Results of a high-resolution genome screen of 437 Alzheimer's Disease families
Results of a high-resolution genome screen of 437 Alzheimer's Disease families
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DOI：
10.1093/hmg/ddg007
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发表时间：
2003-01-01
影响因子：
3.5
通讯作者：
Tanzi, RE
中科院分区：
文献类型：
--
作者：
Blacker, D;Bertram, L;Tanzi, RE
阿尔茨海默病 (AD) 是一种具有复杂遗传性的晚年毁灭性神经退行性疾病。三个已知基因的突变会导致罕见的早发性常染色体显性 AD，而编码载脂蛋白 E (APOE) 的基因中常见的多态性 (epsilon4) 是更典型的晚发性（> 60 岁）AD 的危险因素。最近的一项研究得出结论，还有多达四个额外基因对这种疾病具有同等或更大的影响。我们对 437 个 AD 家庭进行了 9 cM 基因组筛查，这是美国国家心理健康研究所 (NIMH) 的完整样本，我们的团队在过去十年中对此进行了仔细的确定、评估和跟踪。通过执行标准参数和非参数连锁分析，我们根据 Lander 和 Kruglyak 标准在染色体 19q13 上观察到“高度显着”的连锁峰，该峰可能代表 APOE。 1q23、3p26、4q32、5p14、6p21、6q27、9q22、10q24、11q25、14q22、15q26 和 21q22 上的另外 12 个位置符合“暗示性”连锁的标准[即至少在我们的一项分析中，两点 Lod 评分 (TLS) 大于或等于 1.9 和/或多点 Lod 评分 (MLS) 大于或等于 2.2]。尽管其中一些肯定会被证明是假阳性，但这些连锁信号应该为未来的研究提供一个有价值的框架，旨在识别晚发性 AD 的其他易感基因。
Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (epsilon4) in the gene encoding apolipoprotein E (APOE) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22--met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) greater than or equal to1.9 and/or multipoint lod score (MLS) greater than or equal to2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.