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

• Project/Area Number: 16590262
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human genetics
• Research Institution: Osaka University
• Principal Investigator: KAMINO Kouzin Oaska University, Graduate School of Medicine, Instructor, 医学系研究科, 助手 (40307955)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2004: ¥2,600,000 (Direct Cost: ¥2,600,000)
• Keywords: 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

Research Abstract

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.

Research Products

• [Journal Article] Albumin gene encoding free fatty acid and beta amyloid transporter is genetically associated with Alzheimer disease. (2006)
  • Author(s): 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
  • Journal Title: Psyichiatry and Clinical Neuroscience 60・Supple 1
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A novel alternative splice variant of nicastrin and its implication in Alzheimer disease. (2006)
  • Author(s): Mitsuda N, Yamagata HD, Zhong W, Aoto M, Akatsu H, Uekawa N, Kamino K, Taguchi K, Yamamoto T, Maruyama M, Kosaka K, Takeda M, Kondo I, Miki T
  • Journal Title: Life Sciences 78・21 Pages: 2444-2448
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Variations in the Brain-Derived Neurotrophic Factor (BDNF) gene have no significant association with autopsy-confirmed Alzheimer's disease or Dementia with Lewy bodies in Japanese subjects. (2006)
  • Author(s): Akatsu H, Yamagata H, Kawamata J, Kamino K, Takeda M, Yamamoto T, Miki T, Tooyama I, Shimohama S, Kosaka K, Okada H
  • Journal Title: Dementia and Geriatric Cognitive Disorders (In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Albumin gene encoding free fatty acid and beta amyloid transporter is genetically associated with Alzheimer disease. (2006)
  • Author(s): 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.
  • Journal Title: Psychiatry and Clinical Neuroscience 60-Suppl 1
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A novel alternative splice variant of nicastrin and its implication in Alzheimer disease. (2006)
  • Author(s): Mitsuda N, Yamagata HD, Zhong W, Aoto M, Akatsu H, Uekawa N, Kamino K, Taguchi K, Yamamoto T, Maruyama M, Kosaka K, Takeda M, Kondo I, Miki T.
  • Journal Title: Life Sciences 78-21 Pages: 2444-2448
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Albumin gene encoding FFA and beta amyloid transporter is a risk gen for Alzheimer disease. (2006)
  • Author(s): 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.
  • Journal Title: Psychiatry and Clinical Neuroscience (In press)
• [Journal Article] Variations in the Brain-Derived Neurotrophic Factor (BDNF) Gene have no significant association with autopsy-confirmed Alzheimer's disease or Dementia with Lewy bodies in Japanese subjects. (2006)
  • Author(s): Akatsu H, Yamagata H, Kawamata J, Kamino K, Takeda M, Yamamoto T, Miki T, Tooyama I, Shimohama S, Kosaka K, Okada H.
  • Journal Title: Dementia and Geriatric Cognitive Disorders (In press)
• [Journal Article] A novel alternative splice variant of nicastrin and its implication in Alzheimer disease. (2006)
  • Author(s): Mitsuda N, Yamagata HD, Zhong W, Aoto M, Akatsu H, Uekawa N, Kamino K, Taguchi K, Yamamoto T, Maruyama M, Kosaka K, Takeda M, Kondo I, Miki T.
  • Journal Title: Life Science (In press)
• [Journal Article] Identification of susceptibility genes for sporadic Alzheimer's disease using hippocampus-related cadidate genes. (2005)
  • Author(s): Taguchi K, Yamagata H, Zhong W, Kamino K, Akatsu H, Hata R, Yamamoto T, Kosaka K, Takeda M, Kondo I, Miki T
  • Journal Title: Annals of Neurology 57・4 Pages: 585-588
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Lymphocyte-specific protein tyrosine kinase is a novel risk gene for Alzheimer disease. (2005)
  • Author(s): Zhong W, Yamagata H, Taguchi K, Akatsu H, Kamino K, Yamamoto T, Kosaka K, Takeda M, Kondo I, Miki T
  • Journal Title: Journal of Neurological Science 238・1-2 Pages: 53-57
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 骨折と痴呆(認知症) (2005)
  • Author(s): 紙野晃人, 武田雅俊
  • Journal Title: 臨床と研究 82・6 Pages: 972-977
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 認知症 (2005)
  • Author(s): 紙野晃人, 武田雅俊
  • Journal Title: 最新医学 9・増刊号 Pages: 1993-2001
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] TAFI polymorphisms at amino acids 147 and 325 are not risk factors for cerebral infarction. (2005)
  • Author(s): Akatsu H, Yamagata H, Chen Y, Miki T, Kamino K, Takeda M, Campbell W, Kondo I, Kosaka K, Yamamoto T, Okada H.
  • Journal Title: Annals of Neurology 57-4 Pages: 585-588
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of susceptibility genes for sporadic Alzheimer's disease using hippocampus-related cadidate genes. (2005)
  • Author(s): Taguchi K, Yamagata H, Zhong W, Kamino K, Akatsu H, Hata R, Yamamoto T, Kosaka K, Takeda M, Kondo I, Miki T.
  • Journal Title: Journal of Neurological Science 238-1/2 Pages: 53-57
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Fracture and dementia. (2005)
  • Author(s): Kamino K, Takeda M.
  • Journal Title: The Japanese Journal of Clinical and Experimental Medicine 82-6 Pages: 972-977
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Dementia. (2005)
  • Author(s): Kamino K, Takeda M.
  • Journal Title: The Medical Frontline 9-Supple ed Pages: 1993-2001
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of susceptibility genes for sporadic Alzheimer's disease using hippocampus-related cadidate genes. (2005)
  • Author(s): Taguchi K, Yamagata H, Zhong W, Kamino K, Akatsu H, Hata R, Yamamoto T, Kosaka K, Takeda M, Kondo I, Miki T.
  • Journal Title: Annals of Neurology 57 Pages: 585-588
• [Journal Article] Lymphocyte-specific protein tyrosine kinase is a novel risk gene for Alzheimer disease. (2005)
  • Author(s): Zhong W, Yamagata H, Taguchi K, Akatsu H, Kamino K, Yamamoto T, Kosaka K, Takeda M, Kondo I, Miki T.
  • Journal Title: Journal of Neurological Science 238 Pages: 53-57
• [Journal Article] C677T polymorphism of methylenetetrahydrofolate reductase gene affects plasma homocysteine level and a genetic factor of late-onset Alzheimer's disease. (2004)
  • Author(s): Kida T, kamino K, Yamamoto M, Kanayama D, Tanaka T, Kudo T, Takeda M
  • Journal Title: Psychogeriatrics 4・1 Pages: 4-10
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Promoter polymorphism in fibroblast growth factor 1 gene increases risk of definite Alzheimer's disease. (2004)
  • Author(s): Yamagata H, Chen Y, Akatsu H, Kamino K, Ito J, Yokoyama S, Yamamoto T, Kosaka K, Miki T, Kondo I
  • Journal Title: Biochemcal and Biophysical Research Communications 321・2 Pages: 320-323
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Increased incidence of dementia with Lewy bodies in patients carrying the e4-allele of apolipoprotein E. (2004)
  • Author(s): Akatsu H, kamino K, Yamagata H, Isojima D, Kondo I, Yamamoto T, Kida T, Takeda M, Miki T, Kosaka K
  • Journal Title: Psychogeriatrics 4・2 Pages: 24-32
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] TAFI polymorphisms at amino acids 147 and 325 are not risk factors for cerebral infarction. (2004)
  • Author(s): Akatsu H, Yamagata H, Chen Y, Miki T, Kamino K, Takeda M, Campbell W, Kondo I, Kosaka K, Yamamoto T, Okada H
  • Journal Title: British Journal of Haematology 127・4 Pages: 440-447
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] アルツハイマー病疾患関連遺伝子の探索 (2004)
  • Author(s): 紙野晃人, 武田雅俊
  • Journal Title: 臨床精神医学 33・10 Pages: 1335-1341
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] C677T polymorphism of methylenetetrahydrofolate reductase gene affects plasma homocysteine level and a genetic factor of late-onset Alzheimer's disease. (2004)
  • Author(s): Kida T, Kamino K, Yamamoto M, Kanayama D, Tanaka T, Kudo T, Takeda M.
  • Journal Title: Psychogeriatrics 4- Pages: 4-10
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Promoter polymorphism in fibroblast growth factor 1 gene increases risk of definite Alzheimer's disease. (2004)
  • Author(s): Yamagata H, Chen Y, Akatsu H, Kamino K, Ito J, Yokoyama S, Yamamoto T, Kosaka K, Miki T, Kondo I.
  • Journal Title: Biochemcal and Biophysical Research Communications 321-2 Pages: 320-323
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Increased incidence of dementia with Lewy bodies in patients carrying the e4-allele of apolipoprotein E. (2004)
  • Author(s): Akatsu H, Kamino K, Yamagata H, Isojima D, Kondo I, Yamamoto T, Kida T, Takeda M, Miki T, Kosaka K.
  • Journal Title: Psychogeriatrics 4-2 Pages: 24-32
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Lymphocyte-specific protein tyrosine kinase is a novel risk gene for Alzheimer disease. (2004)
  • Author(s): Zhong W, Yamagata H, Taguchi K, Akatsu H, Kamino K, Yamamoto T, Kosaka K, Takeda M, Kondo I, Miki T.
  • Journal Title: British Journal of Haematology 127-4 Pages: 440-447
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Search for genes related to Alzheimer's disease (Japanese). (2004)
  • Author(s): Kamino K, Takeda M.
  • Journal Title: Japanese Journal of Clinical Psychiatry 33-10 Pages: 1335-1341
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Clinical assessment of the genetic risk functions in Alzheimer's disease. (2004)
  • Author(s): Kamino K, Kida T, Takeda M.
  • Journal Title: Molecular Neurobiology of Alzheimer Disease and Related Disorders (Takeda M, Tanaka T, Cacabelos R, Eds) Pages: 31-41
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Alzheimer's γ-secretase mechanism produces amyloid-β-protein like peptides simultaneously with release of intracellular signaling fragments. (2004)
  • Author(s): Okochi M, Fukumori A, Satoh Y, Aidaralieva N, Tanii H, Kamino K, Tanaka T, Kudo T, Takeda M.
  • Journal Title: Molecular Neurobiology of Alzheimer Disease and Related Disorders (Takeda M, Tanaka T, Cacabelos R, Eds) Pages: 71-78
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] C677T polymorphism of methylenetetrahydrofolate reductase gene affects plasma homocysteine level and a genetic factor of late-onset Alzheimer's disease. (2004)
  • Author(s): Kida T, Kamino K, Yamamoto M, Kanayama D, Tanaka T, Kudo T, Takeda M.
  • Journal Title: Psychogeriatrics 4・4 Pages: 4-10
• [Journal Article] Promoter polymorphism in fibroblast growth factor 1 gene increases risk of definite Alzheimer's disease. (2004)
  • Author(s): Yamagata H, Chen Y, Akatsu H, Kamino K, Ito J, Yokoyama S, Yamamoto T, Kosaka K, Miki T, Kondo I.
  • Journal Title: Biochem Biophys Res Commun 321 Pages: 320-323
• [Journal Article] Variations in the Brain-Derived Neurotrophic Factor (BDNF) Gene have no significant association with autopsy-confirmed Alzheimer's disease or Dementia with Lewy bodies in Japanese subjects.
  • Author(s): Akatsu H, Yamagata H, Kawamata J, Kamino K, Takeda M, Yamamoto T, Miki T, Tooyama I, Shimohama S, Kosaka K, Okada H.
  • Journal Title: Dementia and Geriatric Cognitive Disorders (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] 老年病・認知症〜長寿の秘訣〜 (2006)
  • Author(s): 紙野晃人
  • Publisher: メディカルレビュー社
• [Book] Molecular Neurobiology of Alzheimer Disease and Related Disorders (Clinical assessment of the genetic risk functions in Alzheimer's disease.) (2004)
  • Author(s): Kamino K, Kida T, Takeda M
  • Total Pages: 8
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Molecular Neurobiology of Alzheimer Disease and Related Disorders (Alzheimer'sγ-secretase mechanism produces amyloid-β-protein like peptides simultaneously with release of intracellular signaling fragments.) (2004)
  • Author(s): Okochi M, Fukumori A, Satoh Y, Aidaralieva N, Tanii H, Kamino K, Tanaka T, Kudo T, Takeda M
  • Total Pages: 11
  • Description: 「研究成果報告書概要(和文)」より