Genetic analyses of intracranial aneurysms

2009 Fiscal Year Final Research Report

• Project/Area Number: 17019007
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokai University (2006-2009); The University of Tokyo (2005)
• Principal Investigator: INOUE Ituro Tokai University, 医学部, 教授 (00192500)
• Project Period (FY): 2005 – 2009
• Keywords: 脳動脈瘤 / 疾患遺伝子 / ゲノム / 連鎖解析

Research Abstract

Saccular intracranial aneurysms (IAs) are balloon-like dilations of the intracranial arterial wall; their hemorrhage results in severe neurologic impairment and death. We identified three new loci showing strong evidence for association with IA. Together, these 5 loci explain ~5% of the genetic risk of IA. It is noteworthy that 3 of these putative risk genes encode regulators of the cell cycle. These findings have implications for the pathogenesis and pre-clinical diagnosis of IA. Despite the gene identification with the largest scale GWAS, the whole picture of the susceptibilities underlying IA is not still uncovered.

Research Products

• [Journal Article] Genome-wide association study of intracranial aneurysms identifies 5 risk loci. (2010)
  • Author(s): Yasuno K, Bilguvar K, Bijlenga P, Kee ALS, Krischek B, Auburger G, Simon M, Krex D, Arlier Z, Nayak N, Ruigrok Y, Niemela M, Tajima A, Frauberg M, Tamas D, Wirjatijasa F, Hata A, Jordi B, Oszvald A, Kasuya H, Gulam Z, Schoch B, Pankaj S, Stuer C, Roelof R, Beck J, Sola T, Ricciardi F, Aromaa A, Illig T, Schreiber S, Duijin CM, Berg LH, Claire P, Carole P, Roder C, Ozturk A, Gaal E, Jeremy W, Berg D, Geisen C, Christoph F, Paul S, Alex F, State MW, Wichmann HE, Breteler MMB, Wijmenga C, Mane S, Juan JE, Sandalcioglu IE, Meyer B, Raabe A, Daniel R, Jaaskelainen A, Hemesniemi J, Rinkel GJE, Zewnbutsu H, Inoue I, Palotie A, Cambien F, Nakamura Y, Lifton RP, Guenel M.
  • Journal Title: Nat Genet 43 Pages: 420-425
  • Peer Reviewed
• [Journal Article] Meta-analysis of genetic association studies: methodologies, between-study heterogeneity and winner's curse. (2009)
  • Author(s): Nakaoka H, Inoue I
  • Journal Title: J Hum Genet 54 Pages: 615-623
  • Peer Reviewed
• [Journal Article] The phenotype and genotype experiment object model (PaGE-OM): a robust data structure for information related to DNA variation. (2009)
  • Author(s): Brookes AJ, Lehvaslaiho H, Muilu J, Shigemoto Y, Oroguchi T, Tomiki T, Mukaiyama A, Konagaya A, Kojima T, Inoue I, Kuroda M, Mizushima H, Thorisson GA, Dash D, Rajeevan H, Darlison MW, Woon M, Fredman D, Smith AV, Senger M, Naito K, Sugawara H
  • Journal Title: Hum Mutat 30 Pages: 968-977
  • Peer Reviewed
• [Journal Article] Association analysis of genes involved in the maintenance of the integrity of the extracellular matrix with intracranial aneurysms in a Japanese cohort. (2009)
  • Author(s): Ruigrok YM, Rinkel GJ, Wijmenga C, Kasuya H, Tajima A, Takahashi T, Hata A, Inoue I, Krischek B
  • Journal Title: Cerebrovasc Dis 28 Pages: 131-134
  • Peer Reviewed
• [Journal Article] Genome-wide association database developed in the Japanese Integrated Database Project. (2009)
  • Author(s): Koike A, Nishida N, Inoue I, Tsuji S, Tokunaga K.
  • Journal Title: J Hum Genet 54 Pages: 543-546
• [Journal Article] Further evidence for an association between mandibular height and the growth hoemone receptor genes in a Japanese population. (2009)
  • Author(s): Tomoyasu Y, Yamaguchi T, Tajima A, Inoue I, Maki K.
  • Journal Title: Am J Orthod Dentofacial Orthop 136 Pages: 536-541
  • Peer Reviewed
• [Journal Article] Susceptibility loci for intracranial aneurysm in Europe and Japanese populations. (2008)
  • Author(s): Bilguvar K, Yasuno K, Niemela M, Ruigrok YM, Fraunberg M, Duijn CM, Berg LH, Mane S, Mason C, Choi M, Gaaal E, Bayri Y, Kolb L, Arlier Z, Ravuri S, Ronkainen A, Tajima A, Laakso A, Hata A, Kasuya H, Koivisto T, Rinne J, Ohman J, Breteler MMB, Wijmenga C, State MW, Rinkel GJE, Hernesniemi J, Jaaskelainen JE, Palotie A, Inoue I, Lifton RP, Gunel M.
  • Journal Title: Nat Genet 40 Pages: 1472-1477
  • Peer Reviewed
• [Journal Article] Evaluating the performance of Affymetrix SNP Array 6. 0 platform with 400 Japanese individuals. (2008)
  • Author(s): Nishida N, Koike A, Tajima A, Ogasawara Y, Ishibashi Y, Uehara Y, Inoue I, Tokunaga K
  • Journal Title: BMC Genomics 9 Pages: 431
  • Peer Reviewed
• [Journal Article] Network-based gene expression analysis of intracranial aneurysm tissue reveals role of antigen presenting cells. (2008)
  • Author(s): Krischek B, Kasuya H, Tajima A, Akagawa H, Sasaki T, Yoneyama T, Ujiie H, Kubo O, Bonin M, Takakura K, Hori T, Inoue I
  • Journal Title: Neuroscience 154 Pages: 1398-1407
  • Peer Reviewed
• [Journal Article] Gene expression in a canine basilar artery vasospasm model: a genome-wide network-based analysis. (2008)
  • Author(s): Sasahara A, Kasuya H, Krischek B, Tajima A, Onda H, Sasaki T, Akagawa H, Hori T, Inoue I
  • Journal Title: Neurosurg Rev 31 Pages: 283-290
  • Peer Reviewed
• [Journal Article] Identification of SNP markers for common CNV regions and association analysis of risk of subarachnoid aneurismal hemorrhage in Japanese population. (2008)
  • Author(s): Bae JS, Cheong HS, Kim JO, Lee SO, Kim EM, Lee HW, Kim S, Kim JW, Cui T, Inoue I, Shin HD
  • Journal Title: Biochem Biophys Res Commun 373 Pages: 593-596
  • Peer Reviewed
• [Journal Article] Large-scale analysis of Macaca fasciccularis transcripts and inference of genetic divergence between M. (2008)
  • Author(s): Osada N, Hashimoto K, Kameoka Y, Hirata M, Tamura R, Uno Y, Inoue I, Hida M, Suzuki Y, Sugano S, Terao K, Kusuda J, Takahashi I
  • Journal Title: fasciccularis and M. mulatta. BMC Genomics 9 Pages: 90
  • Peer Reviewed
• [Journal Article] Increased expression of ephrin A1 in brain arteriovenous malformation. (2007)
  • Author(s): Sasahara A, Kasuya H, Akagawa H, Ujiie H, Kubo O, Sasaki T, Onda H, Sakamoto Y, Krischek B, Hori T, Inoue I
  • Journal Title: Neurosurg Rev 30 Pages: 299-305
  • Peer Reviewed
• [Journal Article] Gene expression changes during the chondrogenic differentiation of human mesenchymal stem cells (2007)
  • Author(s): Ikeda R, Tsukahara S, Yoshida K, Inoue I
  • Journal Title: J Biol Sci 7 Pages: 729-736
  • Peer Reviewed
• [Journal Article] Systematic screening of lysyl oxidase-like (LOXL) family genes demonstrates that LOXL2 is a susceptibility gene to intracranial aneurysms. (2007)
  • Author(s): Akagawa H, Narita A, Yamada H, Tajima A, Krischek B, Kasuya H, Hori T, Kubota M, Saeki N, Hata A, Mizutani M, Inoue I
  • Journal Title: Hum Genet 121 Pages: 377-387
  • Peer Reviewed
• [Journal Article] The alanine/threonine polymorphism of the alpha-1-antichymotrypsin (SERPINA3) gene and ruptured intracranial aneurysms in the Japanese population. (2006)
  • Author(s): Krischek B, Akagawa H, Tajima A, Narita A, Kasuya H, Hori T, Inoue I
  • Journal Title: Cerebrovasc Dis 23 Pages: 46-49
  • Peer Reviewed
• [Journal Article] Using endothelial nitric oxide synthase gene polymorphisms to identify intracranial aneurysms more prone to rupture in Japanese patients. (2006)
  • Author(s): Krischek B, Kasuya H, Akagawa H, Tajima A, Narita A, Onda H, Hori T, Inoue I
  • Journal Title: J Neurosurg 105 Pages: 717-722
  • Peer Reviewed
• [Journal Article] A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms. (2006)
  • Author(s): Akagawa H, Tajima A, Sakamoto Y, Krischek B, Yoneyama T, Kasuya H, Onda H, Hori T, Kubota M, Machida T, Saeki N, Hata A, Hashiguchi K, Kimura E, Kim C-J, Yang T-K, Lee J-Y, Kimm K, Inoue I.
  • Journal Title: Hum Mol Genet 15 Pages: 1722-1734
  • Peer Reviewed
• [Journal Article] Is there any evidence for linkage on chromosome 17cen in affected Japanese sib-pairs with an intracranial aneurysm? (2006)
  • Author(s): Krischek B, Narita A, Akagawa H, Kasuya H, Tajima A, Onda H, Yoneyama T, Hori T, Inoue I
  • Journal Title: J Hum Genet 51 Pages: 491-494
  • Peer Reviewed
• [Journal Article] Collagen Morphology Is Not Associated With the Ala549Pro Polymorphism of the COL1A2 Gene. (2005)
  • Author(s): Krischek B, Kasuya H, Inoue I
  • Journal Title: Stroke 36 Pages: 2068-2069
  • Peer Reviewed
• [Journal Article] Endothelial nitric oxidase synyhase T-786C single nucleotide polymorphism is not a factor influencing aneurysm size. (2005)
  • Author(s): Akagawa H, Kasuya H, Onda H, Yoneyama T, Choi K-Y, Lee W-J, Hong S-W, Yang T-K, Kim C-J, Hori T, Inoue I
  • Journal Title: J Neurosurgery 95 Pages: 622-625
  • Peer Reviewed
• [Journal Article] Differential Effects of chromosome 9p21 variation on subphenotypes of intracranial aneurysm: site distribution.
  • Author(s): Nakaoka H, Takahashi T, Akiyama K, Cui T, Tajima A, Krischek B, Kasuya H, Hata A, Inoue I
  • Journal Title: Stroke (in press)
  • Peer Reviewed
• [Journal Article] Association of the Jun dimerization protein 2 gene with intracranial aneurysms in Japanese and Korean cohorts as compared to a Dutch cohort.
  • Author(s): Krischek B, Tajima A, Akagawa H, Narita A, Ruigrok Y, Rinkel G, Wijmenga C, Feigi GC, Kim CJ, Hori T, Tatagiba M, Kasuya H, Inoue I
  • Journal Title: Neuroscience (in press)
  • Peer Reviewed
• [Journal Article] Positional effects of polymorphisms in probe-target sequences on genoplot images of oligonucleotide microarrays.
  • Author(s): Cui TL, Nakaoka H, Akiyama K, Kamura H, Hosomichi K, Bae J, Cheong H, Shin H, Yada T, Inoue I
  • Journal Title: Genet Mol Res (in press)
  • Peer Reviewed
• [Remarks] 日本経済新聞2006年10月9日「脳卒中予防へ成果-くも膜下出血、関連遺伝子を同定-」
• [Remarks] NHKニュース2008年11月10日「くも膜下出血に関連遺伝子」
• [Remarks] 毎日新聞2008年11月10日「くも膜下出血:発症高める脳動脈瘤の遺伝子領域特定」
• [Remarks] 日本経済新聞200年11月10日「脳動脈瘤-原因遺伝子3種解明東海大、リスク最大7倍に」
• [Remarks] 科学新聞2008年11月14日「脳動脈瘤解明に道-日米胸中の遺伝子多型同定」