Dense SNP Genotyping and Sequencing of the 12cM 9q22 Alzheimer?s Candidate Region

12cM 9q22 阿尔茨海默病候选区域的密集 SNP 基因分型和测序

• 批准号: 7883315
• 负责人: RODNEY T PERRY
• 金额: $ 18.89万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883315
• 关键词: 19q13; 9q21; 9q22; Affect; Alzheimer' s Disease; Apolipoprotein E; Area; Candidate Disease Gene; Caring; Cause of Death; Cells; Chromosomes; Copy Number Polymorphism; DAP kinase; DNA; DNA Sequence; Data; Data Set; Databases; Disease; Disease susceptibility; Family; Frequencies; Functional RNA; Future; Genes; Genetic; Genetic Risk; Genetic Variation; Genome Scan; Genotype; Goals; Golgi Apparatus; Haplotypes; Individual; Late Onset Alzheimer Disease; Lead; Link; Lod Score; Maps; Microsatellite Repeats; National Institute of Mental Health; Participant; Pathology; Phosphoproteins; Population; Prevention; Publishing; Receptor Protein-Tyrosine Kinases; Reporting; Risk; Risk Marker; Sampling; Scanning; Siblings; Signal Transduction; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Susceptibility Gene; Testing; United States; Variant; base; case control; cohort; cost; follow-up; genetic variant; genome-wide linkage; improved; interest; novel; public health relevance; repository; ubiquilin

DESCRIPTION (provided by applicant): AD is the sixth leading cause of death in the United States and national direct and indirect annual costs of caring for individuals with AD are at least $100 billion. The majority of cases (90-95%) are late-onset AD (LOAD) that can show familial clustering without a clear Mendelian mode of inheritance. Several chromosomal regions have been consistently identified that may harbor LOAD loci in genome-wide linkage scans on several cohorts. In our original genome scan of the NIMH-ADGI sibling cohort of 1439 individuals from 437 families we identified six candidate regions of interest (CRI) with multipoint LOD scores (MLS) > 2.0 {Blacker, 2003 #1067}. Next to the 19q13 peak, which probably represents APOE, the 9q22 signal was the next most suggestive, with a peak MLS = 2.9 at 101 cM and located between 78 and 126 cM. We have followed-up the 9q22 linkage signal by genotyping additional microsatellites within this region and have confirmed the linkage signal with an increase of the MLS from 2.9 at 101 cM to 3.8 at 95 cM and the 1 LOD interval narrowed from 21.5 cM to 11 cM (~92-103 cM) {Perry, 2007 #2444}. Evidence for linkage in the 9q21-31 region has also been confirmed in data sets containing NIMH and other LOAD families. Furthermore, single nucleotide polymorphisms (SNPs) located in three genes adjacent to this 1 LOD region of 11 cM, Ubiquilin 1 (UBQLN1, 84.6 cM, Build 36) Death-Associated Protein Kinase 1 (DAPK1, 90.9 cM), and Golgi Phosphoprotein 2 (GOLPH2, 87.1 cM) have been reported to be significantly associated with AD in the NIMH sample and other data sets. They and we provide evidence that additional variants in this or other AD susceptibility genes remain to be identified in this region. We recently reported a significant association (P=0.009) of a three SNP haplotype in the middle of the neurotrophic tyrosine receptor kinase 2 (NTRK2) gene, located at 84.6 cM, to the NIMH cohort {Chen, 2008 #2458}. Thus, there is consistent and compelling evidence suggesting the 9q22 CRI harbors one or more AD susceptibility genes and a dense SNP mapping array is the next logical step to identify additional susceptibility genes in this 1 LOD region of 11 cM. In order to obtain at least 80% power to detect an OR of 1.5 or more, we will need to obtain another larger dataset of AD samples, such as available at the National Cell Repository for Alzheimer's Disease (NCRAD) consisting of ~850 families with affected siblings (~2,070 samples). Although it would be preferable to genotype all htSNPs representing all LD blocks in the entire 11 cM CRI, budgetary constraints limit us for this approach. We believe genes are of first priority and therefore propose to identify and genotype htSNPs in LD blocks covering all the genes, SNPs located between these blocks, and SNPs located in intergenic areas of the 9q22 CRI where copy number variations (CNVs) are known to be located. Any preliminary signals from this approach are then followed by sequencing to identify possible new variants in LD with these signals. This should sufficiently cover the region for identification of possible functional variants of genes contributing to LOAD risk in this region on 9q22. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the sixth leading cause of death in the United States and national direct and indirect annual costs of caring for individuals with AD are at least $100 billion. Identification of genes involved in AD would lead to better understanding of the cause and pathology of the disease and thus lead to improved treatment and eventual prevention of this devastating disease in the future.

描述（由申请人提供）：AD是美国第六大死因，全国每年护理AD患者的直接和间接费用至少为1000亿美元。大多数病例（90-95%）是迟发性AD（LOAD），可显示家族聚集性，无明确的孟德尔遗传模式。几个染色体区域已被一致确定，可能窝藏负载基因座在全基因组连锁扫描几个队列。在我们对来自437个家族的1439个个体的NIMH-ADGI同胞群组的原始基因组扫描中，我们鉴定了具有多点LOD得分（MLS）> 2.0的六个候选感兴趣区域（CRI）{Blacker，2003#1067}。在19 q13峰（可能代表APOE）旁边，9 q22信号是下一个最具暗示性的信号，峰值MLS = 2.9，位于101 cM处，位于78和126 cM之间。我们通过对该区域内的其他微卫星进行基因分型来跟踪9 q22连锁信号，并证实了连锁信号，MLS从101 cM处的2.9增加到95 cM处的3.8，1 LOD区间从21.5 cM缩小到11 cM（~92-103 cM）{佩里，2007 #2444}。在9 q21 -31区域的联系的证据也已在包含NIMH和其他LOAD家族的数据集中得到证实。此外，位于邻近11 cM的1 LOD区域的三个基因中的单核苷酸多态性（SNP），即泛素1（UBQLN 1，84.6 cM，Build 36）、死亡相关蛋白激酶1（DAPK 1，90.9 cM）和高尔基体磷蛋白2（GOLPH 2，87.1 cM），已被报道与NIMH样本和其他数据集中的AD显著相关。他们和我们提供的证据表明，在这个或其他AD易感基因的其他变异仍有待确定在这一地区。我们最近报道了位于神经营养酪氨酸受体激酶2（NTRK 2）基因中间的三个SNP单倍型（位于84.6cM）与NIMH群组的显著关联（P=0.009）{Chen，2008 #2458}。因此，有一致的和令人信服的证据表明，9 q22 CRI窝藏一个或多个AD易感基因和一个密集的SNP定位阵列是下一个合乎逻辑的步骤，以确定额外的易感基因在这个11 cM的1 LOD区域。为了获得至少80%的功效来检测OR为1.5或更大的AD样本，我们需要获得另一个更大的AD样本数据集，例如国家阿尔茨海默病细胞储存库（NCRAD）中提供的数据集，该数据集由约850个具有受影响兄弟姐妹的家庭组成（约2，070个样本）。尽管优选对代表整个11 cM CRI中所有LD区块的所有htSNP进行基因分型，但预算限制限制了我们采用这种方法。我们认为基因是第一优先，因此提出在覆盖所有基因的LD块中鉴定和基因分型htSNPs，位于这些块之间的SNPs，以及位于9 q22 CRI的基因间区域的SNPs，其中已知拷贝数变异（CNVs）位于该区域。然后对来自该方法的任何初步信号进行测序，以鉴定具有这些信号的LD中可能的新变体。这应足以覆盖该区域，以鉴定9 q22上该区域中导致LOAD风险的基因的可能功能变体。 公共卫生相关性：阿尔茨海默病（AD）是美国第六大死亡原因，全国每年用于照顾AD患者的直接和间接费用至少为1000亿美元。参与AD的基因的鉴定将导致更好地理解疾病的原因和病理，从而导致改善治疗和最终预防这种毁灭性疾病的未来。