire of genes that predispose to MS and modulate its presentation. Their identification is now possible as a result of rapid progress in defining the landscape of genetic organization and cataloging variation across the human genome. This proposal builds on the availability of new, high-quality genome-wide association results and comprehensive phenotypic data in a large longitudinal MS cohort. We propose three main research goals:
Specific Aim 1 describes a 1,000 cases/1,000 controls high-resolution genome-wide association screen, together with a multi-analytical approach to map unambiguous association signals from sequence and copy number polymorphisms, leading to testable hypotheses as to which are the specific allelic variants conferring susceptibility. In addition, confirmed disease SNPs will be tested in a multi-case familial dataset to determine the minimal combination of genes that differentiate affected and unaffected family members. Data will be analyzed to model the relative contribution of the confirmed allelic variants in susceptibility.
Specific Aim 2 takes advantage of the wealth of phenotypic data available for the different datasets to assess disease course, clinical variables, and correlations to genotype. Cross-sectional and longitudinal clinical data, such as age and site of disease onset, disability at entry of study and progression, treatment, and changes in lesion distribution and burden will be incorporated into the analysis of genetic data.
This aim directly addresses the question of clinical heterogeneity in MS and the correlation between different phenotypes and genotypes. The availability of a large and well-characterized cohort as described here, coupled with the aid of high-powered laboratory technologies, provides an outstanding opportunity to identify and characterize MS-related genes. This information may reveal novel targets for therapy.

Public Health Relevance

Multiple sclerosis (MS), the prototypic demyelinating disease in humans, is a common cause of neurological dysfunction arising from early to middle adulthood. No curative therapy is currently available and approximately 90% of afflicted individuals are ultimately disabled. The socioeconomic consequences of this long-lasting disease are staggering as 75-85% of patients are eventually unemployed and at high risk for social isolation. MS is the second most costly neurological disorder after Alzheimer's disease. We aim to map genes that code for products involved in MS susceptibility. We anticipate that there may be several genes involved in MS. These genes may work independently or together, and affect susceptibility in concert with environmental factors. Particular combinations of inherited genes may also determine when symptoms develop, or how the disease progresses. Their identification will help to define the basic etiology of MS, improve risk assessment, and influence therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS026799-23
Application #
8259698
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
1988-12-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
23
Fiscal Year
2012
Total Cost
$331,209
Indirect Cost
$116,834
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Palanichamy, Arumugam; Jahn, Sarah; Nickles, Dorothee et al. (2014) Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J Immunol 193:580-6
Bankoti, Jaishree; Apeltsin, Leonard; Hauser, Stephen L et al. (2014) In multiple sclerosis, oligoclonal bands connect to peripheral B-cell responses. Ann Neurol 75:266-76
Schlaeger, Regina; Papinutto, Nico; Panara, Valentina et al. (2014) Spinal cord gray matter atrophy correlates with multiple sclerosis disability. Ann Neurol 76:568-80
Baranzini, Sergio E (2014) The role of antiproliferative gene Tob1 in the immune system. Clin Exp Neuroimmunol 5:132-136
Harbo, Hanne F; Isobe, Noriko; Berg-Hansen, Pal et al. (2014) Oligoclonal bands and age at onset correlate with genetic risk score in multiple sclerosis. Mult Scler 20:660-8
Ban, Maria; Caillier, Stacy; Mero, Inger-Lise et al. (2013) No evidence of association between mutant alleles of the CYP27B1 gene and multiple sclerosis. Ann Neurol 73:430-2
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
Schulze-Topphoff, Ulf; Casazza, Simona; Varrin-Doyer, Michel et al. (2013) Tob1 plays a critical role in the activation of encephalitogenic T cells in CNS autoimmunity. J Exp Med 210:1301-9
Isobe, N; Damotte, V; Lo Re, V et al. (2013) Genetic burden in multiple sclerosis families. Genes Immun 14:434-40
Gourraud, Pierre-Antoine; Sdika, Michael; Khankhanian, Pouya et al. (2013) A genome-wide association study of brain lesion distribution in multiple sclerosis. Brain 136:1012-24

Showing the most recent 10 out of 58 publications