Association analysis of MAPT H1 haplotype and subhaplotypes in Parkinson's disease
Association analysis of MAPT H1 haplotype and subhaplotypes in Parkinson's disease
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DOI：
10.1002/ana.21157
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发表时间：
2007-08-01
影响因子：
11.2
通讯作者：
Payami, Haydeh
中科院分区：
文献类型：
--
作者：
Zabetian, Cyrus P.;Hutter, Carolyn M.;Payami, Haydeh
目的：染色体17 q21上约900 kb的倒位多态性，包括微管相关蛋白tau（MAPT）基因，定义了两个单倍型进化枝H1和H2。几项小型病例对照研究观察到帕金森病（PD）患者中H1/H1双倍型略微显著过量，其中一项研究报告了与MAPT外显子1至4区域的相关性。我们试图复制这些findings.Methods：我们对1,762名PD患者和2,010名对照组进行基因分型，以确定区分H1和H2分支的单核苷酸多态性（SNP）。我们还分析了4个SNPs，这些SNPs定义了先前报道的与PD或其他神经退行性疾病相关的HI内的亚单倍型。结果：在调整了年龄、性别和部位后，我们观察到H1/H1双倍型与PD风险之间存在强相关性（H1/H1与H1/H2和H2/H2的比值比为1.46; 95%置信区间为1.25-1.69; p = 8 x 10（-7））。这种效应在家族性和散发性亚组、男性和女性以及早发性和迟发性疾病中都很明显。在H1/H1个体，有没有显着差异的情况下和对照组之间的整体频率分布的Hi subhaplotype.Interpretation：我们的数据提供了强有力的证据表明，H I分支，其中包含MAPT和其他几个基因，是一个危险因素PD。然而，将这一发现归因于MAPT特定区域内的变异还为时过早。现在需要在大量个体中对H1进化枝进行彻底的精细定位，以确定改变PD易感性的潜在功能变体。
Objective: An inversion polymorphism of approximately 900kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene defines two haplorype clades, HI and H2. Several small case-control studies have observed a marginally significant excess of the H1/H1 diplotype among patients with Parkinson's disease (PD), and one reported refining the association to a region spanning exons 1 to 4 of MAPT. We sought to replicate these findings.Methods: We genotyped 1,762 PD patients and 2,010 control subjects for a single nucleotide polymorphism (SNP) that differentiates the HI and H2 clades. We also analyzed four SNPs that define subhaplotypes within HI previously reported to associate with PD or other neurodegenerative disorders.Results: After adjusting for age, sex, and site, we observed a robust association between the H1/H1 diplotype and PD risk (odds ratio for H1/H1 vs H1/H2 and H2/H2, 1.46; 95% confidence interval, 1.25-1.69; p = 8 x 10(-7)). The effect was evident in both familial and sporadic subgroups, men and women, and early- and late-onset disease. Within H1/H1 individuals, there was no significant difference between cases and control subjects in the overall frequency distribution of Hi subhaplotypes.Interpretation: Our data provide strong evidence that the H I clade, which contains MAPT and several other genes, is a risk factor for PD. However, attributing this finding to variants within a specific region of MAPT is premature. Thorough fine-mapping of the H1 clade in large numbers of individuals is now needed to identify the underlying functional variant(s) that alter susceptibility for PD.