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)：AD是美国第六大死因，全国每年照顾AD患者的直接和间接成本至少为1000亿美元。大多数病例(90%-95%)是晚发性AD(LOAD)，可显示家族聚集性，但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，已经一致地识别出几个染色体区域可能包含加载基因座。在我们最初对来自437个家庭的1439个个体的NIMH-ADGI同胞队列的基因组扫描中，我们用多点LOD分数(MLS)和GT；2.0确定了6个候选感兴趣区(CRI)。在可能代表APOE的19q13峰旁边，9q22信号是第二个最具提示性的信号，在101 cM处有一峰MLS=2.9，位于78-126 cM之间。我们通过对该区域内额外的微卫星进行基因分型，对9q22连锁信号进行了跟踪，并确认了该连锁信号，MLS从101 cM的2.9增加到95 cM的3.8，1 LOD间隔从21.5 cM缩小到11 cM(~92-103 cM)(Perry，2007#2444)。9q21-31区域连锁的证据也在包含NIMH和其他负载家族的数据集中得到了证实。此外，在NIMH样本和其他数据集中，位于这11 cM的这1个LOD区域附近的三个基因上的单核苷酸多态(SNPs)、Ubiqulin 1(UBQLN1，84.6 cM，Build 36)、死亡相关蛋白激酶1(DAPK1，90.9 cM)和高尔基磷蛋白2(GOLPH2，87.1 cM)已被报道与AD显著相关。他们和我们提供的证据表明，这个或其他AD易感基因中的其他变异仍有待在该区域识别。我们最近报道了位于神经营养酪氨酸受体激酶2(NTRK2)基因中间84.6cM的三个SNP单倍型与NIMH队列的显著关联(P=0.009)[Chen，20082458}。因此，有一致和令人信服的证据表明，9q22CRI含有一个或多个AD易感基因，密集的SNP定位阵列是在这个11 cM的1LOD区域识别额外易感基因的下一个合乎逻辑的步骤。为了获得至少80%的能力来检测OR为1.5或更高，我们将需要获得另一个更大的AD样本数据集，如国家阿尔茨海默病细胞库(NCRAD)提供的，该数据集包含约850个有受影响兄弟姐妹的家庭(~2,070个样本)。尽管对代表整个11 cM CRI中所有LD区块的所有htSNP进行基因分型会更好，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位的，因此建议对覆盖所有基因的LD区块中的htSNP、位于这些区块之间的SNP以及位于9q22 CRI基因间区的SNP进行识别和分型，其中拷贝数变异(CNV)位于已知区域。这种方法产生的任何初步信号随后进行测序，以确定LD中可能存在的具有这些信号的新变体。这应该足以覆盖该区域，以确定在9q22该区域导致负荷风险的基因可能的功能变异。 公共卫生相关性：阿尔茨海默病(AD)是美国第六大死亡原因，全国每年照顾AD患者的直接和间接成本至少为1000亿美元。识别与阿尔茨海默病有关的基因将有助于更好地了解该病的病因和病理，从而改进治疗并最终预防这一毁灭性疾病。