Narayan Pritika, Dragunow Mike
School of Biological Sciences and Centre for Brain Research, University of Auckland, Auckland, New Zealand.
Department of Pharmacology and Centre for Brain Research, University of Auckland, Auckland, New Zealand.
Adv Exp Med Biol. 2017;978:321-336. doi: 10.1007/978-3-319-53889-1_17.
Substantial progress has been made in identifying Alzheimer's disease (AD) risk-associated variants using genome-wide association studies (GWAS). The majority of these risk variants reside in noncoding regions of the genome making their functional evaluation difficult; however, they also infer the presence of unconventional regulatory regions that may reside at these locations. We know from these studies that rare familial cases of AD account for less than 5% of all AD cases and autosomal dominant mutations in APP, PSEN1 and PSEN2 account for less than 10% of the genetic basis of these familial cases [1]. The sporadic form of AD, while more complex, still has a substantial genetic component evidenced by observational studies where 30-48% of AD patients have a first degree relative who is also affected [2]. In addition, the strongest risk factor after age is the APOE E4 polymorphism, and more than 20 other risk variants have been identified to date, reviewed in two recent papers [3, 4]. Monozygotic twin studies have revealed a discordance for AD, implicating that a combination of epigenetic and genetic factors are likely involved in the development of AD [5].
利用全基因组关联研究（GWAS）在识别阿尔茨海默病（AD）风险相关变异方面已取得重大进展。这些风险变异中的大多数位于基因组的非编码区域，这使得对其进行功能评估变得困难；然而，它们也暗示了可能位于这些位置的非常规调控区域的存在。从这些研究中我们知道，AD的罕见家族病例占所有AD病例的比例不到5%，APP、PSEN1和PSEN2中的常染色体显性突变占这些家族病例遗传基础的比例不到10%[1]。AD的散发性形式虽然更为复杂，但观察性研究表明其仍有很大的遗传成分，30 - 48%的AD患者有一位同样患病的一级亲属[2]。此外，年龄之后最强的风险因素是APOE ε4多态性，迄今为止已鉴定出20多种其他风险变异，最近的两篇论文对此进行了综述[3, 4]。同卵双胞胎研究显示AD存在不一致性，这意味着表观遗传和遗传因素的组合可能参与了AD的发病过程[5]。
