Bertoli-Avella Aida M, Dekker Marieke C J, Aulchenko Yurii S, Houwing-Duistermaat Jeanine J, Simons Erik, Testers Leon, Pardo Luba M, Rademaker Tessa A M, Snijders Pieter J L M, van Swieten John C, Bonifati Vincenzo, Heutink Peter, van Duijn Cornelia M, Oostra Ben A
Genetic-Epidemiologic Unit, Department of Clinical Genetics and Department of Epidemiology & Biostatistics, Erasmus MC Rotterdam, PO Box 1738, 3000 DR, Rotterdam, The Netherlands.
Hum Genet. 2006 Mar;119(1-2):51-60. doi: 10.1007/s00439-005-0108-7. Epub 2005 Dec 14.
We studied patients with idiopathic Parkinson's disease (PD) from an isolated population in the Netherlands aiming to map gene(s) involved in PD susceptibility. A total of 109 parkinsonism patients were independently ascertained, of whom 62 presented late-onset, idiopathic PD. Genealogical research showed that 45 index cases with idiopathic PD were linked to a common ancestor, indicating familiar clustering among the patients. This strong familial clustering was highly significant (P = 0.005) when compared to random controls from the same population. We performed a genome wide scan using 382 polymorphic markers in 44 distantly related PD patients plus 112 unaffected first-degree relatives and spouses. Our genome wide association analysis (DISLAMB) revealed evidence of association at a nominal P-value < 0.01 for markers D2S2333, D4S405, D9S158, D13S153. Other regions on chromosomes 3p, 4q, 14q, 17p and 17q were found at a significance level of P < 0.05. In a follow-up study, we investigated all the positive regions using a denser marker set and a larger sample (total of 630 individuals including all late-onset PD patients). The strongest evidence for association remained for the 9q and 14q region. A significant association was found for marker D9S1838 (OR = 2.0, 95% CI 1.1-3.5, P = 0.014) and D14S65 (OR = 3.2, 95% CI 1.7-6.1, P < 0.001). Moreover, a common haplotype with excess of sharing among late-onset PD cases was observed on both regions. Our results suggest the existence of two loci influencing PD susceptibility on chromosome 9q and 14q.
我们对来自荷兰一个孤立人群的特发性帕金森病（PD）患者进行了研究，旨在确定与PD易感性相关的基因。总共独立确定了109例帕金森综合征患者，其中62例为晚发性特发性PD。系谱研究表明，45例特发性PD索引病例与一位共同祖先有关联，这表明患者中存在家族聚集现象。与来自同一人群的随机对照相比，这种强烈的家族聚集具有高度显著性（P = 0.005）。我们使用382个多态性标记对44例远亲PD患者以及112例未受影响的一级亲属和配偶进行了全基因组扫描。我们的全基因组关联分析（DISLAMB）显示，标记D2S2333、D4S405、D9S158、D13S153在名义P值<0.01时存在关联证据。在3号染色体短臂、4号染色体长臂、14号染色体长臂、17号染色体短臂和17号染色体长臂上的其他区域在P<0.05的显著性水平上被发现。在后续研究中，我们使用更密集的标记集和更大的样本（总共630人，包括所有晚发性PD患者）对所有阳性区域进行了调查。9号染色体长臂和14号染色体长臂区域仍然是关联的最有力证据。发现标记D9S1838（比值比=2.0，95%可信区间1.1 - 3.5，P = 0.014）和D14S65（比值比=3.2，95%可信区间1.7 - 6.1，P<0.001）存在显著关联。此外，在这两个区域均观察到一种在晚发性PD病例中共享过多的常见单倍型。我们的结果表明在9号染色体长臂和（和）14号染色体长臂上存在两个影响PD易感性的基因座。
