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We review current thinking on the aetiology of multiple sclerosis, how genetic susceptibility interacts with environmental risk factors at the population level, multiple sclerosis-associated risk factors and contemporary causation theory.Two large genomic studies have confirmed the unambiguous associations with the DRB1 and DQB alleles of the human leucocyte antigen class II region. No other region with genome-wide significance has been identified. Family-based genetic epidemiological approaches have found no evidence of nongenetic transmissibility. This indicates that the action of the environment in influencing multiple sclerosis risk is operative at a macroenvironmental or population level, and not within families or the microenvironment. Environmental factors receiving renewed attention include vitamin D status, Epstein–Barr virus infection and smoking. Bradford Hill's criteria for causation have been modified and should be adopted as a framework for demonstrating causation in relationship to multiple sclerosis.Multiple sclerosis is a complex disease because of interaction between genes and the environment. Any theory of causation for a specific agent will have to be congruent with the biology of the disease.