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Cell Type Specificity of Intralocus Interactions Reveals Oligodendrocyte Intrinsic Mechanisms For Multiple Sclerosis

37 Pages Posted: 16 Sep 2019 Sneak Peek Status: Review Complete

See all articles by Daniel C. Factor

Daniel C. Factor

Case Western Reserve University - Department of Genetics and Genome Sciences

Anna M. Barbeau

Whitehead Institute for Biomedical Research

Mayur Madhavan

Case Western Reserve University - Department of Genetics and Genome Sciences

Sagar Nisraiyya

Whitehead Institute for Biomedical Research

Parker A. Hall

Massachusetts Institute of Technology (MIT) - Whitehead Institute for Biomedical Research

Fadi J. Najm

Case Western Reserve University - Department of Genetics and Genome Sciences

Tyler E. Miller

Case Western Reserve University - Department of Genetics and Genome Sciences

Zachary S. Nevin

Case Western Reserve University - Department of Genetics and Genome Sciences

Robert Karl

Case Western Reserve University - Department of Genetics and Genome Sciences

Bruna R. Lima

Whitehead Institute for Biomedical Research

Kathryn E.A. Hazel

Whitehead Institute for Biomedical Research

An T. Hoang

Whitehead Institute for Biomedical Research

Gursimran K. Dhillon

Case Western Reserve University - Department of Genetics and Genome Sciences

Christina Volsko

Cleveland Clinic - Department of Neurosciences

Cynthia F. Bartels

Case Western Reserve University - Department of Genetics and Genome Sciences

Drew J. Adams

Case Western Reserve University - Department of Genetics and Genome Sciences

Ranjan Dutta

Cleveland Clinic - Department of Neurosciences

Alexey Kozlenkov

James J. Peters Veterans Affairs Medical Center

Stella Dracheva

James J. Peters Veterans Affairs Medical Center

Peter Scacheri

Case Western Reserve University - Department of Genetics and Genome Sciences

Paul Tesar

Case Western Reserve University - Department of Genetics and Genome Sciences

Olivia Corradin

Whitehead Institute for Biomedical Research

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Abstract

Multiple sclerosis (MS) is an autoimmune disease characterized by attack on oligodendrocytes within the central nervous system (CNS). Despite widespread use of immunomodulatory therapies, patients face progressive disability due to failure of myelin regeneration and loss of neurons, suggesting additional cellular pathologies. Here, we describe a general approach for identifying specific cell types in which a disease allele exerts a pathogenic effect.  Applying this approach to MS risk loci, we pinpoint likely pathogenic cell types for 70%. In addition to T cell loci, we unexpectedly identified myeloid and CNS-specific risk loci, including two sites that dysregulate transcriptional pause release in oligodendrocytes. Functional studies demonstrated inhibition of transcriptional elongation is a dominant pathway blocking oligodendrocyte maturation. Furthermore, pause release factors are frequently dysregulated in MS brain tissue and are associated with white matter microstructure. These data implicate cell-intrinsic aberrations outside of the immune system and suggest new avenues for therapeutic development.

Keywords: genetics, Multiple sclerosis, oligodendrocytes, GWAS, dissecting risk loci, computational methods, statistical genetics

Suggested Citation

Factor, Daniel C. and Barbeau, Anna M. and Madhavan, Mayur and Nisraiyya, Sagar and Hall, Parker A. and Najm, Fadi J. and Miller, Tyler E. and Nevin, Zachary S. and Karl, Robert and Lima, Bruna R. and Hazel, Kathryn E.A. and Hoang, An T. and Dhillon, Gursimran K. and Volsko, Christina and Bartels, Cynthia F. and Adams, Drew J. and Dutta, Ranjan and Kozlenkov, Alexey and Dracheva, Stella and Scacheri, Peter and Tesar, Paul and Corradin, Olivia, Cell Type Specificity of Intralocus Interactions Reveals Oligodendrocyte Intrinsic Mechanisms For Multiple Sclerosis (September 13, 2019). CELL-D-19-02520. Available at SSRN: https://ssrn.com/abstract=3453290 or http://dx.doi.org/10.2139/ssrn.3453290
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Daniel C. Factor

Case Western Reserve University - Department of Genetics and Genome Sciences

2511 Overlook Road
Cleveland Heights, OH
United States

Anna M. Barbeau

Whitehead Institute for Biomedical Research

455 Main Street
Cambridge, MA 02142
United States

Mayur Madhavan

Case Western Reserve University - Department of Genetics and Genome Sciences

2511 Overlook Road
Cleveland Heights, OH
United States

Sagar Nisraiyya

Whitehead Institute for Biomedical Research

455 Main Street
Cambridge, MA 02142
United States

Parker A. Hall

Massachusetts Institute of Technology (MIT) - Whitehead Institute for Biomedical Research

455 Main Street
Cambridge, MA 02142
United States

Fadi J. Najm

Case Western Reserve University - Department of Genetics and Genome Sciences

2511 Overlook Road
Cleveland Heights, OH
United States

Tyler E. Miller

Case Western Reserve University - Department of Genetics and Genome Sciences

2511 Overlook Road
Cleveland Heights, OH
United States

Zachary S. Nevin

Case Western Reserve University - Department of Genetics and Genome Sciences

2511 Overlook Road
Cleveland Heights, OH
United States

Robert Karl

Case Western Reserve University - Department of Genetics and Genome Sciences ( email )

2511 Overlook Road
Cleveland Heights, OH
United States

Bruna R. Lima

Whitehead Institute for Biomedical Research

455 Main Street
Cambridge, MA 02142
United States

Kathryn E.A. Hazel

Whitehead Institute for Biomedical Research

455 Main Street
Cambridge, MA 02142
United States

An T. Hoang

Whitehead Institute for Biomedical Research

455 Main Street
Cambridge, MA 02142
United States

Gursimran K. Dhillon

Case Western Reserve University - Department of Genetics and Genome Sciences

2511 Overlook Road
Cleveland Heights, OH
United States

Christina Volsko

Cleveland Clinic - Department of Neurosciences

Cleveland, OH
United States

Cynthia F. Bartels

Case Western Reserve University - Department of Genetics and Genome Sciences

2511 Overlook Road
Cleveland Heights, OH
United States

Drew J. Adams

Case Western Reserve University - Department of Genetics and Genome Sciences

2511 Overlook Road
Cleveland Heights, OH
United States

Ranjan Dutta

Cleveland Clinic - Department of Neurosciences ( email )

Cleveland, OH
United States

Alexey Kozlenkov

James J. Peters Veterans Affairs Medical Center

Bronx, NY
United States

Stella Dracheva

James J. Peters Veterans Affairs Medical Center

Bronx, NY
United States

Peter Scacheri

Case Western Reserve University - Department of Genetics and Genome Sciences ( email )

2511 Overlook Road
Cleveland Heights, OH
United States

Paul Tesar

Case Western Reserve University - Department of Genetics and Genome Sciences

2511 Overlook Road
Cleveland Heights, OH
United States

Olivia Corradin (Contact Author)

Whitehead Institute for Biomedical Research ( email )

455 Main Street
Cambridge, MA 02142
United States

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