The role of body fat in multiple sclerosis susceptibility and severity: A Mendelian randomisation study

Objective: The objective of this study was to explore the potential causal associations of body mass index, height, weight, fat mass, fat percentage and non-fat mass in the whole body, arms, legs and trunk (henceforth, ‘anthropometric measures’) with multiple sclerosis (MS) risk and severity. We also investigated the potential for reverse causation between anthropometric measures and MS risk. Methods: We conducted a two-sample univariable, multivariable and bidirectional Mendelian randomisation (MR) analysis. Results: A range of features linked to obesity (body mass index, weight, fat mass and fat percentage) were risk factors for MS development and worsened the disease’s severity in MS patients. Interestingly, we were able to demonstrate that height and non-fat mass have no association with MS risk or MS severity. We demonstrated that the association between anthropometric measures and MS is not subject to bias from reverse causation. Conclusions: Our findings provide evidence from human genetics that a range of features linked to obesity is an important contributor to MS development and MS severity, but height and non-fat mass are not. Importantly, these findings also identify a potentially modifiable factor that may reduce the accumulation of further disability and ameliorate MS severity.