Desikan R S, Schork A J, Wang Y, Witoelar A, Sharma M, McEvoy L K, Holland D, Brewer J B, Chen C-H, Thompson W K, Harold D, Williams J, Owen M J, O'Donovan M C, Pericak-Vance M A, Mayeux R, Haines J L, Farrer L A, Schellenberg G D, Heutink P, Singleton A B, Brice A, Wood N W, Hardy J, Martinez M, Choi S H, DeStefano A, Ikram M A, Bis J C, Smith A, Fitzpatrick A L, Launer L, van Duijn C, Seshadri S, Ulstein I D, Aarsland D, Fladby T, Djurovic S, Hyman B T, Snaedal J, Stefansson H, Stefansson K, Gasser T, Andreassen O A, Dale A M
Department of Radiology, University of California, San Diego, La Jolla, CA, USA.
Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA.
Mol Psychiatry. 2015 Dec;20(12):1588-95. doi: 10.1038/mp.2015.6. Epub 2015 Feb 17.
We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10(-7)). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration.
我们研究了阿尔茨海默病（AD）和帕金森病（PD）之间的遗传重叠。利用近期大型全基因组关联研究（GWAS）（共89904名个体）的汇总统计数据（P值），我们试图鉴定与AD和PD均相关的单核苷酸多态性（SNP）。我们发现并重复验证了17号染色体上扩展的微管相关蛋白tau（MAPT）区域内的rs393152的A等位基因与AD和PD均存在关联（五项独立AD队列的荟萃分析P值 = 1.65×10⁻⁷）。在独立数据集中，我们发现rs393152的A等位基因对内嗅皮质和海马体内的脑内MAPT转录水平和体积损失具有剂量依赖性效应。我们的研究结果确定了与tau相关的MAPT基因座是AD和PD之间的遗传重叠位点，并且在先前工作的基础上，我们表明MAPT区域会增加阿尔茨海默病神经退行性变的风险。
