Morris Huw R, Steele John C, Crook Richard, Wavrant-De Vrièze Fabienne, Onstead-Cardinale Luisa, Gwinn-Hardy Katrina, Wood Nick W, Farrer Matthew, Lees Andrew J, McGeer P L, Siddique Teepu, Hardy John, Perez-Tur Jordi
Department of Molecular Pathogenesis and Sara Koe PSP Research Centre, Queen Square Brain Bank for Neurological Disorders, Insatitute of Neurology, University College London, London, England, UK.
Arch Neurol. 2004 Dec;61(12):1889-97. doi: 10.1001/archneur.61.12.1889.
Parkinsonism-dementia complex (PDC) is a neurofibrillary tangle degeneration involving the deposition of Alzheimer-type tau, predominantly in the mesial temporal cortex, brainstem, and basal ganglia. It occurs in focal geographic isolates, including Guam and the Kii peninsula of Japan. The familial clustering of the disease has suggested that a genetic factor could be important in its etiology.
To determine whether a genetic locus could be identified, linked, or associated with PDC.
We performed a genome-wide association study of 22 Guamanian PDC and 19 control subjects using 834 microsatellite markers with an approximate genome-wide marker density of 4.4 centimorgans.
Two-point association analysis identified 17 markers (P<.015). Each of these markers then underwent conventional linkage analysis in 5 families with PDC. One marker, D20S103, generated a logarithm of odds score of greater than 1.5. Multipoint association analysis also highlighted 2 other areas on chromosome 14q (adjacent to D14S592, 59.2 megabases [M]) and chromosome 20 (adjacent to D20S470, 17.4 M) with multipoint association logarithm of the odds scores of greater than 2. The areas around D20S103, D14S592, and D20S470 were further analyzed by association using additional microsatellite markers and by conventional linkage analysis. This did not provide further evidence for the role of these areas in PDC.
This study has not identified a single gene locus for PDC, confirming the impression of a geographic disease isolate with a complex genetic, a genetic/environmental etiology, or a purely environmental etiology.
帕金森病痴呆综合征（PDC）是一种神经原纤维缠结性变性疾病，主要累及内侧颞叶皮质、脑干和基底神经节，伴有阿尔茨海默型tau蛋白沉积。该病发生于局部地理隔离地区，包括关岛和日本的纪伊半岛。疾病的家族聚集性提示遗传因素可能在其病因中起重要作用。
确定是否能识别出与PDC相关、连锁或关联的基因座。
我们使用834个微卫星标记对22名关岛PDC患者和19名对照受试者进行了全基因组关联研究，全基因组标记密度约为4.4厘摩。
两点关联分析确定了17个标记（P<0.015）。然后，对5个PDC家族中的每个标记进行常规连锁分析。一个标记D20S103产生的优势对数得分大于1.5。多点关联分析还突出显示了14号染色体上另外两个区域（与D14S592相邻，59.2兆碱基[M]）和20号染色体上的区域（与D20S470相邻，17.4 M），多点关联优势对数得分大于2。使用额外的微卫星标记通过关联分析和常规连锁分析对D20S103、D14S592和D20S470周围区域进行了进一步分析。这并未为这些区域在PDC中的作用提供进一步证据。
本研究未确定PDC的单个基因座，证实了这种地理隔离疾病具有复杂遗传、遗传/环境病因或纯环境病因的印象。
