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首页> 外文期刊>Annals of Human Genetics >Linkage and Association Study of Late-Onset Alzheimer Disease Families Linked to 9p21.3
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Linkage and Association Study of Late-Onset Alzheimer Disease Families Linked to 9p21.3

机译：与9p21.3相关的晚期阿尔茨海默氏病家族的联系和关联研究

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A chromosomal locus for late-onset Alzheimer disease (LOAD) has previously been mapped to 9p21.3. The most significant results were reported in a sample of autopsy-confirmed families. Linkage to this locus has been independently confirmed in AD families from a consanguineous Israeli-Arab community. In the present study we analyzed an expanded clinical sample of 674 late-onset AD families, independently ascertained by three different consortia. Sample subsets were stratified by site and autopsy-confirmation. Linkage analysis of a dense array of SNPs across the chromosomal locus revealed the most significant results in the 166 autopsy-confirmed families of the NIMH sample. Peak HLOD scores of 4.95 at D9S741 and 2.81 at the nearby SNP rs2772677 were obtained in a dominant model. The linked region included the cyclin-dependent kinase inhibitor 2A gene (CDKN2A), which has been suggested as an AD candidate gene. By re-sequencing all exons in the vicinity of CDKN2A in 48 AD cases, we identified and genotyped four novel SNPs, including a non-synonymous, a synonymous, and two variations located in untranslated RNA sequences. Family-based allelic and genotypic association analysis yielded significant results in CDKN2A (rs11515: PDT p = 0.003, genotype-PDT p = 0.014). We conclude that CDKN2A is a promising new candidate gene potentially contributing to AD susceptibility on chromosome 9p.
机译：早发性阿尔茨海默病（LOAD）的染色体位点先前已定位到9p21.3。在尸检确认的家庭样本中报告了最重要的结果。在一个近亲的以色列阿拉伯人的公元家庭中已经独立地证实了与该基因座的联系。在本研究中，我们分析了由三个不同的财团独立确定的674个晚期AD家庭的扩展临床样本。通过部位和尸检确认将样本子集分层。在整个染色体位点上密集排列的SNP的连锁分析显示，在166个经过尸检确认的NIMH样本家族中，最显着的结果。在显性模型中，D9S741的HLOD峰值得分为4.95，附近的SNP rs2772677的HLOD得分为2.81。所连接的区域包括细胞周期蛋白依赖性激酶抑制剂2A基因（CDKN2A），已被证明是AD候选基因。通过对48个AD病例中CDKN2A附近的所有外显子进行重新测序，我们鉴定并基因分型了四个新的SNP，包括非同义的，同义的和位于未翻译的RNA序列中的两个变异。基于家族的等位基因和基因型关联分析在CDKN2A中产生了显着结果（rs11515：PDT p = 0.003，基因型-PDT p = 0.014）。我们得出结论，CDKN2A是一个有前途的新候选基因，可能会导致9p号染色体上的AD易感性。

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