Gene detection in regions linked to Alzheimer's disease

描述(申请人提供)：在基因组扫描中检测到的晚发性阿尔茨海默病(LOAD)的所有区域中，只有几个区域持续提供阳性结果，表明它们可能含有LOAD易感基因。其中一个区域靠近10号染色体上的着丝粒。我们最近在我们的NIMH遗传学起始家系的子集中发现了一个强烈的连锁发现，并伴随着亲本起源效应。我们现在已经调查了阿拉巴马大学收集的另一个独立的家系子集，并在该地区复制了父母起源效应。在精细定位后的组合母系谱系中，多点LOD得分为3.53，达到全基因组意义的保守阈值。我们的1-LOD间隔为15厘米宽，每个标记的当前密度为1.4厘米(信息量=0.7)。我们的第一个目标是进行关联分析，比较来自我们家族的病例与认知健康且没有阿尔茨海默病家族病史的对照组。我们将对242名病例和242名对照进行基因分型，这些SNP是从HapMap项目的基因分型中挑选出来的，在高加索人中被发现是非冗余的(不是在完美的LD中)，并包括50个用于纠正种群亚结构的基因组控制标记。我们预计这一目标将把研究范围缩小到少数几个与疾病相关的地区。随后将在独立样本中进行基于家庭的关联分析，以便确认或拒绝。在目标2中，我们将进一步分析已确认或令人信服的相关区域(S)，对其中更多已知的变异进行基因分型，并通过核苷酸测序在表达、保守和已知功能区域检测到变异。我们还将在目标1中由于低连锁不平衡而导致复盖率不足的地区对额外的SNPs进行基因分型。最后，在目标3中，我们将分析已确认和令人信服的区域(S)，以检测已知或预测将转录的序列在大脑中的表达，并检查病例和对照之间以及正、负相关等位基因/单倍型之间是否存在表达差异。

DESCRIPTION (provided by applicant): Of all the regions that have been detected in genome scans for late onset Alzheimer's disease (LOAD) only a few have consistently provided positive findings, suggesting that they likely harbor a LOAD susceptibility gene. One such region is close to the centromere on chromosome 10. We recently reported a strong linkage finding in this region in our subset of the NIMH genetics initiative pedigrees, accompanied by a parent of origin effect. We have now investigated an additional independent subset of pedigrees, those collected by the University of Alabama, and replicated the parental origin effect in the region. In the combined maternal pedigree set after fine mapping the multipoint LOD score is 3.53 reaching the conservative threshold for genome-wide significance. Our 1-LOD interval is 15 cM wide with our current density of 1.4 cM per marker (information content =0.7). Our first aim is to perform an association analysis comparing cases from our families with controls that are cognitively healthy and have no family history of Alzheimer's disease. We will genotype 242 cases and 242 controls for 3,000 SNPs selected from those genotyped for the HapMap project and found to be non-redundant (not in perfect LD) in Caucasians and including 50 genomic control markers for correction of population substructure. We expect this aim to narrow down the finding to a few disease associate regions. Those will be followed up with a family based association analysis in an independent sample in order to be confirmed or rejected. In aim 2 we will further analyze the confirmed or convincing associated region(s) by genotyping more known variation within them and variation detected through nucleotide sequencing in expressed, conserved and known functional areas. We will also genotype additional SNPs in areas where the coverage in aim 1 was inadequate due to low linkage disequilibrium. Finally in aim 3 we will analyze the confirmed and convincing region(s) to detect expression in the brain of sequences known or predicted to be transcribed and we will examine the presence of expression variation between cases and controls and between positively and negatively associated alleles/haplotypes.