The influence of genetics on intracranial aneurysm formation and rupture: current knowledge and its possible impact on future treatment

  • B. Krischek
  • M. Tatagiba
Part of the Advances and Technical Standards in Neurosurgery book series (NEUROSURGERY, volume 33)


The etiology of intracranial aneurysm formation and rupture remains mostly unknown, but lately several studies have increasingly supported the role of genetic factors. In reports so far, genome-wide linkage studies suggest several susceptibility loci that may contain one or more predisposing genes. Depending on the examined ethnic population, several different non-matching chromosomal regions have been found. Studies of several candidate genes report association with intracranial aneurysms. To date, no single gene has been identified as responsible for intracranial aneurysm formation or rupture.

In addition to the well-published environmental factors, such as alcohol intake, hypertension and smoking, only the recent progress in molecular genetics enables us to investigate the possible genetic determinants of this disease. Although a familial predisposition is the strongest risk factor for the development of intracranial aneurysms, the mode of Mendelian inheritance is uncertain in most families. Therefore, multiple genetic susceptibilities in conjunction with the environmental factors are considered to act together in the disease’s etiology. Accordingly, researchers performed linkage studies and case-control association studies for the genetic analysis and have identified several genes to be susceptible to intracranial aneurysms. The identification of susceptible genes may lead to the understanding of the mechanism of formation and rupture and possibly lead to the development of a pharmacological therapy. Furthermore, should it be possible to identify a genetic marker associated with an increased risk of formation and rupture of an intracranial aneurysm, the necessity for screening and urgency of treatment could be determined more easily.

In this review we summarize the current knowledge of intracranial aneurysm genetics and also discuss the method to detect the causalities. In view of the recent advances made in this field, we also give an outlook on possible future genetically engineered therapies, whose development are well underway.


Cerebral aneurysms subarachnoid hemorrhage genetic intracerebral hemorrhage 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Akagawa H, Narita A, Yamada H, Tajima A, Krischek B, Kasuya H, Hori T, Kubota M, Saeki N, Hata A, Mizutani T, Inoue I (2007) Systematic screening of lysyl oxidase-like (LOXL) family genes demonstrates that LOXL2 is a susceptibility gene to intracranial aneurysms. Hum Genet 121(3–4): 377–387PubMedGoogle Scholar
  2. 2.
    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 CJ, Yang TK, Lee JY, Kimm K, Inoue I (2006) A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms. Hum Mol Genet 15: 1722–1734PubMedGoogle Scholar
  3. 3.
    Allen M, Heinzmann A, Noguchi E, Abecasis G, Broxholme J, Ponting CP, Bhattacharyya S, Tinsley J, Zhang Y, Holt R, Jones EY, Lench N, Carey A, Jones H, Dickens NJ, Dimon C, Nicholls R, Baker C, Xue L, Townsend E, Kabesch M, Weiland SK, Carr D, von Mutius E, Adcock IM, Barnes PJ, Lathrop GM, Edwards M, Moffatt MF, Cookson WO (2003) Positional cloning of a novel gene influencing asthma from chromosome 2q14. Nat Genet 35: 258–263PubMedGoogle Scholar
  4. 4.
    Armstrong K, Eisen A, Weber B (2000) Assessing the risk of breast cancer. N Engl J Med 342: 564–571PubMedGoogle Scholar
  5. 5.
    Camenzind E, Steg PG, Wijns W (2007) Stent thrombosis late after implantation of firstgeneration drug-eluting stents: a cause for concern. Circulation 115: 1440–1455PubMedGoogle Scholar
  6. 6.
    Castillo-Davis CI (2005) The evolution of noncoding DNA: how much junk, how much func? Trends Genet 21: 533–536PubMedGoogle Scholar
  7. 7.
    Chen AF, Jiang SW, Crotty TB, Tsutsui M, Smith LA, O’Brien T, Katusic ZS (1997) Effects of in vivo adventitial expression of recombinant endothelial nitric oxide synthase gene in cerebral arteries. Proc Natl Acad Sci USA 94: 12568–12573PubMedGoogle Scholar
  8. 8.
    Chen Y, Pawlikowska L, Yao JS, Shen F, Zhai W, Achrol AS, Lawton MT, Kwok PY, Yang GY, Young WL (2006) Interleukin-6 involvement in brain arteriovenous malformations. Ann Neurol 59: 72–80PubMedGoogle Scholar
  9. 9.
    Chu Y, Iida S, Lund DD, Weiss RM, DiBona GF, Watanabe Y, Faraci FM, Heistad DD (2003) Gene transfer of extracellular superoxide dismutase reduces arterial pressure in spontaneously hypertensive rats: role of heparin-binding domain. Circ Res 92: 461–468PubMedGoogle Scholar
  10. 10.
    Chu Y, Miller JD, Heistad DD (2007) Gene therapy for stroke: 2006 overview. Curr Hypertens Rep 9: 19–24PubMedGoogle Scholar
  11. 11.
    Chu Y, Weintraub N, Heistad DD (2005) Gene therapy and cardiovascular diseases. In: Runge M, Patterson C (eds) Principles of molecular cardiology. Humana Press, Totowa, New JerseyGoogle Scholar
  12. 12.
    Chyatte D, Bruno G, Desai S, Todor DR (1999) Inflammation and intracranial aneurysms. Neurosurgery 45: 1137–1146PubMedGoogle Scholar
  13. 13.
    Chyatte D, Reilly J, Tilson MD (1990) Morphometric analysis of reticular and elastin fibers in the cerebral arteries of patients with intracranial aneurysms. Neurosurgery 26: 939–943PubMedGoogle Scholar
  14. 14.
    Cohen JC, Kiss RS, Pertsemlidis A, Marcel YL, McPherson R, Hobbs HH (2004) Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305: 869–872PubMedGoogle Scholar
  15. 15.
    Crompton MR (1966) The comparative pathology of cerebral aneurysms. Brain 89: 789–796PubMedGoogle Scholar
  16. 16.
    De Francesco L (2006) Genetic profiteering. Nat Biotechnol 24: 888–890PubMedGoogle Scholar
  17. 17.
    Dichgans M, Markus HS (2005) Genetic association studies in stroke: methodological issues and proposed standard criteria. Stroke 36: 2027–2031PubMedGoogle Scholar
  18. 18.
    Ellegala DB, Day AL (2005) Ruptured cerebral aneurysms. N Engl J Med 352: 121–124PubMedGoogle Scholar
  19. 19.
    Farnham JM, Camp NJ, Neuhausen SL, Tsuruda J, Parker D, MacDonald J, Cannon-Albright LA (2004) Confirmation of chromosome 7q11 locus for predisposition to intracranial aneurysm. Hum Genet 114: 250–255PubMedGoogle Scholar
  20. 20.
    Feigin VL, Rinkel GJ, Lawes CM, Algra A, Bennett DA, van Gijn J, Anderson CS (2005) Risk factors for subarachnoid hemorrhage: an updated systematic review of epidemiological studies. Stroke 36: 2773–2780PubMedGoogle Scholar
  21. 21.
    Fernandez-Lopez A, Garrido-Martin EM, Sanz-Rodriguez F, Pericacho M, Rodriguez-Barbero A, Eleno N, Lopez-Novoa JM, Duwell A, Vega MA, Bernabeu C, Botella LM (2007) Gene expression fingerprinting for human hereditary hemorrhagic telangiectasia. Hum Mol Gen 16: 1515–1533PubMedGoogle Scholar
  22. 22.
    Finlay HM, Whittaker P, Canham PB (1998) Collagen organization in the branching region of human brain arteries. Stroke 29: 1595–1601PubMedGoogle Scholar
  23. 23.
    Flotte TR, Carter BJ (1995) Adeno-associated virus vectors for gene therapy. Gene Ther 2: 357–362PubMedGoogle Scholar
  24. 24.
    Frosch M, Anthony D, De Girolami U (2004) The central nervous system. In: Kumar V, Fausto N, Abbas A (eds) Robbins & Cotran pathologic basis of disease. Elsevier Saunders, PhiladelphiaGoogle Scholar
  25. 25.
    Frosen J, Piippo A, Paetau A, Kangasniemi M, Niemela M, Hernesniemi J, Jaaskelainen J (2004) Remodeling of saccular cerebral artery aneurysm wall is associated with rupture: histological analysis of 24 unruptured and 42 ruptured cases. Stroke 35: 2287–2293PubMedGoogle Scholar
  26. 26.
    Greenberg M (2000) SAH and aneurysms. In: Greenberg M (ed) Handbook of neurosurgery. Thieme Medical, New YorkGoogle Scholar
  27. 27.
    Gretarsdottir S, Sveinbjornsdottir S, Jonsson HH, Jakobsson F, Einarsdottir E, Agnarsson U, Shkolny D, Einarsson G, Gudjonsdottir HM, Valdimarsson EM, Einarsson OB, Thorgeirsson G, Hadzic R, Jonsdottir S, Reynisdottir ST, Bjarnadottir SM, Gudmundsdottir T, Gudlaugsdottir GJ, Gill R, Lindpaintner K, Sainz J, Hannesson HH, Sigurdsson GT, Frigge ML, Kong A, Gudnason V, Stefansson K, Gulcher JR (2002) Localization of a susceptibility gene for common forms of stroke to 5q12. Am J Hum Genet 70: 593–603PubMedGoogle Scholar
  28. 28.
    Gretarsdottir S, Thorleifsson G, Reynisdottir ST, Manolescu A, Jonsdottir S, Jonsdottir T, Gudmundsdottir T, Bjarnadottir SM, Einarsson OB, Gudjonsdottir HM, Hawkins M, Gudmundsson G, Gudmundsdottir H, Andrason H, Gudmundsdottir AS, Sigurdardottir M, Chou TT, Nahmias J, Goss S, Sveinbjornsdottir S, Valdimarsson EM, Jakobsson F, Agnarsson U, Gudnason V, Thorgeirsson G, Fingerle J, Gurney M, Gudbjartsson D, Frigge ML, Kong A, Stefansson K, Gulcher JR (2003) The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet 35: 131–138PubMedGoogle Scholar
  29. 29.
    Grond-Ginsbach C, Schnippering H, Hausser I, Weber R, Werner I, Steiner HH, Luttgen N, Busse O, Grau A, Brandt T (2002) Ultrastructural connective tissue aberrations in patients with intracranial aneurysms. Stroke 33: 2192–2196PubMedGoogle Scholar
  30. 30.
    Gunel M, Awad IA, Anson J, Lifton RP (1995) Mapping a gene causing cerebral cavernous malformation to 7q11.2–q21. Proc Natl Acad Sci USA 92: 6620–6624PubMedGoogle Scholar
  31. 31.
    Harrod CG, Batjer HH, Bendok BR (2005) Deficiencies in estrogen-mediated regulation of cerebrovascular homeostasis may contribute to an increased risk of cerebral aneurysm pathogenesis and rupture in menopausal and postmenopausal women. Med Hypotheses 66: 736–756PubMedGoogle Scholar
  32. 32.
    Heistad DD (2006) Gene therapy for vascular disease. Vascul Pharmacol 45: 331–333PubMedGoogle Scholar
  33. 33.
    Helgadottir A, Manolescu A, Thorleifsson G, Gretarsdottir S, Jonsdottir H, Thorsteinsdottir U, Samani NJ, Gudmundsson G, Grant SF, Thorgeirsson G, Sveinbjornsdottir S, Valdimarsson EM, Matthiasson SE, Johannsson H, Gudmundsdottir O, Gurney ME, Sainz J, Thorhallsdottir M, Andresdottir M, Frigge ML, Topol EJ, Kong A, Gudnason V, Hakonarson H, Gulcher JR, Stefansson K (2004) The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet 36: 233–239PubMedGoogle Scholar
  34. 34.
    Herz J, Gerard RD (1993) Adenovirus-mediated transfer of low density lipoprotein receptor gene acutely accelerates cholesterol clearance in normal mice. Proc Natl Acad Sci USA 90: 2812–2816PubMedGoogle Scholar
  35. 35.
    Hoheisel JD (2006) Microarray technology: beyond transcript profiling and genotype analysis. Nat Rev 7: 200–210Google Scholar
  36. 36.
    Inagawa T, Ishikawa S, Aoki H, Takahashi M, Yoshimoto H (1988) Aneurysmal subarachnoid hemorrhage in Izumo City and Shimane Prefecture of Japan. Incidence. Stroke 19: 170–175Google Scholar
  37. 37.
    Inci S, Spetzler RF (2000) Intracranial aneurysms and arterial hypertension: a review and hypothesis. Surg Neurol 53: 530–540PubMedGoogle Scholar
  38. 38.
    Ingall T, Asplund K, Mahonen M, Bonita R (2000) A multinational comparison of subarachnoid hemorrhage epidemiology in the WHO MONICA stroke study. Stroke 31: 1054–1061PubMedGoogle Scholar
  39. 39.
    Ingall TJ, Whisnant JP, Wiebers DO, O’Fallon WM (1989) Has there been a decline in subarachnoid hemorrhage mortality? Stroke 20: 718–724PubMedGoogle Scholar
  40. 40.
    Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nat Genet 29: 306–309PubMedGoogle Scholar
  41. 41.
    Iwamoto H, Kiyohara Y, Fujishima M, Kato I, Nakayama K, Sueishi K, Tsuneyoshi M (1999) Prevalence of intracranial saccular aneurysms in a Japanese community based on a consecutive autopsy series during a 30-year observation period. The Hisayama study. Stroke 30: 1390–1395PubMedGoogle Scholar
  42. 42.
    Jamous MA, Nagahiro S, Kitazato KT, Satomi J, Satoh K (2005a) Role of estrogen deficiency in the formation and progression of cerebral aneurysms. Part I: experimental study of the effect of oophorectomy in rats. J Neurosurg 103: 1046–1051PubMedGoogle Scholar
  43. 43.
    Jamous MA, Nagahiro S, Kitazato KT, Tamura T, Kuwayama K, Satoh K (2005b) Role of estrogen deficiency in the formation and progression of cerebral aneurysms. Part II: experimental study of the effects of hormone replacement therapy in rats. J Neurosurg 103: 1052–1057PubMedGoogle Scholar
  44. 44.
    Juvela S (2002) Natural history of unruptured intracranial aneurysms: risks for aneurysm formation, growth, and rupture. Acta Neurochir Suppl 82: 27–30PubMedGoogle Scholar
  45. 45.
    Kataoka K, Taneda M, Asai T, Kinoshita A, Ito M, Kuroda R (1999) Structural fragility and inflammatory response of ruptured cerebral aneurysms. A comparative study between ruptured and unruptured cerebral aneurysms. Stroke 30: 1396–1401PubMedGoogle Scholar
  46. 46.
    Kato T, Hattori H, Yorifuji T, Tashiro Y, Nakahata T (2001) Intracranial aneurysms in Ehlers-Danlos syndrome type IV in early childhood. Pediatr Neurol 25: 336–339PubMedGoogle Scholar
  47. 47.
    Khurana VG, Meissner I, Sohni YR, Bamlet WR, McClelland RL, Cunningham JM, Meyer FB (2005) The presence of tandem endothelial nitric oxide synthase gene polymorphisms identifying brain aneurysms more prone to rupture. J Neurosurg 102: 526–531PubMedGoogle Scholar
  48. 48.
    Khurana VG, Weiler DA, Witt TA, Smith LA, Kleppe LS, Parisi JE, Simari RD, O’Brien T, Russell SJ, Katusic ZS (2003) A direct mechanical method for accurate and efficient adenoviral vector delivery to tissues. Gene Ther 10: 443–452PubMedGoogle Scholar
  49. 49.
    Kim DH, Van Ginhoven G, Milewicz DM (2005) Familial aggregation of both aortic and cerebral aneurysms: evidence for a common genetic basis in a subset of families. Neurosurgery 56: 655–661PubMedGoogle Scholar
  50. 50.
    Kiyohara Y, Ueda K, Hasuo Y, Wada J, Kawano H, Kato I, Sinkawa A, Ohmura T, Iwamoto H, Omae T, et al. (1989) Incidence and prognosis of subarachnoid hemorrhage in a Japanese rural community. Stroke 20: 1150–1155PubMedGoogle Scholar
  51. 51.
    Kosierkiewicz TA, Factor SM, Dickson DW (1994) Immunocytochemical studies of atherosclerotic lesions of cerebral berry aneurysms. J Neuropathol Exp Neurol 53: 399–406PubMedGoogle Scholar
  52. 52.
    Krex D, Kotteck K, Konig IR, Ziegler A, Schackert HK, Schackert G (2004) Matrix metalloproteinase-9 coding sequence single-nucleotide polymorphisms in caucasians with intracranial aneurysms. Neurosurgery 55: 207–212PubMedGoogle Scholar
  53. 53.
    Krex D, Rohl H, Konig IR, Ziegler A, Schackert HK, Schackert G (2003) Tissue inhibitor of metalloproteinases-1,-2, and-3 polymorphisms in a white population with intracranial aneurysms. Stroke 34: 2817–2821PubMedGoogle Scholar
  54. 54.
    Krex D, Ziegler A, Schackert HK, Schackert G (2001) Lack of association between endoglin intron 7 insertion polymorphism and intracranial aneurysms in a white population: evidence of racial/ethnic differences. Stroke 32: 2689–2694PubMedGoogle Scholar
  55. 55.
    Krischek B, Inoue I, Kasuya H (2005) Response to letter: collagen morphology is not associated with the Ala549Pro polymorphism of the COL1A2 gene. Stroke 36: 2068–2955Google Scholar
  56. 56.
    Krischek B, Inoue I (2006a) The genetics of intracranial aneurysms. J Hum Genet 51: 587–594PubMedGoogle Scholar
  57. 57.
    Krischek B, Kasuya H, Akagawa H, Tajima A, Narita A, Onda H, Hori T, Inoue I (2006b) Using endothelial nitric oxide synthase gene polymorphisms to identify intracranial aneurysms more prone to rupture in Japanese patients. J Neurosurg 105: 717–722PubMedGoogle Scholar
  58. 58.
    Krischek B, Narita A, Akagawa H, Kasuya H, Tajima A, Onda H, Yoneyama T, Hori T, Inoue I (2006c) Is there any evidence for linkage on chromosome 17cen in affected Japanese sib-pairs with an intracranial aneurysm? J Hum Genet 51: 491–494PubMedGoogle Scholar
  59. 59.
    Kuivaniemi H, Prockop DJ, Wu Y, Madhatheri SL, Kleinert C, Earley JJ, Jokinen A, Stolle C, Majamaa K, Myllyla VV, Norrgard O, Schievink WI, Mokri B, Fukawa O, ter Berg JWM, De Paepe A, Lozano AM, Leblanc R, Ryynanen M, Baxter BT, Shikata H, Ferrell RE, Tromp G (1993) Exclusion of mutations in the gene for type III collagen (COL3A1) as a common cause of intracranial aneurysms or cervical artery dissections: results from sequence analysis of the coding sequences of type III collagen from 55 unrelated patients. Neurology 43: 2652–2658PubMedGoogle Scholar
  60. 60.
    Labauge P, Denier C, Bergametti F, Tournier-Lasserve E (2007) Genetics of cavernous angiomas. Lancet Neurol 6: 237–244PubMedGoogle Scholar
  61. 61.
    Mazighi M, Tchetche D, Goueffic Y, San Juan A, Louedec L, Henin D, Michel JB, Jacob MP, Feldman LJ (2006) Percutaneous transplantation of genetically-modified autologous fibroblasts in the rabbit femoral artery: a novel approach for cardiovascular gene therapy. J Vasc Surg 44: 1067–1075PubMedGoogle Scholar
  62. 62.
    Meschia JF, Brott TG, Brown RD Jr (2005) Genetics of cerebrovascular disorders. Mayo Clin Proc 80: 122–132PubMedGoogle Scholar
  63. 63.
    Morita A, Fujiwara S, Hashi K, Ohtsu H, Kirino T (2005) Risk of rupture associated with intact cerebral aneurysms in the Japanese population: a systematic review of the literature from Japan. J Neurosurg 102: 601–606PubMedGoogle Scholar
  64. 64.
    Nahed BV, Bydon M, Ozturk AK, Bilguvar K, Bayrakli F, Gunel M (2007) Genetics of intracranial aneurysms. Neurosurgery 60: 213–225PubMedGoogle Scholar
  65. 65.
    Nahed BV, Seker A, Guclu B, Ozturk AK, Finberg K, Hawkins AA, DiLuna ML, State M, Lifton RP, Gunel M (2005) Mapping a Mendelian form of intracranial aneurysm to 1p34.3-p36.13. Am J Hum Genet 76: 172–179PubMedGoogle Scholar
  66. 66.
    Nanba R, Kuroda S, Tada M, Ishikawa T, Houkin K, Iwasaki Y (2006) Clinical features of familial moyamoya disease. Childs Nerv Syst 22: 258–262PubMedGoogle Scholar
  67. 67.
    NY Cp (2006) The abdominal aortic aneurysm. Genetics, pathophysiology, and molecular biology. Proceedings of a conference. April 3–5, 2006. New York, USA. Ann NYAcad Sci 1085: 1–408Google Scholar
  68. 68.
    Olson JM, Vongpunsawad S, Kuivaniemi H, Ronkainen A, Hernesniemi J, Ryynanen M, Kim LL, Tromp G (2002) Search for intracranial aneurysm susceptibility gene(s) using Finnish families. BMC Med Genet 3: 7PubMedGoogle Scholar
  69. 69.
    Onda H, Kasuya H, Yoneyama T, Hori T, Nakajima T, Inoue I (2003) Endoglin is not a major susceptibility gene for intracranial aneurysm among Japanese. Stroke 34: 1640–1644PubMedGoogle Scholar
  70. 70.
    Onda H, Kasuya H, Yoneyama T, Takakura K, Hori T, Takeda J, Nakajima T, Inoue I (2001) Genomewide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7q11. Am J Hum Genet 69: 804–819PubMedGoogle Scholar
  71. 71.
    Ooboshi H, Welsh MJ, Rios CD, Davidson BL, Heistad DD (1995) Adenovirus-mediated gene transfer in vivo to cerebral blood vessels and perivascular tissue. Circ Res 77: 7–13PubMedGoogle Scholar
  72. 72.
    Ozturk AK, Nahed BV, Bydon M, Bilguvar K, Goksu E, Bademci G, Guclu B, Johnson MH, Amar A, Lifton RP, Gunel M (2006) Molecular genetic analysis of two large kindreds with intracranial aneurysms demonstrates linkage to 11q24–25 and 14q23–31. Stroke 37: 1021–1027PubMedGoogle Scholar
  73. 73.
    Pradat PF, Kennel P, Naimi-Sadaoui S, Finiels F, Orsini C, Revah F, Delaere P, Mallet J (2001) Continuous delivery of neurotrophin 3 by gene therapy has a neuroprotective effect in experimental models of diabetic and acrylamide neuropathies. Hum Gene Ther 12: 2237–2249PubMedGoogle Scholar
  74. 74.
    Ribourtout E, Raymond J (2004) Gene therapy and endovascular treatment of intracranial aneurysms. Stroke 35: 786–793PubMedGoogle Scholar
  75. 75.
    Richling B (2006) History of endovascular surgery: personal accounts of the evolution. Neurosurgery 59: S30–S38PubMedGoogle Scholar
  76. 76.
    Rinkel GJ, Djibuti M, Algra A, van Gijn J (1998) Prevalence and risk of rupture of intracranial aneurysms: a systematic review. Stroke 29: 251–256PubMedGoogle Scholar
  77. 77.
    Ronkainen A, Hernesniemi J, Puranen M, Niemitukia L, Vanninen R, Ryynanen M, Kuivaniemi H, Tromp G (1997) Familial intracranial aneurysms. Lancet 349: 380–384PubMedGoogle Scholar
  78. 78.
    Ross M, Pawlina W (2006) Histology: text & atlas. Lippincott Williams & Wilkins, BaltimoreGoogle Scholar
  79. 79.
    Ruigrok YM, Rinkel GJ, Wijmenga C (2005) Genetics of intracranial aneurysms. Lancet Neurol 4: 179–189PubMedGoogle Scholar
  80. 80.
    Schievink WI, Michels VV, Piepgras DG (1994) Neurovascular manifestations of heritable connective tissue disorders. A review. Stroke 25: 889–903PubMedGoogle Scholar
  81. 81.
    Schievink WI, Schaid DJ, Michels VV, Piepgras DG (1995) Familial aneurysmal subarachnoid hemorrhage: a community-based study. J Neurosurg 83: 426–429PubMedGoogle Scholar
  82. 82.
    Simon M, Franke D, Ludwig M, Aliashkevich AF, Koster G, Oldenburg J, Bostrom A, Ziegler A, Schramm J (2006) Association of a polymorphism of the ACVRL1 gene with sporadic arteriovenous malformations of the central nervous system. J Neurosurg 104: 945–949PubMedGoogle Scholar
  83. 83.
    Stapf C, Mohr J (2004) Aneurysms and subarachnoid hemorrhage — epidemiology. In: Le Roux P, Winn H, Newell D (eds) Management of cerebral aneurysms. Saunders, PhiladelphiaGoogle Scholar
  84. 84.
    Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT, Hjaltason O, Birgisdottir B, Jonsson H, Gudnadottir VG, Gudmundsdottir E, Bjornsson A, Ingvarsson B, Ingason A, Sigfusson S, Hardardottir H, Harvey RP, Lai D, Zhou M, Brunner D, Mutel V, Gonzalo A, Lemke G, Sainz J, Johannesson G, Andresson T, Gudbjartsson D, Manolescu A, Frigge ML, Gurney ME, Kong A, Gulcher JR, Petursson H, Stefansson K (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71: 877–892PubMedGoogle Scholar
  85. 85.
    Stehbens WE (1989) Etiology of intracranial berry aneurysms. J Neurosurg 70: 823–831PubMedGoogle Scholar
  86. 86.
    Stehbens WE (1999) Relationship of cerebral aneurysms and medial raphes. Surg Neurol 52: 536–538PubMedGoogle Scholar
  87. 87.
    Styrkarsdottir U, Cazier JB, Kong A, Rolfsson O, Larsen H, Bjarnadottir E, Johannsdottir VD, Sigurdardottir MS, Bagger Y, Christiansen C, Reynisdottir I, Grant SF, Jonasson K, Frigge ML, Gulcher JR, Sigurdsson G, Stefansson K (2003) Linkage of osteoporosis to chromosome 20p12 and association to BMP2. PLoS Biol 1: E69PubMedGoogle Scholar
  88. 88.
    Tabor HK, Risch NJ, Myers RM (2002) Candidate-gene approaches for studying complex genetic traits: practical considerations. Nat Rev 3: 391–397Google Scholar
  89. 89.
    Takenaka K, Sakai H, Yamakawa H, Yoshimura S, Kumagai M, Nakashima S, Nozawa Y, Sakai N (1999) Polymorphism of the endoglin gene in patients with intracranial saccular aneurysms. J Neurosurg 90: 935–938PubMedGoogle Scholar
  90. 90.
    Tanaka H, Ueda Y, Date C, Baba T, Yamashita H, Hayashi M, Shoji H, Owada K, Baba KI, Shibuya M, Kon T, Detels R (1981) Incidence of stroke in Shibata, Japan: 1976–1978. Stroke 12: 460–466PubMedGoogle Scholar
  91. 91.
    Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop GM, Chabriat H, Mas JL, Cabanis EA, Baudrimont M, Maciazek J, Bach MA, Bousser MG (1993) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet 3: 256–259PubMedGoogle Scholar
  92. 92.
    Tulamo R, Frosen J, Junnikkala S, Paetau A, Pitkaniemi J, Kangasniemi M, Niemela M, Jaaskelainen J, Jokitalo E, Karatas A, Hernesniemi J, Meri S (2006) Complement activation associates with saccular cerebral artery aneurysm wall degeneration and rupture. Neurosurgery 59: 1069–1076PubMedGoogle Scholar
  93. 93.
    van den Berg JS, Pals G, Arwert F, Hennekam RC, Albrecht KW, Westerveld A, Limburg M (1999) Type III collagen deficiency in saccular intracranial aneurysms. Defect in gene regulation? Stroke 30: 1628–1631PubMedGoogle Scholar
  94. 94.
    von der Leyen HE, Gibbons GH, Morishita R, Lewis NP, Zhang L, Nakajima M, Kaneda Y, Cooke JP, Dzau VJ (1995) Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. Proc Natl Acad Sci USA 92: 1137–1141PubMedGoogle Scholar
  95. 95.
    Wermer MJ, van der Schaaf IC, Algra A, Rinkel GJ (2007) Risk of rupture of unruptured intracranial aneurysms in relation to patient and aneurysm characteristics. An updated metaanalysis. Stroke 38: 1404–1410PubMedGoogle Scholar
  96. 96.
    Winn HR, Jane JA Sr, Taylor J, Kaiser D, Britz GW (2002) Prevalence of asymptomatic incidental aneurysms: review of 4568 arteriograms. J Neurosurg 96: 43–49PubMedGoogle Scholar
  97. 97.
    Wolfberg AJ (2006) Genes on the Web — direct-to-consumer marketing of genetic testing. N Engl J Med 355: 543–545PubMedGoogle Scholar
  98. 98.
    Yamada S, Utsunomiya M, Inoue K, Nozaki K, Inoue S, Takenaka K, Hashimoto N, Koizumi A (2004) Genome-wide scan for Japanese familial intracranial aneurysms: linkage to several chromosomal regions. Circulation 110: 3727–3733PubMedGoogle Scholar
  99. 99.
    Yamada S, Utsunomiya M, Inoue K, Nozaki K, Miyamoto S, Hashimoto N, Takenaka K, Yoshinaga T, Koizumi A (2003) Absence of linkage of familial intracranial aneurysms to 7q11 in highly aggregated Japanese families. Stroke 34: 892–900PubMedGoogle Scholar
  100. 100.
    Yoneyama T, Kasuya H, Onda H, Akagawa H, Hashiguchi K, Nakajima T, Hori T, Inoue I (2004) Collagen type I alpha2 (COL1A2) is the susceptible gene for intracranial aneurysms. Stroke 35: 443–448PubMedGoogle Scholar
  101. 101.
    Yoshimoto T, Mizoi K (1997) Importance of management of unruptured cerebral aneurysms. Surg Neurol 47: 522–525PubMedGoogle Scholar
  102. 102.
    Yoshimura K, Aoki H, Ikeda Y, Fujii K, Akiyama N, Furutani A, Hoshii Y, Tanaka N, Ricci R, Ishihara T, Esato K, Hamano K, Matsuzaki M (2005) Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase. Nat Med 11: 1330–1338PubMedGoogle Scholar

Copyright information

© Springer-Verlag/Wien 2008

Authors and Affiliations

  • B. Krischek
    • 1
  • M. Tatagiba
    • 1
  1. 1.Department of NeurosurgeryUniversity of TuebingenTuebingenGermany

Personalised recommendations