Approved research

Polygenic Prediction of Susceptibility and Progression in Multiple Sclerosis

Lay summary

Multiple sclerosis is a chronic disease of the central nervous system (CNS) that affects more than two million individuals worldwide. It is typically diagnosed between the third and fourth decade of life, occurs more frequently in women than men, and is considered the most common cause of nontraumatic neurological disability in young adults. Although the trigger(s) of MS remains unknown, its pathogenesis is best explained by a multifactorial model that incorporates interactions between genetic, epigenetic, and infectious, nutritional, climatic, or other environmental influences. This array of factors results in the loss of immune homeostasis and self-tolerance, manifested in brain and spinal cord infiltration by activated peripheral mononuclear cells and the development of unregulated pathologic inflammatory responses against structural components of the CNS. The central goal of our project is to identify and characterize major genetic factors that modulate disease risk and presentation in MS. MS is a complex disease whose understanding has been transformed by advances in molecular genetics. A number of breakthrough discoveries in the past decade, have set the stage for an upgraded model of disease pathogenesis and progression. Deciphering the MS clinical features represents the next frontier of genetic research, as understanding functional roles of known and novel genes in the course of MS can reveal fundamental disease mechanisms and provide insights into new therapeutic opportunities and much-needed biomarker for diagnosis and tracking of disease activity over time. In this application, we propose a year-long project to interrogate unique UK Biobank and IMSGC patient cohorts with novel analytical approaches to characterize underlying genetic architecture of MS risk and progression.