Advertisement

Current Genetic Medicine Reports

, Volume 5, Issue 1, pp 8–14 | Cite as

The Genetics of Intracranial Aneurysms

  • Antti E. Lindgren
  • Arttu Kurtelius
  • Mikael von und zu Fraunberg
Neurogenetics and Psychiatric Genetics (M Hiltunen and DR Marenda, Section Editors)
  • 113 Downloads
Part of the following topical collections:
  1. Neurogenetics and Psychiatric Genetics

Abstract

Purpose of Review

Saccular intracranial aneurysm (sIA) is a relatively common intracranial arterial pathology with a prevalence of approximately 3%. Rupture of sIA causes subarachnoid hemorrhage, which is the third most frequent form of stroke and which predominantly affects the working-age population. The underlying causes of IA are complex, and the role of genetics in its pathobiology is poorly characterized. This review summarizes the latest research on sIA genetics, focusing on the large genome-wide association study (GWAS) approach.

Recent Findings

The six GWAS papers published since 2008 identified several IA risk loci in multiple populations. However, the risk exerted by these loci explains only a fraction of the observed genetic risk in sIA disease.

Summary

Improved sequencing techniques, such as whole exome or genome sequencing, may further clarify the role of genetics in sIA disease. Population-specific loci in isolates may reveal novel pathways associated with sIA disease. The ultimate goal is to develop therapies that prevent the formation, growth, and rupture of sIAs.

Keywords

Saccular intracranial aneurysm Genetics Subarachnoid hemorrhage 

Notes

Compliance with Ethical Standards

Conflict of Interest

Antti E. Lindgren, Arttu Kurtelius, and Mikael von und zu Fraunberg declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This review article did not involve any studies with human or animal subjects that were performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: •Of importance •• Of major importance

  1. 1.
    Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol. 2011;10:626–36.CrossRefPubMedGoogle Scholar
  2. 2.
    Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009;8:355–69. doi: 10.1016/S1474-4422(09)70025-0.CrossRefPubMedGoogle Scholar
  3. 3.
    Karamanakos PN, von Und Zu Fraunberg M, Bendel S, Huttunen T, Kurki M, Hernesniemi J, et al. Risk factors for three phases of 12-month mortality in 1657 patients from a defined population after acute aneurysmal subarachnoid hemorrhage. World Neurosurg. Elsevier Inc.2012;78:631–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Huttunen J, Lindgren A, Kurki MI, Huttunen T, Frösen J, von und zu Fraunberg M, et al. Antidepressant use after aneurysmal subarachnoid hemorrhage. Stroke. 2016;47:2242–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Huttunen J, Kurki MI, von Und Zu Fraunberg M, Koivisto T, Ronkainen A, Rinne J, et al. Epilepsy after aneurysmal subarachnoid hemorrhage: a population-based, long-term follow-up study. Neurology. 2015;84:2229–37. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25948726 CrossRefPubMedGoogle Scholar
  6. 6.
    Lindgren AE, Kurki MI, Riihinen A, Koivisto T, Ronkainen A, Rinne J, et al. Hypertension predisposes to the formation of saccular intracranial aneurysms in 467 unruptured and 1053 ruptured patients in Eastern Finland. Ann Med. 2014;46:169–76. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24579936 CrossRefPubMedGoogle Scholar
  7. 7.
    Kotowski M, Naggara O, Darsaut TE, Nolet S, Gevry G, Kouznetsov E, et al. Safety and occlusion rates of surgical treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis of the literature from 1990 to 2011. J Neurol Neurosurg Psychiatry. 2013;84:42–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23012447 CrossRefPubMedGoogle Scholar
  8. 8.
    Naggara O, Darsaut T, Trystram D, Tselikas L, Raymond J. Unruptured intracranial aneurysms: why we must not perpetuate the impasse for another 25 years. Lancet Neurol. 2014;13:537–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24849854 CrossRefPubMedGoogle Scholar
  9. 9.
    Korja M, Lehto H, Juvela S. Lifelong rupture risk of intracranial aneurysms depends on risk factors: a prospective Finnish cohort study. Stroke. 2014;45:1958–63.CrossRefPubMedGoogle Scholar
  10. 10.
    • Ronkainen A, Hernesniemi J, Puranen M, Niemitukia L, Vanninen R, Ryynanen M, et al. Familial intracranial aneurysms. Lancet. 1997;349:380–4. Early study demonstrating increased prevalence of intracranial aneurysms among first-degree relatives of patients with intracranial aneurysms CrossRefPubMedGoogle Scholar
  11. 11.
    Chambers WR, Harper BF, Simpson JR. Familial incidence of congenital aneurysms of cerebral arteries: report of cases of ruptured aneurysms in father and son. J Am Med Assoc. 1954;155:358–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/13151928 CrossRefPubMedGoogle Scholar
  12. 12.
    Brown BM, Soldevilla F. MR angiography and surgery for unruptured familial intracranial aneurysms in persons with a family history of cerebral aneurysms. AJR Am J Roentgenol. 1999;173:133–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10397113 CrossRefPubMedGoogle Scholar
  13. 13.
    Ruigrok YM, Rinkel GJE, Wijmenga C. Familial intracranial aneurysms. Stroke. 2004;35:e59–60. author reply e59–60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14963266 CrossRefPubMedGoogle Scholar
  14. 14.
    Mackey J, Brown RD, Moomaw CJ, Hornung R, Sauerbeck L, Woo D, et al. Familial intracranial aneurysms: is anatomic vulnerability heritable? Stroke. 2013;44:38–42. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23204049 CrossRefPubMedGoogle Scholar
  15. 15.
    Ruigrok YM, Rinkel GJE, Algra A, Raaymakers TWM, Van Gijn J. Characteristics of intracranial aneurysms in patients with familial subarachnoid hemorrhage. Neurology. 2004;62:891–4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15037688 CrossRefPubMedGoogle Scholar
  16. 16.
    Huttunen T, von und zu Fraunberg M, Frösen J, Lehecka M, Tromp G, Helin K, et al. Saccular intracranial aneurysm disease: distribution of site, size, and age suggests different etiologies for aneurysm formation and rupture in 316 familial and 1454 sporadic eastern Finnish patients. Neurosurgery. 2010;66:631–8. discussion 638. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20190670 CrossRefPubMedGoogle Scholar
  17. 17.
    Bromberg JE, Rinkel GJ, Algra A, van Duyn CM, Greebe P, Ramos LM, et al. Familial subarachnoid hemorrhage: distinctive features and patterns of inheritance. Ann Neurol. 1995;38:929–34. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8526466 CrossRefPubMedGoogle Scholar
  18. 18.
    • Greving JP, Wermer MJH, Brown RD, Morita A, Juvela S, Yonekura M, et al. Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies. Lancet Neurol. 2014;13:59–66. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24290159. Comprehensive study of risk factors for rupture of incidental intracranial aneurysms. The authors developed a scoring system for prediction of rupture risk CrossRefPubMedGoogle Scholar
  19. 19.
    ter Laan M, Kerstjens-Frederikse WS, Metzemaekers JDM, van Dijk JMC, Groen RJM. Concordant symptomatic intracranial aneurysm in a monozygotic twin: a case report and review of the literature. Twin Res Hum Genet. 2009;12:295–300. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19456222 CrossRefPubMedGoogle Scholar
  20. 20.
    Mackey J, Brown RD, Sauerbeck L, Hornung R, Moomaw CJ, Koller DL, et al. Affected twins in the familial intracranial aneurysm study. Cerebrovasc Dis. 2015;39:82–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25571891 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Korja M, Silventoinen K, McCarron P, Zdravkovic S, Skytthe A, Haapanen A, et al. Genetic epidemiology of spontaneous subarachnoid hemorrhage: Nordic twin study. Stroke. 2010;41:2458–62. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20847318 CrossRefPubMedGoogle Scholar
  22. 22.
    Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol. 2011;10:626–36. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21641282 CrossRefPubMedGoogle Scholar
  23. 23.
    Pfohman M, Criddle LM. Epidemiology of intracranial aneurysm and subarachnoid hemorrhage. J Neurosci Nurs. 2001;33:39–41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11233360 CrossRefPubMedGoogle Scholar
  24. 24.
    Schievink WI, Riedinger M, Maya MM. Frequency of incidental intracranial aneurysms in neurofibromatosis type 1. Am J Med Genet A. 2005;134A:45–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15690406 CrossRefPubMedGoogle Scholar
  25. 25.
    Birkeland P, Gardner K, Kesse-Adu R, Davies J, Lauritsen J, Rom Poulsen F, et al. Intracranial aneurysms in sickle-cell disease are associated with the hemoglobin SS genotype but not with Moyamoya syndrome. Stroke. 2016;47:1710–3. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27301940 CrossRefPubMedGoogle Scholar
  26. 26.
    Lozano AM, Leblanc R. Cerebral aneurysms and polycystic kidney disease: a critical review. Can J Neurol Sci. 1992;19:222–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1623450 PubMedGoogle Scholar
  27. 27.
    Schievink WI, Torres VE, Piepgras DG, Wiebers DO. Saccular intracranial aneurysms in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 1992;3:88–95. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1391712 PubMedGoogle Scholar
  28. 28.
    Chapman AB, Rubinstein D, Hughes R, Stears JC, Earnest MP, Johnson AM, et al. Intracranial aneurysms in autosomal dominant polycystic kidney disease. N Engl J Med. 1992;327:916–20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1513348 CrossRefPubMedGoogle Scholar
  29. 29.
    Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet (London, England). 2007;369:1287–301. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17434405 CrossRefGoogle Scholar
  30. 30.
    Ruigrok YM, Buskens E, Rinkel GJ. Attributable risk of common and rare determinants of subarachnoid hemorrhage. Stroke. 2001;32:1173–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11340228 CrossRefPubMedGoogle Scholar
  31. 31.
    Gieteling EW, Rinkel GJE. Characteristics of intracranial aneurysms and subarachnoid haemorrhage in patients with polycystic kidney disease. J Neurol. 2003;250:418–23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12700905 CrossRefPubMedGoogle Scholar
  32. 32.
    Olson JM, Vongpunsawad S, Kuivaniemi H, Ronkainen A, Hernesniemi J, Ryynänen M, et al. Search for intracranial aneurysm susceptibility gene(s) using Finnish families. BMC Med Genet. 2002;3:7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12153705 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    • van der Voet M, Olson JM, Kuivaniemi H, Dudek DM, Skunca M, Ronkainen A, et al. Intracranial aneurysms in Finnish families: confirmation of linkage and refinement of the interval to chromosome 19q13.3. Am J Hum Genet. 2004;74:564–71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14872410. Genome-wide linkage study revealing a susceptibility locus for intracranial aneurysms in a large pedigreed population CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Mineharu Y, Inoue K, Inoue S, Yamada S, Nozaki K, Hashimoto N, et al. Model-based linkage analyses confirm chromosome 19q13.3 as a susceptibility locus for intracranial aneurysm. Stroke. 2007;38:1174–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17322081 CrossRefPubMedGoogle Scholar
  35. 35.
    Yamada S, Utsunomiya M, Inoue K, Nozaki K, Inoue S, Takenaka K, et al. Genome-wide scan for Japanese familial intracranial aneurysms: linkage to several chromosomal regions. Circulation. 2004;110:3727–33. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15569837 CrossRefPubMedGoogle Scholar
  36. 36.
    Ruigrok YM, Wijmenga C, Rinkel GJE, van’t Slot R, Baas F, Wolfs M, et al. Genomewide linkage in a large Dutch family with intracranial aneurysms: replication of 2 loci for intracranial aneurysms to chromosome 1p36.11-p36.13 and Xp22.2-p22.32. Stroke. 2008;39:1096–102. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18309175 CrossRefPubMedGoogle Scholar
  37. 37.
    Ozturk AK, Nahed BV, Bydon M, Bilguvar K, Goksu E, Bademci G, et al. Molecular genetic analysis of two large kindreds with intracranial aneurysms demonstrates linkage to 11q24-25 and 14q23-31. Stroke. 2006;37:1021–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16497978 CrossRefPubMedGoogle Scholar
  38. 38.
    Onda H, Kasuya H, Yoneyama T, Takakura K, Hori T, Takeda J, et al. Genomewide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7q11. Am J Hum Genet. 2001;69:804–19. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11536080 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Santiago-Sim T, Depalma SR, Ju KL, McDonough B, Seidman CE, Seidman JG, et al. Genomewide linkage in a large Caucasian family maps a new locus for intracranial aneurysms to chromosome 13q. Stroke. 2009;40:S57–60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19064780 CrossRefPubMedGoogle Scholar
  40. 40.
    Farnham JM, Camp NJ, Neuhausen SL, Tsuruda J, Parker D, MacDonald J, et al. Confirmation of chromosome 7q11 locus for predisposition to intracranial aneurysm. Hum Genet. 2004;114:250–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14605871 CrossRefPubMedGoogle Scholar
  41. 41.
    Maller J, George S, Purcell S, Fagerness J, Altshuler D, Daly MJ, et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet. 2006;38:1055–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16936732 CrossRefPubMedGoogle Scholar
  42. 42.
    Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119–24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23128233 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    •• Bilguvar K, Yasuno K, Ruigrok Y. Susceptibility loci for intracranial aneurysm in European and Japanese populations. Nat Genet. 2008;40:1472–7. Available from: http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.240.html. First genome-wide association study of intracranial aneurysm disease CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    •• Yasuno K, Bilguvar K, Bijlenga P, Low SK, Krischek B, Auburger G, et al. Genome-wide association study of intracranial aneurysm identifies three new risk loci. Nat Genet. 2010;42:420–5. Available from: http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.563.html. Follow-up study for the first genome-wide association study of intracranial aneurysm disease CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    • Yasuno K, Bakırcıoğlu M, Low S-K, Bilgüvar K, Gaál E, Ruigrok YM, et al. Common variant near the endothelin receptor type A (EDNRA) gene is associated with intracranial aneurysm risk. Proc Natl Acad Sci U S A. 2011;108:19707–12. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22106312 . Second follow-up study for the first genome-wide association study of intracranial aneurysm disease CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Akiyama K, Narita A, Nakaoka H, Cui T, Takahashi T, Yasuno K, et al. Genome-wide association study to identify genetic variants present in Japanese patients harboring intracranial aneurysms. J Hum Genet. 2010;55:656–61. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20613766 CrossRefPubMedGoogle Scholar
  47. 47.
    Low S-K, Takahashi A, Cha P-C, Zembutsu H, Kamatani N, Kubo M, et al. Genome-wide association study for intracranial aneurysm in the Japanese population identifies three candidate susceptible loci and a functional genetic variant at EDNRA. Hum Mol Genet. 2012;21:2102–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22286173 CrossRefPubMedGoogle Scholar
  48. 48.
    Foroud T, Lai D, Koller D, Van’t Hof F, Kurki MI, Anderson CS, et al. Genome-wide association study of intracranial aneurysm identifies a new association on chromosome 7. Stroke. 2014;45:3194–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25256182 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    • Gaál EI, Salo P, Kristiansson K, Rehnström K, Kettunen J, Sarin AP, et al. Intracranial aneurysm risk locus 5q23.2 is associated with elevated systolic blood pressure. Myers AJ, editor. PLoS Genet. 2012;8:e1002563. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22438818. This study connects a susceptibility locus for intracranial aneurysm disease with a common risk factor for the disease, i.e. increased systolic blood pressure CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    • Kurki MI, Gaál EI, Kettunen J, Lappalainen T, Menelaou A, Anttila V, et al. High risk population isolate reveals low frequency variants predisposing to intracranial aneurysms. PLoS Genet. 2014;10:e1004134. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24497844. Follow-up study for the first genome-wide association study taking advantage of population isolates, familial enrichment, dense genotype imputation and alternate phenotyping CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Farlow JL, Lin H, Sauerbeck L, Lai D, Koller DL, Pugh E, et al. Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm. PLoS One. 2015;10:e0121104. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25803036 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    van ‘t Hof FNG, Ruigrok YM, Lee CH, Ripke S, Anderson G, de Andrade M, et al. Shared genetic risk factors of intracranial, abdominal, and thoracic aneurysms. J. Am. Heart Assoc. 2016 5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27418160
  53. 53.
    Lee H-J, Yi J-S, Lee H-J, Lee I-W, Park K-C, Yang J-H. Dysregulated expression profiles of microRNAs of experimentally induced cerebral aneurysms in rats. J Korean Neurosurg Soc. 2013;53:72–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23560169 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Holcomb M, Ding Y-H, Dai D, McDonald RJ, McDonald JS, Kallmes DF, et al. RNA-sequencing analysis of messenger RNA/microRNA in a rabbit aneurysm model identifies pathways and genes of interest. AJNR. Am. J. Neuroradiol 2015 36:1710–1715. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26228879

Copyright information

© Springer Science + Business Media New York 2017

Authors and Affiliations

  • Antti E. Lindgren
    • 1
    • 2
  • Arttu Kurtelius
    • 1
    • 2
  • Mikael von und zu Fraunberg
    • 1
    • 2
  1. 1.Neurosurgery of NeuroCenterKuopio University HospitalKuopioFinland
  2. 2.Neurosurgery, Institute of Clinical MedicineUniversity of Eastern FinlandKuopioFinland

Personalised recommendations