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，这表明它们可能含有LOAD易感基因。其中一个区域靠近第10号染色体上的着丝粒。我们最近报告了在我们的NIMH遗传倡议谱系子集中在该区域发现的强烈联系，伴随着父母的起源效应。我们现在调查了另一个独立的谱系子集，这些谱系是由阿拉巴马大学收集的，并在该地区复制了亲本起源效应。在精细定位后的母系组合中，多点LOD评分为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，每个标记的电流密度为1.4 cM（信息含量=0.7）。我们的第一个目标是进行关联分析，将来自我们家庭的病例与认知健康且没有阿尔茨海默病家族史的对照组进行比较。我们将对242例病例和242例对照进行基因分型，其中3,000个snp来自于用于HapMap项目的基因分型，并在白种人中发现非冗余（非完美LD），包括50个用于校正群体亚结构的基因组控制标记。我们希望这一目标能将发现范围缩小到几个与疾病相关的区域。随后将在独立样本中进行基于家庭的关联分析，以确认或拒绝。在目标2中，我们将进一步分析确认的或令人信服的相关区域，通过对其中更多已知变异进行基因分型，并通过对表达区、保守区和已知功能区的核苷酸测序检测变异。我们还将在目标1中由于低连锁不平衡而覆盖率不足的地区对其他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，以检测已知或预测转录序列在大脑中的表达，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.