The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.
The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.
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DOI：
10.3233/jad-2011-110824
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发表时间：
2012
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影响因子：
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通讯作者：
Williams J
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作者：
Gerrish A;Russo G;Richards A;Moskvina V;Ivanov D;Harold D;Sims R;Abraham R;Hollingworth P;Chapman J;Hamshere M;Pahwa JS;Dowzell K;Williams A;Jones N;Thomas C;Stretton A;Morgan AR;Lovestone S;Powell J;Proitsi P;Lupton MK;Brayne C;Rubinsztein DC;Gill M;Lawlor B;Lynch A;Morgan K;Brown KS;Passmore PA;Craig D;McGuinness B;Todd S;Johnston JA;Holmes C;Mann D;Smith AD;Love S;Kehoe PG;Hardy J;Mead S;Fox N;Rossor M;Collinge J;Maier W;Jessen F;Kölsch H;Heun R;Schürmann B;van den Bussche H;Heuser I;Kornhuber J;Wiltfang J;Dichgans M;Frölich L;Hampel H;Hüll M;Rujescu D;Goate AM;Kauwe JS;Cruchaga C;Nowotny P;Morris JC;Mayo K;Livingston G;Bass NJ;Gurling H;McQuillin A;Gwilliam R;Deloukas P;Davies G;Harris SE;Starr JM;Deary IJ;Al-Chalabi A;Shaw CE;Tsolaki M;Singleton AB;Guerreiro R;Mühleisen TW;Nöthen MM;Moebus S;Jöckel KH;Klopp N;Wichmann HE;Carrasquillo MM;Pankratz VS;Younkin SG;Jones L;Holmans PA;O'Donovan MC;Owen MJ;Williams J
AβPP、PSEN 1和PSEN 2的罕见突变导致不常见的早发性阿尔茨海默病（AD），而MAPT的常见变异与其他神经退行性疾病的风险相关。我们试图确定这些基因中的常见遗传变异是否会给老年人（>65岁）发生的常见AD形式带来风险。因此，我们在一个由3,940例病例和13,373例对照组成的大型病例对照样本中检测了这些位点的单核苷酸多态性与晚发性AD（LOAD）的相关性。单标记分析没有发现任何达到全基因组意义的变异，这一结果得到了其他最近的全基因组关联研究的支持。然而，我们使用全基因方法确实观察到MAPT位点的显著关联（p = 0.009）。我们还观察到AD和标记rs 9468之间的暗示性关联，该标记rs 9468定义了H1单倍型，H1单倍型是跨越MAPT基因的扩展单倍型，并且先前已涉及其他神经退行性疾病，包括帕金森病，进行性核上性麻痹和皮质基底节变性。总之，AβPP、PSEN 1、PSEN 2和MAPT的常见变异不太可能对LOAD的易感性产生重大影响。然而，在MAPT中观察到的全基因效应表明可能对疾病风险有贡献，需要进一步研究。
Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer’s disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson’s disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.