Alzheimer's disease (AD) is a genetically heterogeneous neurodegenerative disorder caused by fully penetrant single gene mutations in a minority of cases, while the majority of cases are sporadic or show modest familial clustering. These cases are of late onset and likely result from the interaction of many genes and the environment. More than 30 loci have been implicated in AD by a combination of linkage, genome-wide association, and whole genome/exome sequencing. We have learned from these studies that perturbations in endolysosomal, lipid metabolism, and immune response pathways substantially contribute to sporadic AD pathogenesis. We review here current knowledge about functions of AD susceptibility genes, highlighting cells of the myeloid lineage as drivers of at least part of the genetic component in late-onset AD. Although targeted resequencing utilized for the identification of causal variants has discovered coding mutations in some AD-associated genes, a lot of risk variants lie in noncoding regions. Here we discuss the use of functional genomics approaches that integrate transcriptomic, epigenetic, and endophenotype traits with systems biology to annotate genetic variants, and to facilitate discovery of AD risk genes. Further validation in cell culture and mouse models will be necessary to establish causality for these genes. This knowledge will allow mechanism-based design of novel therapeutic interventions in AD and promises coherent implementation of treatment in a personalized manner.

中文翻译：

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解开阿尔茨海默病的遗传风险

阿尔茨海默病（AD）是一种遗传异质性神经退行性疾病，由少数病例中完全渗透性单基因突变引起，而大多数病例是散发性的或表现出适度的家族聚集性。这些病例发病较晚，可能是许多基因与环境相互作用的结果。通过连锁、全基因组关联和全基因组/外显子组测序的组合，超过 30 个基因座与 AD 相关。我们从这些研究中了解到，内溶酶体、脂质代谢和免疫反应途径的扰动在很大程度上导致了散发性 AD 发病机制。我们在此回顾了有关 AD 易感性基因功能的最新知识，强调骨髓谱系细胞是晚发性 AD 中至少部分遗传成分的驱动因素。尽管用于识别致病变异的靶向重测序已发现一些 AD 相关基因的编码突变，但许多风险变异位于非编码区域。在这里，我们讨论使用功能基因组学方法将转录组学、表观遗传和内表型特征与系统生物学相结合来注释遗传变异，并促进 AD 风险基因的发现。需要在细胞培养和小鼠模型中进一步验证以确定这些基因的因果关系。这些知识将允许基于机制设计 AD 的新型治疗干预措施，并有望以个性化的方式连贯地实施治疗。