Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility
Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility
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DOI：
10.1126/science.aav7188
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发表时间：
2019-09-27
期刊：
影响因子：
56.9
通讯作者：
De Jager, Philip L.
中科院分区：
文献类型：
--
作者：
Patsopoulos, Nikolas A.;Baranzini, Sergio E.;De Jager, Philip L.
多发性硬化症（MS）是一种中枢神经系统（CNS）的炎症和退行性疾病，常发生于年轻人。在过去的十年中，易感性的遗传结构的某些元素已经逐渐出现，但大多数遗传风险的MS仍然是未知的。理由MS遗传图谱的早期版本已经强调了免疫系统的适应性臂的作用，涉及多种不同的T细胞亚群。我们通过对47,429例MS病例和68,374例对照受试者的基因型数据进行MS遗传关联研究，扩展了我们对MS易感性的认识。我们通过对我们发现的易感性变异的功能影响进行深入和全面的评估来增强这一分析。我们确定了233个与MS易感性具有统计学独立性的关联，这些关联在全基因组范围内具有显著性。主要组织相容性复合体（MHC）包含32个这样的关联，其中一个是性染色体上的第一个MS位点，位于X染色体上。剩下的200个关联在常染色体非MHC基因组中发现。我们的全基因组分区方法和大规模复制工作允许评估不符合我们严格的显著性阈值的其他变体，例如416个具有统计学复制证据但未达到全基因组统计学显著性水平的变体。这些基因座中有许多可能是真正的易感基因座。全基因组和暗示效应共同解释了MS的估计遗传力的~48%。使用基因表达模式和表观基因组特征的图谱，我们记录了MS易感基因座的富集在许多不同的免疫细胞类型和组织中是明显的，而在组织水平的大脑概况中没有富集。我们通过分析由人诱导多能干细胞衍生的神经元以及纯化的原代人星形胶质细胞和小胶质细胞产生的新数据来扩展注释分析，观察到在人类小胶质细胞（大脑的常驻免疫细胞）中观察到MS基因的富集，但不是在星形胶质细胞或神经元中。此外，我们已经通过鉴定那些影响免疫细胞或大脑中附近基因表达的变体来表征许多MS易感性变体的功能后果。最后，我们应用了一套方法来优先考虑551个推定的MS易感基因，这些基因可能是满足全基因组意义阈值的MS变体的靶基因。MS易感基因的这一广泛列表将我们的知识扩展了两倍以上，并突出了与可能导致MS发作的B、T、自然杀伤细胞和骨髓细胞的发育、成熟和终末分化相关的过程。这些分析将我们的注意力集中在许多不同的细胞上，其中MS变体的功能应进一步研究。这些MS基因还可以组装成13个编码蛋白质的基因群落，这些蛋白质相互作用;这种更高级的结构开始组装易感性变体组，其功能结果可能集中在某些蛋白质复合物上，所述蛋白质复合物可以优先作为MS预防策略的靶进行进一步评估。结论我们报道了MS易感性的详细遗传和基因组图谱，这几乎解释了这种疾病一半的遗传性。我们强调了外周和大脑常驻免疫系统的几个细胞的重要性，涉及适应性和先天性武器，在…
INTRODUCTIONMultiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system (CNS) that often presents in young adults. Over the past decade, certain elements of the genetic architecture of susceptibility have gradually emerged, but most of the genetic risk for MS remained unknown.RATIONALEEarlier versions of the MS genetic map had highlighted the role of the adaptive arm of the immune system, implicating multiple different T cell subsets. We expanded our knowledge of MS susceptibility by performing a genetic association study in MS that leveraged genotype data from 47,429 MS cases and 68,374 control subjects. We enhanced this analysis with an in-depth and comprehensive evaluation of the functional impact of the susceptibility variants that we uncovered.RESULTSWe identified 233 statistically independent associations with MS susceptibility that are genome-wide significant. The major histocompatibility complex (MHC) contains 32 of these associations, and one, the first MS locus on a sex chromosome, is found in chromosome X. The remaining 200 associations are found in the autosomal non-MHC genome. Our genome-wide partitioning approach and large-scale replication effort allowed the evaluation of other variants that did not meet our strict threshold of significance, such as 416 variants that had evidence of statistical replication but did not reach the level of genome-wide statistical significance. Many of these loci are likely to be true susceptibility loci. The genome-wide and suggestive effects jointly explain ~48% of the estimated heritability for MS.Using atlases of gene expression patterns and epigenomic features, we documented that enrichment for MS susceptibility loci was apparent in many different immune cell types and tissues, whereas there was an absence of enrichment in tissue-level brain profiles. We extended the annotation analyses by analyzing new data generated from human induced pluripotent stem cell–derived neurons as well as from purified primary human astrocytes and microglia, observing that enrichment for MS genes is seen in human microglia, the resident immune cells of the brain, but not in astrocytes or neurons. Further, we have characterized the functional consequences of many MS susceptibility variants by identifying those that influence the expression of nearby genes in immune cells or brain. Last, we applied an ensemble of methods to prioritize 551 putative MS susceptibility genes that may be the target of the MS variants that meet a threshold of genome-wide significance. This extensive list of MS susceptibility genes expands our knowledge more than twofold and highlights processes relating to the development, maturation, and terminal differentiation of B, T, natural killer, and myeloid cells that may contribute to the onset of MS. These analyses focus our attention on a number of different cells in which the function of MS variants should be further investigated.Using reference protein-protein interaction maps, these MS genes can also be assembled into 13 communities of genes encoding proteins that interact with one another; this higher-order architecture begins to assemble groups of susceptibility variants whose functional consequences may converge on certain protein complexes that can be prioritized for further evaluation as targets for MS prevention strategies.CONCLUSIONWe report a detailed genetic and genomic map of MS susceptibility, one that explains almost half of this disease’s heritability. We highlight the importance of several cells of the peripheral and brain resident immune systems—implicating both the adaptive and innate arms—in the …