Sieh Weiva, Choi Yoonha, Chapman Nicola H, Craig Ulla-Katrina, Steinbart Ellen J, Rothstein Joseph H, Oyanagi Kiyomitsu, Garruto Ralph M, Bird Thomas D, Galasko Douglas R, Schellenberg Gerard D, Wijsman Ellen M
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Hum Mol Genet. 2009 Oct 1;18(19):3725-38. doi: 10.1093/hmg/ddp300. Epub 2009 Jun 30.
Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a fatal neurodegenerative disease found in the Chamorro people of Guam and other Pacific Island populations. The etiology is unknown, although both genetic and environmental factors appear important. To identify loci for ALS/PDC, we conducted both genome-wide linkage and association analyses, using approximately 400 microsatellite markers, in the largest sample assembled to date, comprising a nearly complete sample of all living and previously sampled deceased cases. A single, large, complex pedigree was ascertained from a village on Guam, with smaller families and a case-control sample ascertained from the rest of Guam by population-based neurological screening and archival review. We found significant evidence for two regions with novel ALS/PDC loci on chromosome 12 and supportive evidence for the involvement of the MAPT region on chromosome 17. D12S1617 on 12p gave the strongest evidence of linkage (maximum LOD score, Z(max) = 4.03) in our initial scan, with additional support in the complete case-control sample in the form of evidence of allelic association at this marker and another nearby marker. D12S79 on 12q also provided significant evidence of linkage (Z(max) = 3.14) with support from flanking markers. Our results suggest that ALS/PDC may be influenced by as many as three loci, while illustrating challenges that are intrinsic in genetic analyses of isolated populations, as well as analytical strategies that are useful in this context. Elucidation of the genetic basis of ALS/PDC should improve our understanding of related neurodegenerative disorders including Alzheimer disease, Parkinson disease, frontotemporal dementia and ALS.
肌萎缩侧索硬化症/帕金森病痴呆综合征（ALS/PDC）是一种在关岛查莫罗人及其他太平洋岛屿人群中发现的致命性神经退行性疾病。尽管遗传因素和环境因素似乎都很重要，但其病因尚不清楚。为了确定ALS/PDC的基因座，我们进行了全基因组连锁分析和关联分析，使用了约400个微卫星标记，样本量是迄今为止最大的，包括了所有在世和之前采样的已故病例的几乎完整样本。从关岛的一个村庄确定了一个单一的、大型的复杂家系，通过基于人群的神经学筛查和档案审查，从关岛其他地区确定了较小的家系和病例对照样本。我们发现12号染色体上有两个具有新型ALS/PDC基因座的区域有显著证据，并且有证据支持17号染色体上的MAPT区域与之相关。在我们最初的扫描中，12p上的D12S1617给出了最强的连锁证据（最大对数优势分数，Z(max)=4.03），在完整的病例对照样本中，该标记及附近另一个标记的等位基因关联证据提供了额外支持。12q上的D12S79也提供了显著的连锁证据（Z(max)=3.14），侧翼标记也提供了支持。我们的结果表明，ALS/PDC可能受多达三个基因座的影响，同时也说明了在隔离人群的遗传分析中固有的挑战以及在此背景下有用的分析策略。阐明ALS/PDC的遗传基础应能增进我们对包括阿尔茨海默病、帕金森病、额颞叶痴呆和ALS在内的相关神经退行性疾病的理解。
