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: 8098085
• 负责人: RODNEY T PERRY
• 金额: $ 14.37万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8098085
• 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; 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）：阿尔茨海默病是美国第六大死亡原因，全国每年用于照顾阿尔茨海默病患者的直接和间接费用至少为1000亿美元。大多数病例（90-95%）为迟发性AD (LOAD)，可表现为家族聚集性，没有明确的孟德尔遗传模式。在几个队列的全基因组连锁扫描中，已经一致地确定了几个染色体区域可能含有LOAD位点。在我们对来自437个家庭的1439个NIMH-ADGI兄弟姐妹队列的原始基因组扫描中，我们确定了6个候选感兴趣区域（CRI），多点LOD评分（MLS）为bbb2.0 {Blacker, 2003 #1067}。在19q13峰（可能代表APOE）之后，9q22信号在101 cM处的MLS = 2.9，位于78 - 126 cM之间，是下一个最有暗示意义的信号。我们对该区域的9q22连锁信号进行了进一步的基因分型，证实了该连锁信号的MLS从101 cM处的2.9增加到95 cM处的3.8,1 LOD间隔从21.5 cM缩小到11 cM (~92-103 cM) {Perry, 2007 #2444}。在包含NIMH和其他LOAD家族的数据集中也证实了9q21-31区域的关联证据。此外，据报道，在NIMH样本和其他数据集中，位于11 cM的1 LOD区域附近的三个基因的单核苷酸多态性（snp），泛素1 （UBQLN1, 84.6 cM, Build 36）死亡相关蛋白激酶1 （DAPK1, 90.9 cM）和高尔基磷酸化蛋白2 （GOLPH2, 87.1 cM）与AD显著相关。他们和我们提供的证据表明，在该地区，这种或其他阿尔茨海默病易感基因的其他变异仍有待发现。我们最近报道了位于84.6 cM的神经营养酪氨酸受体激酶2 （NTRK2）基因中间的三个SNP单倍型与NIMH队列的显著关联（P=0.009） [Chen, 2008 #2458]。因此，有一致且令人信服的证据表明9q22 CRI含有一个或多个阿尔茨海默病易感基因，密集的SNP定位阵列是下一步在11cm的1lod区域鉴定其他易感基因的逻辑步骤。为了获得至少80%的功率来检测1.5或更高的OR，我们将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库（NCRAD）中包含约850个有患病兄弟姐妹的家庭（约2,070个样本）。尽管对整个11 cM CRI中代表所有LD块的所有htsnp进行基因型比较可取，但预算限制了我们采用这种方法。我们认为基因是最重要的，因此我们提出在覆盖所有基因的LD区、位于这些区之间的SNPs以及位于拷贝数变异（CNVs）已知所在的9q22 CRI基因间区域的SNPs进行鉴定和基因分型。从这种方法得到的任何初步信号之后，接着进行测序，以确定具有这些信号的LD可能的新变体。这应该足以覆盖该区域，以鉴定可能导致9q22上该区域LOAD风险的基因的功能变异。