An autosomal genomic screen for dementia in an extended Amish family
An autosomal genomic screen for dementia in an extended Amish family
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DOI：
10.1016/j.neulet.2004.12.065
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发表时间：
2005-05-13
影响因子：
2.5
通讯作者：
Pericak-Vance, MA
中科院分区：
文献类型：
--
作者：
Ashley-Koch, AE;Shao, Y;Pericak-Vance, MA
载脂蛋白 E (APOE) 是唯一被普遍证实的迟发性阿尔茨海默病 (LOAD) 易感基因，尽管许多位点被认为可调节 LOAD 风险。孤立群体（例如阿米什人）的遗传同质性可能为识别 LOAD 易感基因提供更大的能力。这些特殊人群中的人群同质性可能会减少导致复杂疾病的易感基因总数，从而提高识别任何一种易感基因的能力。阿米什人的痴呆症在临床上与普通人群的 LOAD 无法区分。先前对阿米什人的研究表明，APOE-4 易感等位基因的频率显着降低，但痴呆症具有显着的家族聚集性 [M.A.佩里卡克-万斯，C.C.约翰逊，J.13。里姆勒，A.M.桑德斯，L.C.罗宾逊，E.G. D'Hondt，C.E. Jackson，J.L. Haines，阿米什人群中的阿尔茨海默病和载脂蛋白 E-4 等位基因，Ann。内罗尔。 39（1996）700-704]。这些数据表明，独立于 APOE 的遗传病因可能是该人群中观察到的痴呆的基础。在本次分析中，我们重点关注一个大型、多重近交的阿米什家族（24 名样本个体；其中 10 人受到影响）。我们使用依赖于模型的“仅受影响”分析（显性和隐性）和独立于模型的受影响相对配对分析完成了基因组筛选，以识别新的 LOAD 基因座（n = 316 个遗传标记）。八条染色体（2q、5q、6q、7p、8p、8q、11p、18p、19q 和 19q）上的标记获得了有趣的结果（lod > 1.5 或 p < 0.01）。最高的总体得分是染色体 I I p 上的多点 lod 得分 3.1。我们发现的大多数区域之前并未通过远交种群的基因组筛选检测到，并且可能代表种群对 LOAD 的特异性易感性。这些位点目前正在 LOAD 研究中进行进一步调查，其中包括其他阿米什家族。 (c) 2005 Elsevier Ireland Ltd. 保留所有权利。
Apolipoprotein E(APOE) is the only universally confirmed susceptibility gene for late-onset Alzheimer disease (LOAD), although many loci are believed to modulate LOAD risk. The genetic homogeneity of isolated populations, such as the Amish, potentially provide increased power to identify LOAD susceptibility genes. Population homogeneity in these special populations may reduce the total number of susceptibility genes contributing to the complex disorder, thereby increasing the ability to identify any one susceptibility gene. Dementia in the Amish is clinically indistinguishable from LOAD in the general population. Previous studies in the Amish demonstrated a significantly decreased frequency of the APOE-4 susceptibility allele, but significant familial clustering of dementia [M.A. Pericak-Vance, C.C. Johnson, J.13. Rimmler, A.M. Saunders, L.C. Robinson, E.G. D'Hondt, C.E. Jackson, J.L. Haines, Alzheimer's disease and apolipoprotein E-4 allele in an Amish population, Ann. Neurol. 39 (1996) 700-704]. These data suggested that a genetic etiology independent of APOE may underlie the dementia observed in this population. In the present analysis, we focused on a large, multiplex, inbred Amish family (24 sampled individuals; 10 of whom are affected). We completed a genomic screen to identify novel LOAD loci (n = 316 genetic markers), using both model-dependent "affecteds-only" analysis (dominant and recessive) and model-independent affected relative pair analysis. Interesting results (lod > 1.5 or p < 0.01) were obtained for markers on eight chromosomes (2q, 5q, 6q, 7p, 8p, 8q, 11p, 18p, 19q, and 19q). The highest overall score was a multipoint lod score of 3.1 on chromosome I I p. Most regions we identified were not previously detected by genomic screens of outbred populations and may represent population-specific susceptibilities to LOAD. These loci are currently under further investigation in a study of LOAD including additional Amish families. (c) 2005 Elsevier Ireland Ltd. All rights reserved.