Grupe Andrew, Abraham Richard, Li Yonghong, Rowland Charles, Hollingworth Paul, Morgan Angharad, Jehu Luke, Segurado Ricardo, Stone David, Schadt Eric, Karnoub Maha, Nowotny Petra, Tacey Kristina, Catanese Joseph, Sninsky John, Brayne Carol, Rubinsztein David, Gill Michael, Lawlor Brian, Lovestone Simon, Holmans Peter, O'Donovan Michael, Morris John C, Thal Leon, Goate Alison, Owen Michael J, Williams Julie
Celera Diagnostics, 1401 Harbor Bay Parkway, Alameda, CA 94502, USA.
Hum Mol Genet. 2007 Apr 15;16(8):865-73. doi: 10.1093/hmg/ddm031. Epub 2007 Feb 22.
This study sets out to identify novel susceptibility genes for late-onset Alzheimer's disease (LOAD) in a powerful set of samples from the UK and USA (1808 LOAD cases and 2062 controls). Allele frequencies of 17 343 gene-based putative functional single nucleotide polymorphisms (SNPs) were tested for association with LOAD in a discovery case-control sample from the UK. A tiered strategy was used to follow-up significant variants from the discovery sample in four independent sample sets. Here, we report the identification of several candidate SNPs that show significant association with LOAD. Three of the identified markers are located on chromosome 19 (meta-analysis: full sample P = 6.94E - 81 to 0.0001), close to the APOE gene and exhibit linkage disequilibrium (LD) with the APOEepsilon4 and epsilon2/3 variants (0.09 < D'<1). Two of the three SNPs can be regarded as study-wide significant (expected number of false positives reaching the observed significance level less than 0.05 per study). Sixteen additional SNPs show evidence for association with LOAD [P = 0.0010-0.00006; odds ratio (OR) = 1.07-1.45], several of which map to known linkage regions, biological candidate genes and novel genes. Four SNPs not in LD with APOE show a false positive rate of less than 2 per study, one of which shows study-wide suggestive evidence taking account of 17 343 tests. This is a missense mutation in the galanin-like peptide precursor gene (P = 0.00005, OR = 1.2, false positive rate = 0.87).
本研究旨在从英国和美国的大量样本（1808例晚发性阿尔茨海默病患者和2062例对照）中识别晚发性阿尔茨海默病（LOAD）的新易感基因。在一个来自英国的发现性病例对照样本中，对17343个基于基因的推定功能性单核苷酸多态性（SNP）的等位基因频率进行了与LOAD的关联性测试。采用分层策略在四个独立样本集中对发现样本中的显著变异进行后续研究。在此，我们报告了几个与LOAD显著相关的候选SNP的识别情况。所识别的三个标记位于19号染色体上（荟萃分析：全样本P = 6.94E - 81至0.0001），靠近载脂蛋白E（APOE）基因，并与APOEε4和ε2/3变异体表现出连锁不平衡（LD）（0.09 < D'<1）。这三个SNP中的两个可被视为全研究显著（每个研究达到观察到的显著水平的假阳性预期数小于0.05）。另外16个SNP显示出与LOAD相关的证据[P = 0.0010 - 0.00006；优势比（OR） = 1.07 - 1.45]，其中几个映射到已知的连锁区域、生物学候选基因和新基因。四个与APOE无LD的SNP每个研究的假阳性率小于2，其中一个在考虑17343次测试时显示出全研究的提示性证据。这是甘丙肽样肽前体基因中的一个错义突变（P = 0.00005，OR = 1.2，假阳性率 = 0.87）。
