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10.18.2019

Creating a Detailed Genetic Map of Multiple Sclerosis

Researchers at the John P. Hussman Institute for Human Genomics, led by Jacob L. McCauley, Ph.D., and Margaret A. Pericak-Vance, Ph.D., have completed a study creating a detailed genetic map of multiple sclerosis. Their study, “Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility,” was recently published in the journal Science.

MS is an inflammatory and degenerative disease of the central nervous system that often presents in young adults. While certain elements of the genetic architecture of susceptibility have gradually emerged, most of the genetic risk for MS has remained unknown. It affects an estimated 400,000 people in the United States alone.

As part of the International Multiple Sclerosis Genetic Consortium, Dr. McCauley, an associate professor in the Dr. John T. Macdonald Foundation Department of Human Genetics and director of the Center for Genome Technology and its biorepository facility at the Hussman Institute, and his colleagues identified 233 sites or loci in the human genome that contribute to the onset of MS.

This is the largest MS study to date and is based on the contribution of genetic material from 47,429 MS patients and 68,374 healthy individuals. The study’s findings confirm earlier results and offer a rich new perspective on the molecular events that lead some people to develop MS: It appears that dysfunction of many different immune cell types, both in the peripheral blood and the brain, contributes to triggering a cascade of events that ultimately leads to brain inflammation and neurodegeneration.

Dr. McCauley and Dr. Pericak-Vance, director of the Hussman Institute and the Dr. John T. Macdonald Foundation Professor of Human Genetics, were joined by corresponding author Dr. Philip De Jager, director of the Multiple Sclerosis Center and the Center for Translational & Computational Neuroimmunology at Columbia University Irving Medical Center; Dr. Nikolaos Patsopoulos, director of the Systems Biology and Computational Science Program at the Ann Romney Center for Neurologic Diseases of Brigham & Women’s Hospital and Harvard Medical School; Dr. Tomas Olson from the Karolinska Institute in Stockholm; and Dr. Adrian Ivinson, chief operating officer of the UK Dementia Research Institute.

They looked closely at available data from human brains to assess whether changes in brain cells contribute to the onset of MS. Until now, it appeared that immune cells found in blood that came from the bone marrow played a critical role; the new study confirms this but also implicates microglia, the immune cells that live in the human brain. However, there is little evidence that other brain cells such as neurons that carry electrical signals in the brain are implicated in triggering MS.

“This enormous international endeavor to identify novel genetic findings in MS is an important next step in understanding the biology of MS,” Dr. McCauley said.

This study is a significant milestone in identifying which genetic variants play a role in triggering MS, but it unfortunately does not clarify why some MS patients have a more severe course than others. The International Multiple Sclerosis Genetic Consortium is pursuing that question in other projects.

The results of this study will impact the development of clinical algorithms to manage people at risk of developing MS and the development of treatments for preventing MS. All current treatments aim to stop the inflammation after it has already started, so the study of MS genetics has opened a unique perspective on the earliest events that lead to the disease and that can now be targeted by drug-development efforts. In South Florida, Dr. McCauley’s team is focusing on the study of genetics within the Hispanic MS patient populations.

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