Gene detection in regions linked to Alzheimer's disease

描述（由申请人提供）：在晚发性阿尔茨海默病（LOAD）基因组扫描中检测到的所有区域中，只有少数区域始终提供阳性结果，表明它们可能含有LOAD易感基因。一个这样的区域靠近10号染色体上的着丝粒。我们最近报道了一个强有力的连锁发现，在这个地区在我们的子集的NIMH遗传学倡议谱系，伴随着父母的原产地的影响。我们现在已经调查了另外一个独立的家系子集，这些家系是由亚拉巴马大学收集的，并在该地区复制了亲本来源效应。在精细定位后的组合母系谱系集中，多点LOD得分为3.53，达到全基因组显著性的保守阈值。我们的1-LOD间隔为15 cM宽，我们的电流密度为1.4 cM/标记（信息含量=0.7）。我们的第一个目标是进行关联分析，比较我们家族的病例与认知健康且无阿尔茨海默病家族史的对照组。我们将对242例病例和242例对照进行3,000个SNPs的基因分型，这些SNPs选自HapMap项目的基因分型，并发现在高加索人中是非冗余的（不是完美的LD），包括50个基因组对照标记，用于校正群体亚结构。我们希望这一目标能将发现范围缩小到几个疾病相关区域。这些将在一个独立的样本中进行基于家族的关联分析，以确认或拒绝。在目标2中，我们将进一步分析确认或令人信服的相关区域，方法是对其中更多已知的变异进行基因分型，并通过表达、保守和已知功能区域的核苷酸测序检测变异。我们还将在aim 1中的覆盖率由于低连锁不平衡而不足的地区对额外的SNP进行基因分型。最后，在目标3中，我们将分析确认的和令人信服的区域以检测已知或预测要转录的序列在脑中的表达，并且我们将检查病例和对照之间以及正相关和负相关等位基因/单倍型之间的表达变异的存在。

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.