Elucidation of molecular mechanisms of Parkinson disease based on comprehensive nucleotide sequence analysis of glucocerebrosidase gene.

• Project/Area Number: 20249048
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: The University of Tokyo
• Principal Investigator: TSUJI Syoji The University of Tokyo, 医学部附属病院, 教授 (70150612)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥48,880,000 (Direct Cost: ¥37,600,000、Indirect Cost: ¥11,280,000); Fiscal Year 2010: ¥10,140,000 (Direct Cost: ¥7,800,000、Indirect Cost: ¥2,340,000); Fiscal Year 2009: ¥11,050,000 (Direct Cost: ¥8,500,000、Indirect Cost: ¥2,550,000); Fiscal Year 2008: ¥27,690,000 (Direct Cost: ¥21,300,000、Indirect Cost: ¥6,390,000)
• Keywords: パーキンソン病 / 神経変性 / 孤発性疾患 / 疾患感受性遺伝子 / Gaucher病 / Gaucher 病

Research Abstract

This study aimed to elucidate susceptibility genes for sporadic Parkinson disease. Comprehensive resequencing analysis of GBA (glucocerebrosidase gene) has been conducted using 534 Japanese cases of sporadic Parkinson disease and 544 Japanese healthy controls. We found that the frequency of cases of Parkinson disease with heterozygous variants of GBA was 9.4%, which was significantly more frequent than that of controls (0.37%) with the odds ratio of 28.0 (95% CI : 4.3-238.3, p=6.9X10^<-14>). We furthermore conducted international collaboration to explore whether heterozygous variants of GBA confer such a strong risk for Parkinson disease irrespective of ethnicity. We confirmed that heterozygous variants of GBA confers a strong risk for Parkinson disease irrespective of ethnicity. These results strongly indicate that comprehensive resequencing analysis is necessary to identify rare variants. To enable comprehensive resequencing of large data sets, we applied next generation sequencers to analyze pooled DNA. We demonstrated that we can sensitively and accurately determine the allele frequencies of variants using pooled genomic DNA consisting of 6 samples.

Research Products

• [Journal Article] Multiplexed resequencing analysis to identify rare variants in pooled DNA with barcode indexing employing next-generation sequencer Running Title : Multiplexed resequencing analysis of pooled DNA (2010)
  • Author(s): Mitsui J, Fukuda Y, Azuma K, Tozaki H, Ishiura H, Takahashi Y, Goto J, Tsuji S
  • Journal Title: J.Hum.Genet. 55 Pages: 448-455
  • Peer Reviewed
• [Journal Article] Genetics of neurdegenerative diseases : insights from high-throughput resequencing (2010)
  • Author(s): Tsuji S
  • Journal Title: Hum.Mol.Genet. 19
  • Peer Reviewed
• [Journal Article] Mechanisms of genomic instabilities underlying two common fragile site-associated loci, PARK2 and DMD, in germ cell and cancer cell lines (2010)
  • Author(s): 3. Mitsui J, Takahashi Y, Goto J, Tomiyama H, Ishikawa S, Yoshino H, Minami N, Smith DI, Lesage S, Aburatani H, Nishino I, Brice I, Hattori N, Tsuji S
  • Journal Title: Amer J Hum Genet 87 Pages: 75-89
  • Peer Reviewed
• [Journal Article] CpG Demethylation Enhances Alpha-Synuclein Expression and Affects the Pathogenesis of Parkinson's Disease (2010)
  • Author(s): Matsumoto L, Takuma H, Tamaoka A, Kurisaki H, Date H, Tsuji S, Iwata A
  • Journal Title: PLOS One 5
  • Peer Reviewed
• [Journal Article] Multiplexed resequencing analysis to identify rare variants in pooled DN A with barcode indexing employing next-generation sequencer Running Title : Multiplexed resequencing analysis of pooled DNA. (2010)
  • Author(s): Mitsui J, Fukuda Y, Azuma K, Tozaki H, Ishura H, Takahashi Y, Goto J, Tsuji S.
  • Journal Title: J.Hum.Genet Volume: 55 Pages: 448-445
  • Peer Reviewed
• [Journal Article] Genetics of neurodegenerative diseases : insights from high-throughput resequencing. (2010)
  • Author(s): Tsuji S.
  • Journal Title: Hum.Mol.Genet. Volume: 19
  • Peer Reviewed
• [Journal Article] Multiplexed resequencing analysis to identify rare variants in pooled DNA with barcode indexing employing next-generation sequencer Running Title : Multiplexed resequencing analysis of pooled DNA. (2010)
  • Author(s): Mitsui J, Fukuda Y, Azuma K, Tozaki H, Ishiura H, Takahashi Y, Goto J, Tsuji S.
  • Journal Title: J.Hum.Genet. (in Press, 印刷中)
  • Peer Reviewed
• [Journal Article] Mutations for Gaucher disease confer a high susceptibility to Parkinson disease (2009)
  • Author(s): Mitsui J, Mizuta I, Toyoda A, Ashida R, Takahashi Y, Goto J, Fukuda Y, Date H, Iwata A, Yamamoto M, Hattori N, Murata M, Toda, T, Tsuji S
  • Journal Title: Arch Neurol 66 Pages: 571-6
  • Peer Reviewed
• [Journal Article] International multi-center analysis of glucocerebrosidase mutations in Parkinson disease (2009)
  • Author(s): 390. Sidransky E, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen C-M, Clark ON, Condroyer C, De Marco EV, Drr A, Eblan MJ, Fahn S, Farrer M, Fung H-C, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp R, Lang AE, Lee-Chen G-J, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nalls MA, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan E-K, Tayebi N, Toda T, Troiano A, Tsuji S, Wittstock M, Wolfsberg TG, Wu Y-R, Zabetian CP, Zhao Y, Ziegler SG
  • Journal Title: New Engl J.Med. 361 Pages: 1651-1661
  • Peer Reviewed
• [Journal Article] Mutations for Gaucher disease confer a high susceptibility to Parkinson disease. (2009)
  • Author(s): Mitsui, J, Mizuta, I, Toyoda, A, Ashida, R, Takahashi, Y, Goto, J, Fukuda, Y, Date, H, Iwata, A, Yamamoto, M, Hattori, N, Murata, M, Toda, T, Tsuji, S.
  • Journal Title: Arch Neurol 66 Pages: 571-576
  • Peer Reviewed
• [Journal Article] International multi-center analysis of glucocerebrosidase mutations in Parkinson disease. (2009)
  • Author(s): Sidransky E, Aasly JO, …Mitsui J, …Tsuji S, …Zhao Y, Ziegler SG.
  • Journal Title: New Engl J.Med. 361 Pages: 1651-1661
  • Peer Reviewed
• [Journal Article] Mutations for Gaucher disease confer a high susceptibility to Parkinson disease.
  • Author(s): Mitsui, J, Mizuta, I, Toyoda, A, A shida, R, Takahashi, Y, Goto, J, F ukuda, Y, Date, H, Iwata, A, Yam amoto, M, Hattori, N, Murata, M, Toda, T and Tsuji, S.
  • Journal Title: Arch Neurol(in press)
  • Peer Reviewed
• [Presentation] Heterozygous Rare Variants Associated with Gaucher Disease Confer Robust Susceptibility to Parkinson Disease (2008)
  • Author(s): Mitsui J, Mizuta I, Toyoda A, Ashida R, Takahashi Y, Goto J, Fukuda Y, Date H, Iwata A, Yamamoto M, Hattori N, Murata M, Toda T, Tsuji, S
  • Organizer: The 60th American Academy of Neurology Annual Meeting. Philadelphia
  • Place of Presentation: The United States of America