Construction of the linkage disequilibrium map by SNP analysis and its application in mapping of disease-susceptibility genes

SNP分析连锁不平衡图谱构建及其在疾病易感基因定位中的应用

• 批准号: 16590262
• 负责人: KAMINO Kouzin
• 金额: $ 2.3万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590262/
• 关键词: Down syndrome; Alzheimer disease; chromosome 21; chromosome 12; SNP; linkage disequilibrium; genome scan; genetic factor; 遺伝子; 第12染色体; リスク; 老化; SNP解析; ハプロタイプ解析; 遺伝的リスク

SNP scanning at about 100 kb distance of late onset Alzheimer disease (LOAD) at chromosome 12p and 21 loci were performed, using 188 cases of the patients with LOAD and 375 population-based controls (The 1st stage). We identified disease-related effects in 73 SNPs (out of 389 SNPs,18.8%) at the 12p locus, and 59 SNPs (out of 456 SNPs,14.1%) at the 21 locus. In the 2nd stage, the confirmatory genotyping was done using 375 cases and the same 375 controls. In case of the chromosome l12p locus, 15 SNPs found by logistic regression, 2 SNPs found by haplotype risk effect, and 1 SNP found by age-at-onset correlation at the 1st stage (total 18 SNPs) were indicated significant linkage disequilibriums with LOAD. A risk locus spanning in the range of 300 kb (27.0-27.3 Mb from 12p-ter), harboring one gene relating to transcriptional regulation, coincided to the locus between D12S1042 (27.5 Mb from 12p-ter) and D12S1057 (24.6Mb from 12p-ter). In case of the chromosome 21 locus, 14 SNPs indicated significant risk effects, and notably, DYRK1A gene located in the Down Syndrome Critical Region indicated that a SNP located at upstream was likely functional. The expressional level of the DYRK1A mRNA in the brain was decreased in subjects with homozygous for the risk allele of the DYRK1A gene. However, the expression of DYRK1A mRNA was increased in all patients with LOAD, suggesting that DYRK1A protein could be neuroprotective. The assumption was supported by the evidence that in cell culture experiments, the expression of DYRK1A protein is increased by oxidative stress. These results indicated that construction of the linkage disequilibrium map by SNP genotyping makes possible to identify the disease-susceptibility genes.

对188例晚发性阿尔茨海默病（LOAD）患者和375例正常对照（第一期）进行了12号染色体12 p和21个位点约100 kb距离的SNP扫描。我们在12 p位点的73个SNPs（389个SNPs中的18. 8%）和21个位点的59个SNPs（456个SNPs中的14. 1%）中鉴定出疾病相关效应。在第二阶段中，使用375例病例和相同的375名对照进行确证性基因分型。在染色体l12 p位点，Logistic回归分析发现15个SNP，单倍型风险效应发现2个SNP，第1阶段发病年龄相关发现1个SNP（共18个SNP）与LOAD存在显著连锁不平衡。在D12 S1042（27.5Mb）和D12 S1057（24.6Mb）之间有一个风险基因座，该风险基因座位于300 kb（27.0- 27.3Mb）之间，含有一个与转录调控有关的基因。在21号染色体基因座的情况下，14个SNP指示显著的风险效应，并且值得注意的是，位于唐氏综合征关键区域的DYRK 1A基因指示位于上游的SNP可能是功能性的。DYRK 1A基因危险等位基因纯合子的受试者脑中DYRK 1A mRNA的表达水平降低。而DYRK 1A mRNA在LOAD患者中的表达均增加，提示DYRK 1A蛋白可能具有神经保护作用。在细胞培养实验中，DYRK 1A蛋白的表达因氧化应激而增加，这一假设得到了证据的支持。这些结果表明，通过SNP基因分型构建的连锁不平衡图谱，为疾病易感基因的鉴定提供了可能。

项目成果

Promoter polymorphism in fibroblast growth factor 1 gene increases risk of definite Alzheimer's disease.

成纤维细胞生长因子 1 基因的启动子多态性会增加患阿尔茨海默病的风险。

• 发表时间: 2004
• 期刊: Biochem Biophys Res Commun 321
• 作者: Yamagata H;Chen Y;Akatsu H;Kamino K;Ito J;Yokoyama S;Yamamoto T;Kosaka K;Miki T;Kondo I.
• 通讯作者: Kondo I.

Lymphocyte-specific protein tyrosine kinase is a novel risk gene for Alzheimer disease.

淋巴细胞特异性蛋白酪氨酸激酶是阿尔茨海默病的新风险基因。

• 发表时间: 2005
• 期刊: Journal of Neurological Science 238・1-2
• 作者: Zhong W;Yamagata H;Taguchi K;Akatsu H;Kamino K;Yamamoto T;Kosaka K;Takeda M;Kondo I;Miki T
• 通讯作者: Miki T

Albumin gene encoding FFA and beta amyloid transporter is a risk gen for Alzheimer disease.

编码 FFA 和 β 淀粉样蛋白转运蛋白的白蛋白基因是阿尔茨海默病的危险基因。

• 发表时间: 2006
• 期刊: Psychiatry and Clinical Neuroscience (In press)
• 作者: Kimura R;Kamino K;Yamamoto M;Akatsu H;Uema T;Kobayashi T;Hattori H;Nuripa A;Nessa B;Kudo T;Yamagata H;miki T;Takeda M.
• 通讯作者: Takeda M.

Search for genes related to Alzheimer's disease (Japanese).

搜索与阿尔茨海默病相关的基因（日语）。

• 发表时间: 2004
• 期刊: Japanese Journal of Clinical Psychiatry 33-10
• 作者: Kamino K;Takeda M.
• 通讯作者: Takeda M.

Increased incidence of dementia with Lewy bodies in patients carrying the e4-allele of apolipoprotein E.

携带载脂蛋白 E e4 等位基因的患者路易体痴呆发生率增加。

• 发表时间: 2004
• 期刊: PSYCHOGERIATRICS 4
• 作者: Akatsu H;Kamino K;Yamagata H;Isojima D;Kondo I;Yamamoto T;Kida T;Takeda M;Miki T;Kosaka K.
• 通讯作者: Kosaka K.