Goris An, Vandebergh Marijne, McCauley Jacob L, Saarela Janna, Cotsapas Chris
KU Leuven, Leuven Brain Institute, Department of Neurosciences, Laboratory for Neuroimmunology, Leuven, Belgium.
KU Leuven, Leuven Brain Institute, Department of Neurosciences, Laboratory for Neuroimmunology, Leuven, Belgium.
Lancet Neurol. 2022 Sep;21(9):830-842. doi: 10.1016/S1474-4422(22)00255-1.
Large-scale mapping studies have identified 236 independent genetic variants associated with an increased risk of multiple sclerosis. However, none of these variants are found exclusively in patients with multiple sclerosis. They are located throughout the genome, including 32 independent variants in the MHC and one on the X chromosome. Most variants are non-coding and seem to act through cell-specific effects on gene expression and splicing. The likely functions of these variants implicate both adaptive and innate immune cells in the pathogenesis of multiple sclerosis, provide pivotal biological insight into the causes and mechanisms of multiple sclerosis, and some of the variants implicated in multiple sclerosis also mediate risk of other autoimmune and inflammatory diseases. Genetics offers an approach to showing causality for environmental factors, through Mendelian randomisation. No single variant is necessary or sufficient to cause multiple sclerosis; instead, each increases total risk in an additive manner. This combined contribution from many genetic factors to disease risk, or polygenicity, has important consequences for how we interpret the epidemiology of multiple sclerosis and how we counsel patients on risk and prognosis. Ongoing efforts are focused on increasing cohort sizes, increasing diversity and detailed characterisation of study populations, and translating these associations into an understanding of the biology of multiple sclerosis.
大规模图谱研究已鉴定出236个与多发性硬化症风险增加相关的独立基因变异。然而，这些变异在多发性硬化症患者中并非独有。它们分布于整个基因组，包括主要组织相容性复合体（MHC）中的32个独立变异和X染色体上的一个变异。大多数变异是非编码的，似乎通过对基因表达和剪接的细胞特异性作用发挥功能。这些变异的可能功能表明，适应性免疫细胞和先天性免疫细胞均参与了多发性硬化症的发病机制，为多发性硬化症的病因和发病机制提供了关键的生物学见解，并且一些与多发性硬化症相关的变异也介导了其他自身免疫性疾病和炎性疾病的风险。遗传学通过孟德尔随机化提供了一种证明环境因素因果关系的方法。没有任何一个单一变异是导致多发性硬化症所必需或足够的；相反，每个变异都以累加的方式增加总体风险。许多遗传因素对疾病风险的这种综合作用，即多基因性，对于我们如何解释多发性硬化症的流行病学以及如何就风险和预后向患者提供咨询具有重要影响。正在进行的工作集中在增加队列规模、提高研究人群的多样性和详细特征描述，以及将这些关联转化为对多发性硬化症生物学的理解。
