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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Bove, Riley; Chitnis, Tanuja; Cree, Bruce Ac et al. (2018) SUMMIT (Serially Unified Multicenter Multiple Sclerosis Investigation): creating a repository of deeply phenotyped contemporary multiple sclerosis cohorts. Mult Scler 24:1485-1498
Mack, Steven J; Udell, Julia; Cohen, Franziska et al. (2018) High resolution HLA analysis reveals independent class I haplotypes and amino-acid motifs protective for multiple sclerosis. Genes Immun :
Jia, Xiaoming; Madireddy, Lohith; Caillier, Stacy et al. (2018) Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis. Ann Neurol 84:51-63
Graves, Jennifer S; Henry, Roland G; Cree, Bruce A C et al. (2018) Ovarian aging is associated with gray matter volume and disability in women with MS. Neurology 90:e254-e260
Azevedo, Christina J; Cen, Steven Y; Khadka, Sankalpa et al. (2018) Thalamic atrophy in multiple sclerosis: A magnetic resonance imaging marker of neurodegeneration throughout disease. Ann Neurol 83:223-234
Canto, Ester; Isobe, Noriko; Didonna, Alessandro et al. (2018) Aberrant STAT phosphorylation signaling in peripheral blood mononuclear cells from multiple sclerosis patients. J Neuroinflammation 15:72
Greenfield, Ariele L; Hauser, Stephen L (2018) B-cell Therapy for Multiple Sclerosis: Entering an era. Ann Neurol 83:13-26
Creary, Lisa E; Mallempati, Kalyan C; Gangavarapu, Sridevi et al. (2018) Deconstruction of HLA-DRB1*04:01:01 and HLA-DRB1*15:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis. Mult Scler :1352458518770019
International Multiple Sclerosis Genetics Consortium. Electronic address:; International Multiple Sclerosis Genetics Consortium (2018) Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. Cell 175:1679-1687.e7
Gelfand, Jeffrey M; Cree, Bruce A C; Hauser, Stephen L (2017) Ocrelizumab and Other CD20+ B-Cell-Depleting Therapies in Multiple Sclerosis. Neurotherapeutics 14:835-841

Showing the most recent 10 out of 92 publications