UC Berkeley

Multiple sclerosis (MS) is a chronic, often disabling disease characterized by neurodegeneration and inflammation. It is the most common non-traumatic neurological disorder among young adults. What triggers MS pathology and symptoms over time remains largely unknown. Evidence suggests genetic and environmental factors contribute to risk of MS and there are at least 230 known genetic risk variants. However, much less is known about the effect of multiple environmental and/or genetic risk factors, which can co-occur in the same individual at the same or different times, on MS risk and clinical manifestations. It is important to consider combinations of risk factors because their joint effects may differ from individual effects. Additionally, it might not be possible to tease apart individual effects from highly inter-related variables, so clustering or other methods should be considered. In this dissertation, I utilize computational, statistical, genomic, and epidemiologic approaches to study the role of combinations of genetic and environmental/behavioral risk factors on MS risk and clinical outcomes in humans. Chapter one introduces MS and background relevant for proceeding chapters. Chapter two shows that individual and clusters of co-occurring gut microbes are associated with new brain lesions on MRI and relapses among individuals with pediatric-onset MS. Chapter three shows that adverse childhood experiences, assessed as individual events and combinations of events, are not associated with MS risk or clinical outcomes in our data. Chapter four suggests that MS and migraine (a common comorbidity of MS) may co-occur because they share several genetic variants. Altogether, this dissertation advances our knowledge of risk factors for MS onset and clinical features of disease and will inform future work of gut microbe, comorbidities, and stress research.