 A recent study has provided insight into the genetics underlying the risk of developing multiple sclerosis, a debilitating neurological disease with no known cause or cure. Knowledge of how the disease risk is affected by genetics may improve our understanding of the biology of MS, which might ultimately have implications for MS diagnosis and treatment. The risk of developing MS is known to be influenced by variation within a set of genes coding for human leukocyte antigens, or HLA's, which are used by the immune system to distinguish the body's own cells from infected or foreign cells. Specific HLA variants can either increase or decrease the risk of MS. However, for MS as well as other diseases influenced by multiple genes, important questions remain, including whether genetic risk is determined by additive effects or driven by complex interactions between risk variants. In the particular case of MS, although HLA genes are known to affect risk, it is also unclear whether HLA variants interact with non-HLA risk variants to influence MS risk. The new study examined HLA gene variants in tens of thousands of European MS patients. Certain HLA genetic variants were associated with an elevated risk of MS. These variants were consistently of the HLA subtype that generally plays a role in detecting pathogens and other foreign material outside a cell, known as Class II. In sharp contrast, a subset of variants of the HLA subtype that typically helps to detect foreign material inside a cell, known as Class I, protected against MS. These results confirmed both known and suggested associations between HLA variants and MS, and also revealed novel associations. In British patients in particular, two genetic interactions between Class II HLA variants were identified. In each case, one variant reduced or abolished the increased MS risk associated with a second variant. These interactions were the only two cases of Class II HLA variants decreasing the risk of the disease, and they indicate that the variants had non-additive effects on the likelihood of developing MS. HLA genes and non-HLA genes associated with MS risk instead had additive effects, with no apparent interactions. This work has implications for understanding MS. The HLA genes play a key role in the immune system in general and in MS risk specifically, with greater effects than for non-HLA genes. HLA variants thus provide unique clues for further research into how this disease develops. More specifically, if researchers can understand how Class I HLA variants reduce MS risk, or how Class II HLA interactions mitigate the risk of certain variants, they may discover new ways to improve the diagnosis of MS, and even new ways to treat the disease.