Bertram Lars, Lange Christoph, Mullin Kristina, Parkinson Michele, Hsiao Monica, Hogan Meghan F, Schjeide Brit M M, Hooli Basavaraj, Divito Jason, Ionita Iuliana, Jiang Hongyu, Laird Nan, Moscarillo Thomas, Ohlsen Kari L, Elliott Kathryn, Wang Xin, Hu-Lince Diane, Ryder Marie, Murphy Amy, Wagner Steven L, Blacker Deborah, Becker K David, Tanzi Rudolph E
Genetics and Aging Research Unit, Mass General Institute for Neurodegenerative Disease (MIND), Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Am J Hum Genet. 2008 Nov;83(5):623-32. doi: 10.1016/j.ajhg.2008.10.008. Epub 2008 Oct 30.
Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. To date four genes have been established to either cause early-onset autosomal-dominant AD (APP, PSEN1, and PSEN2(1-4)) or to increase susceptibility for late-onset AD (APOE5). However, the heritability of late-onset AD is as high as 80%, (6) and much of the phenotypic variance remains unexplained to date. We performed a genome-wide association (GWA) analysis using 484,522 single-nucleotide polymorphisms (SNPs) on a large (1,376 samples from 410 families) sample of AD families of self-reported European descent. We identified five SNPs showing either significant or marginally significant genome-wide association with a multivariate phenotype combining affection status and onset age. One of these signals (p = 5.7 x 10(-14)) was elicited by SNP rs4420638 and probably reflects APOE-epsilon4, which maps 11 kb proximal (r2 = 0.78). The other four signals were tested in three additional independent AD family samples composed of nearly 2700 individuals from almost 900 families. Two of these SNPs showed significant association in the replication samples (combined p values 0.007 and 0.00002). The SNP (rs11159647, on chromosome 14q31) with the strongest association signal also showed evidence of association with the same allele in GWA data generated in an independent sample of approximately 1,400 AD cases and controls (p = 0.04). Although the precise identity of the underlying locus(i) remains elusive, our study provides compelling evidence for the existence of at least one previously undescribed AD gene that, like APOE-epsilon4, primarily acts as a modifier of onset age.
阿尔茨海默病（AD）是一种遗传复杂且异质性的疾病。迄今为止，已经确定有四个基因可导致早发性常染色体显性AD（APP、PSEN1和PSEN2(1 - 4)）或增加晚发性AD的易感性（APOE5）。然而，晚发性AD的遗传度高达80%，（6）且许多表型变异至今仍无法解释。我们对一个大型（来自410个家庭的1376个样本）自我报告为欧洲血统的AD家族样本，使用484,522个单核苷酸多态性（SNP）进行了全基因组关联（GWA）分析。我们鉴定出五个SNP，它们与结合患病状态和发病年龄的多变量表型显示出显著或边缘显著的全基因组关联。其中一个信号（p = 5.7 x 10(-14)）由SNP rs4420638引发，可能反映了APOE-ε4，其定位在近端11 kb处（r2 = 0.78）。另外四个信号在另外三个独立的AD家族样本中进行了测试，这些样本由来自近900个家庭的近2700个人组成。其中两个SNP在重复样本中显示出显著关联（合并p值为0.007和0.00002）。具有最强关联信号的SNP（位于14号染色体q31上的rs11159647）在一个由约1400例AD病例和对照组成的独立样本中生成的GWA数据中，也显示出与相同等位基因的关联证据（p = 0.04）。尽管潜在基因座的确切身份仍然难以捉摸，但我们的研究为至少一个先前未描述的AD基因的存在提供了有力证据，该基因与APOE-ε4一样，主要作为发病年龄的修饰因子起作用。
