CANDIDATE GENES FOR VERY LATE ONSET ALZHEIMERS DISEASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在接下来的几年里，基因研究将极大地影响阿尔茨海默病(AD)患者的护理，导致新的诊断工具和生物干预措施来延迟或预防疾病的发生。我们的目标是识别影响AD发病或进展的新的遗传位点。为此，我们评估了作为NIMH AD遗传学计划的一部分收集的262个受影响的同胞对(ASP)的基因组扫描，并包括ApoE基因和年龄作为协变量。我们确定了LOD评分峰值为5.54和4.09的两个区域，在这两个区域中，年龄最大的ASP复发风险最高，并且最有可能分享相同的遗传背景的区域。这些区域位于21号染色体上，靠近APP基因座(Olson，Goddard&Dudek，2001)和20p染色体(Olson，Goddard&Dudek，2002)。我们的目标是识别这些区域和其他区域中的候选基因，同时识别更多的候选区域。我们已经与NIMH、俄勒冈州大脑和衰老研究(OBAS)以及CWRU(UMAC)的衰老和记忆中心建立了合作关系，以继续这些对AD遗传学的研究。最近，我们使用一种新的统计方法将协变量(如年龄、载脂蛋白E基因)纳入分析，报道了20号染色体上与阿尔茨海默病连锁的证据。这些结果表明，高龄受试者(85岁)和在载脂蛋白E基因座上携带e2等位基因的个体更有可能与这个候选区域相关联。20号染色体上的区域包括一个强有力的候选基因，胱抑素C(CST3)，该基因以前在病例对照研究中与AD有关。我们通过对其他标记进行基因分型来缩小候选区域，并确定连锁不平衡的证据作为20号染色体上一个易感基因座的额外支持，进一步研究了这些发现(Goddard等人，2004年)。我们从NIMH AD Genetics Initiative中选择了43名老年兄弟姐妹(89名受试者)，并从俄勒冈州脑老化研究中确定了129名年龄大于84岁的无关对照受试者，以进行该地区的连锁和关联研究。另外评估了14个标记，包括位于CST3内或附近的4个标记。我们将20号染色体上的候选区域缩小到标记D20S174和D20S471之间11.8 cM的区域，其中包括CST3候选基因。此外，我们观察到位于Cst3候选基因附近的标记之间存在关联的证据，对于两个座位的单倍型，p值在0.002到0.08之间。这些结果支持高龄AD患者在CST3附近存在AD易感基因。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Over the next several years, genetic research will greatly impact patient care for individuals with Alzheimer's disease (AD), leading to new diagnostic tools and biological interventions to delay or prevent disease onset. Our goal is to identify novel genetic loci that influence the initiation or progression of AD. Toward this end, we evaluated a genome scan of 262 affected sib pairs (ASPs) collected as part of the NIMH AD Genetics Initiative, and included ApoE genotype and age as covariates. We identified two regions with peak lod scores of 5.54 and 4.09, where the oldest ASPs have the highest recurrence risk, and are most likely to share the regions identical-by-descent. These regions are on chromosome 21 near the APP locus (Olson, Goddard & Dudek, 2001), and on chromosome 20p (Olson, Goddard & Dudek, 2002). Our aim is to identify candidate genes in these regions and others as additional candidate regions are identified. We have established collaborations with NIMH, the Oregon Brain and Aging Study (OBAS), and the Aging and Memory Center at CWRU (UMAC) to continue these investigations into the genetics of AD. Recently, we reported evidence of linkage on chromosome 20 for AD using a novel statistical approach to incorporate covariates (e.g., age, ApoE genotype) into the analysis. These results suggest that very elderly subjects (85 years), and individuals who carry an e2 allele at the ApoE locus are more likely to be linked to this candidate region. The region on chromosome 20 includes a strong candidate gene, cystatin C (CST3), which has previously been associated with AD in case-control studies. We investigated these findings further by genotyping additional markers to narrow the candidate region, and to identify evidence of linkage disequilibrium as additional support for a susceptibility locus on chromosome 20 (Goddard et al.2004). We selected 43 elderly sibships (89 subjects) from the NIMH AD Genetics Initiative based on current age older than 84 years, and identified 129 unrelated control subjects who were older than 84 years from the Oregon Brain Aging Study to conduct linkage and association studies in this region. Fourteen additional markers were evaluated, including four markers located within or near CST3. We narrowed the candidate region on chromosome 20 to an 11.8 cM region between markers D20S174 and D20S471, which includes the CST3 candidate gene. In addition, we observed evidence of association for markers located near the CST3 candidate gene, with p-values between 0.002 and 0.08 for two-locus haplotypes. These results support the presence of a susceptibility locus for AD in the vicinity of CST3 for very elderly subjects with AD.