Skip to main content

Advertisement

SpringerLink
Log in

Genome-Wide Association Study of Intracranial Artery Stenosis Followed by Phenome-Wide Association Study

  • Original Article
  • Published:
Translational Stroke Research Aims and scope Submit manuscript

Abstract

The genetic background of intracranial artery stenosis (ICAS), a major cause of ischemic stroke, remains elusive. We performed the world’s first genome-wide association study (GWAS) of ICAS using DNA samples from Japanese subjects, to identify the genetic factors associated with ICAS and their correlation with clinical features. We also conducted a phenome-wide association study (PheWAS) of the top variant identified via GWAS to determine its association with systemic disease. The GWAS involved 408 patients with ICAS and 349 healthy controls and utilized an Asian Screening Array of venous blood samples. The PheWAS was performed using genotypic and phenotypic data of the Biobank Japan Project, which contained information on 46 diseases and 60 quantitative trait data from > 150,000 Japanese individuals. The GWAS revealed that the East Asian-specific functional variant of RNF213, rs112735431 (c.14429G > A, p.Arg4810Lys), was associated with ICAS (odds ratio, 12.3; 95% CI 5.5 to 27.5; P = 7.8 × 10−10). Stratified analysis within ICAS cases demonstrated that clinical features of those with and without the risk allele were different. PheWAS indicated that high blood pressure and angina were significantly associated with RNF213 rs112735431. The first GWAS of ICAS, which stratifies subpopulations within the ICAS cases with distinct clinical features, revealed that RNF213 rs112735431 was the most significant variant associated with ICAS. Thus, RNF213 rs112735431 shows potential as an important clinical biomarker that characterizes pleiotropic risk in various vascular diseases, such as blood pressure and angina, thereby facilitating personalized medicine for systemic vascular diseases in East Asian populations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request from any investigator.

Code Availability

Not applicable.

References

  1. Banerjee C, Chimowitz MI. Stroke caused by atherosclerosis of the major intracranial arteries. Circ Res. 2017;120:502–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Holmstedt CA, Turan TN, Chimowitz MI. Atherosclerotic intracranial arterial stenosis: risk factors, diagnosis, and treatment. Lancet Neurol. 2013;12:1106–14.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Suri MFK, Qiao Y, Ma X, Guallar E, Zhou J, Zhang Y, Liu L, Chu H, Qureshi AI, Alonso A, Folsom AR, Wasserman BA. Prevalence of intracranial atherosclerotic stenosis using high-resolution magnetic resonance angiography in the general population: the atherosclerosis risk in communities study. Stroke. 2016;47:1187–93.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hoshino T, Sissani L, Labreuche J, Ducrocq G, Lavallée PC, Meseguer E, Guidoux C, Cabrejo L, Hobeanu C, Gongora-Rivera F, Steg PG, Amarenco P, AMISTAD Investigators. Prevalence of systemic atherosclerosis burdens and overlapping stroke etiologies and their associations with long-term vascular prognosis in stroke with intracranial atherosclerotic disease. JAMA Neurol. 2018;75:203–11.

    Article  PubMed  Google Scholar 

  5. Shitara S, Fujiyoshi A, Hisamatsu T, Torii S, Suzuki S, Ito T, Hisatomi A, Shiino A, Nozaki K, Miura K, Ueshima H, SESSA Research Group. Intracranial artery stenosis and its association with conventional risk factors in a general population of Japanese Men. Stroke. 2019;50:2967–9.

    Article  PubMed  Google Scholar 

  6. Derdeyn CP, Chimowitz MI, Lynn MJ, Fiorella D, Turan TN, Janis LS, Montgomery J, Nizam A, Lane BF, Lutsep HL, Barnwell SL, Waters MF, Hoh BL, Hourihane JM, Levy EI, Alexandrov AV, Harrigan MR, Chiu D, Klucznik RP, Johnson MD, Pride GL Jr, Lynch JR, Zaidat OO, Stenting and aggressive medical management for preventing recurrent stroke in intracranial stenosis trial investigators. Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): The final results of a randomised trial. Lancet. 2014;383:333–41.

    Article  PubMed  Google Scholar 

  7. White H, Boden-Albala B, Wang C, Elkind MSV, Rundek T, Wright CB, Sacco RL. Ischemic stroke subtype incidence among Whites, Blacks, and Hispanics. Circulation. 2005;111:1327–31.

    Article  PubMed  Google Scholar 

  8. Ueshima H, Sekikawa A, Miura K, Turin TC, Takashima N, Kita Y, Watanabe M, Kadota A, Okuda N, Kadowaki T, Nakamura Y, Okamura T. Cardiovascular disease and risk factors in Asia: a selected review. Circulation. 2008;118:2702–9.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Gorelick PB, Wong KS, Bae HJ, Pandey DK. Large artery intracranial occlusive disease: a large worldwide burden but a relatively neglected frontier. Stroke. 2008;39:2396–9.

    Article  PubMed  Google Scholar 

  10. Traylor M, Farrall M, Holliday EG, Sudlow C, Hopewell JC, Cheng YC, Fornage M, Ikram MA, Malik R, Bevan S, Thorsteinsdottir U, Nalls MA, Longstreth W, Wiggins KL, Yadav S, Parati EA, Dstefano AL, Worrall BB, Kittner SJ, Khan MS, Reiner AP, Helgadottir A, Achterberg S, Cadenas IF, Abboud S, Schmidt R, Walters M, Chen WM, Ringelstein EB, O’Donnell M, Ho WK, Pera J, Lemmens R, Norrving B, Higgins P, Benn M, Sale M, Kuhlenbaumer G, Doney ALSF, Vicente AM, Delavaran H, Algra A, Davies G, Oliveria SA, Palmer CAN, Deary I, Schmidt H, Pandolfo M, Montaner J, Carty C, de Bakker PIW, Kostulas K, Ferro JM, van Zuydam NR, Valdimarsson E, Nordestgaard BG, Lindgren A, Thijs V, Slowik A, Saleheen D, Pare G, Berger K, Thorleifsson G, Australian Stroke Genetics Collaborative Wellcome Trust Case Control Consortium 2 (WTCCC2), Hofman A, Mosley TH, Mitchell BD, Furie K, Clarke R, Levi C, Seshadri S, Gschwendtner A, Sharma P, Bis JC, Rothwell PM, Rosand J, Meschia JF, Stefanson K, Dichgans M, Markus HS, International Stroke Genetics Consortium. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies. Lancet Neurol. 2012;11:951–62.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, Anderson CD, Chong M, Adams HHH, Ago T, Almgren P, Amouyel P, Ay H, Bartz TM, Benavente OR, Bevan S, Boncoraglio GB, Brown RD Jr., Butterworth AS, Carrera C, Carty CL, Chasman DI, Chen WM, Cole JW, Correa A, Cotlarciuc I, Cruchaga C, Danesh J, de Bakker PIW, DeStefano AL, den Hoed M, Duan Q, Engelter ST, Falcone GJ, Gottesman RF, Grewal RP, Gudnason V, Gustafsson S, Haessler J, Harris TB, Hassan A, Havulinna AS, Heckbert SR, Holliday EG, Howard G, Hsu FC, Hyachinth HI, Ikram MA, Ingelsson E, Irvin MR, Jian X, Conde JJ, Johnson JA, Jukema JW, Kanai M, Keene KL, Kissela BM, Keindorfer DO, Kooperberg C, Kubo M, Lange LA, Langefeld CD, Langenberg C, Launer LJ, Leys D, Lewis CM, Lin WY, Lindgren AG, Lorentzen E, Magnusson PK, Maguire J, Manichaikul A, McArdle PF, Meschia JF, Mitchell BD, Mosley TH, Nalls MA, Ninomiya T, O’Donnell MJ, Psaty BM, Pulit SL, Rannikmae K, Reiner AP, Rexrode KM, Rice K, Rich SS, Ridker PM, Rotter JI, Rundek T, Sacco RL, Sakaue S, Sale MM, Salomaa V, Sapkota BR, Schmidt R, Schmidt C, Schminke U, Sharma P, Slowik A, Sudlow CLM, Tanislav C, Tatlisumak T, Taylor KD, Thijs VNS, Thorleifsson G, Thorsteinsdottir U, Tiedt S, Trompet S, Tzourio C, van Duijn CM, Walters M, Wareham NJ, Smoller SW, Wilson JG, Wiggins KL, Yang Q, Yusuf S, AFGen Consortium, Cohorts for Hear and Aging Research in Genomic Epidemiology (CHARGE), International Genomics of Blood Pressure (iGEN-BP), INVENT Consortium, STARNET, Bis JC, Pastinen T, Ruusalepp A, Schadt EE, Koplev S, Bjorkegren JLM, Codoni V, Civelek M, Smith NL, Tregouet DA, Christopphersen IE, Roselli C, Lubitz SA, Ellinor PT, Tai ES, Kooner JS, Kato N, He J, van der Harst P, Elliot P, Chambers JC, Takeuchi F, Johnson AD, BioBank Japan Cooperative Hospital Group, COMPASS Consortium, EPIC-CVD Consortium, EPIC-InterAct Consortium, International Stroke Genetics Consortium (ISGC), METASTROKE Consortium, Neurology Working Group of the CHARGE Consortium, NINDS Stroke Genetics Network (SiGN), UK Young Lacunar DNA Study, MEGASTROKE Consortium, Sanghera D, Melander O, Jern C, Strbian D, Fernandez-Cadenas I, Longstreth WT Jr., Rolfs A, Hata J, Woo D, Rosand J, Pare G, Hopewell JC, Saleheen D, Stefansson K, Worrall BB, Kittner SJ, Seshardri S, Fornage M, Markus HS, Howson JMM, Kamatani Y, Debette S, Dichgans M. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet. 2018;50:524–37.

  12. Adams HP, Bendixen B, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE. Classification of subtype of acute ischemic stroke. Stroke. 1993;23:35–41.

    Article  Google Scholar 

  13. Kasner SE, Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, Frankel MR, Levine SR, Chaturvedi S, Benesch CG, Sila CA, Jovin TG, Romano JG, Cloft HJ, Warfarin Aspirin Symptomatic Intracranial Disease Trial Investigators. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation. 2006;113:555–63.

    Article  PubMed  Google Scholar 

  14. Okada Y, Momozawa Y, Sakaue S, Kanai M, Ishigaki K, Akiyama M, Kishikawa T, Arai Y, Sasaki T, Kosaki K, Suematsu M, Matsuda K, Yamamoto K, Kubo M, Hirose N, Kamatani Y. Deep whole-genome sequencing reveals recent selection signatures linked to evolution and disease risk of Japanese. Nat Commun. 2018;9:1–10.

    Article  CAS  Google Scholar 

  15. Akiyama M, Ishigaki K, Sakaue S, Momozawa Y, Horikoshi M, Hirata M, Matsuda K, Ikegawa S, Takahasi A, Kanai M, Suzuki S, Matsui D, Naito M, Yamaji T, Iwasaki M, Sawada N, Tanno K, Sasaki M, Hozawa A, Minegishi N, Wakai K, Tsugane S, Shimizu A, Yamamoto M, Okada Y, Okada Y, Murakami Y, Kubo M, Kamatani Y. Characterizing rare and low-frequency height-associated variants in the Japanese population. Nat Commun. 2019;10:4393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nagai A, Hirata M, Kamatani Y, Muto K, Matsuda K, Kiyohara Y, Ninomiya T, Tamakoshi A, Yamagata Z, Mushiroda T, Murakami Y, Yuji K, Furukawa Y, Zembutsu H, Tanaka T, Ohnishi Y, Nakamura Y, BioBank Japan Cooperative Hospital Group, Kubo M. Overview of the BioBank Japan Project: study design and profile. J Epidemiol. 2017;27:S2-8.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Hirata M, Kamatani Y, Nagai A, Kiyohara Y, Ninomiya T, Tamakoshi A, Yamagata Z, Kubo M, Muto K, Mushiroda T, Murakami Y, Yuji K, Furukawa Y, Zembutsu H, Tanaka T, Ohnishi Y, Nakamura Y, BioBank Japan Cooperative Hospital Group, Matsuda K. Cross-sectional analysis of BioBank Japan clinical data: a large cohort of 200,000 patients with 47 common diseases. J Epidemiol. 2017;27:S9-21.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hirata J, Hosomichi K, Sakaue S, Kanai M, Nakaoka H, Ishigaki K, Suzuki K, Akiyama M, Kishikawa T, Ogawa K, Masuda T, Yamamota K, Hirata M, Matsuda K, Momozawa Y, Inou I, Kubo M, Kamatani Y, Okada Y. Genetic and phenotypic landscape of the major histocompatibilty complex region in the Japanese population. Nat Genet. 2019;51:470–80.

    Article  CAS  PubMed  Google Scholar 

  19. Kanai M, Akiyama M, Takahashi A, Matoba N, Momozawa Y, Ikeda M, Iwata N, Ikegawa S, Hirata M, Matsuda K, Kubo M, Okada Y, Kamatani Y. Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases. Nat Genet. 2018;50:390–400.

    Article  CAS  PubMed  Google Scholar 

  20. Liu W, Morito D, Takashima S, Mineharu Y, Kobayashi H, Hitomi T, Hashikata H, Matsuura N, Yamazaki S, Toyoda A, Kikuta KI, Yasushi Takagi, Harad KH, Fujiyama A, Herzig R, Krischeck B, Zou L, Kim JE, Kitakaze M, Miaymoto S, Nagata K, Hashimot N, Koizuimi A. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One. 2011;6:e22542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kamada F, Aoki Y, Narisawa A, Abe Y, Komatsuzaki S, Kikuchi A, Kanno J, Niihori T, Ono M, Ishii N, Owada Y, Fujimura M, Mashimo Y, Suzuki Y, Hata A, Tsuchiya S, Tominaga T, Matsubara Y, Kure S. A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. J Hum Genet. 2011;56:34–40.

    Article  CAS  PubMed  Google Scholar 

  22. Miyawaki S, Imai H, Shimizu M, Yagi S, Ono H, Mukasa A, Nakatomi H, Shimizu T, Saito N. Genetic variant RNF213 c.14576G>A in various phenotypes of intracranial major artery stenosis/occlusion. Stroke. 2013;44:2894–7.

    Article  CAS  PubMed  Google Scholar 

  23. Liao X, Deng J, Dai W, Zhang T, Yan J. Rare variants of RNF213 and moyamoya/non-moyamoya intracranial artery stenosis/occlusion disease risk: a meta-analysis and systematic review. Environ Health Prev Med. 2017;22:75.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Okazaki S, Morimoto T, Kamatani Y, Kamimura T, Kobayashi H, Harada K, Tomita T, Higashiyama A, Takahashi JC, Nakagawa J, Koga M, Toyoda K, Washida K, Saito S, Takahasi A, Hirata M, Matsuda K, Mochizuki H, Chong M, Pare G, O’Donnell M, Ago T, Hata J, Ninomiya T, Dichgans M, Debette S, Kubo M, Koizumi A, Ihara M. Moyamoya disease susceptibility variant RNF213 p.R4810K increases the risk of ischemic stroke attributable to large-artery atherosclerosis. Circulation. 2019;139:295–8.

    Article  CAS  PubMed  Google Scholar 

  25. Grami N, Chong M, Lali R, Mohammadi-Shemirani P, Henshall DE, Rannikmäe K, Pare G. Global assessment of Mendelian stroke genetic prevalence in 101635 individuals from 7 ethnic groups. Stroke. 2020;51:1290–3.

    Article  PubMed  Google Scholar 

  26. Asare Y, Campbell-James TA, Bokov Y, Yu LL, Prestel M, El Bounkari O, Roth S, Megens RTA, Straub T, Thomas K, Yan G, Schneider M, Ziesch N, Tiedt S, Sivestre-Carlos BQ, Huang Y, Schenider M, Malik R, Haffner C, Liesz A, Soehnlein O, Bernhagen J, Dichgans M. Histone deacetylase 9 activates IKK to regulate atherosclerotic plaque vulnerability. Circ Res. 2020;127:811–23.

    Article  CAS  PubMed  Google Scholar 

  27. Kamimura T, Okazaki S, Morimoto T, Kobayashi H, Harada K, Tomita T, Higashiyma A, Yoshimoto T, Takahasi JC, Nakagawara J, Koga M, Toyoda K, Maruyma H, Koizuma A, Ihara M. Prevalence of RNF213 p.R4810K variant in early-onset stroke with intracranial arterial stenosis. Stroke. 2019;50:1561–3.

    Article  CAS  PubMed  Google Scholar 

  28. Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis; Health Labour Sciences Research Grant for Research on Measures for Infractable Diseases. Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Med Chir (Tokyo). 2012;52:245–66.

  29. Kuroda S, Houkin K. Moyamoya disease: current concepts and future perspectives. Lancet Neurol. 2008;7:1056–66.

    Article  PubMed  Google Scholar 

  30. Bang OY, Chung J-W, Kim DH, Won H-H, Yeon JY, Ki C-S, Shin HJ, Kim JS, Hong SC, Kim DK, Koizumi A. Moyamoya disease and spectrums of RNF213 vasculopathy. Transl Stroke Res. 2020;11:580–9.

    Article  PubMed  Google Scholar 

  31. Scholz B, Korn C, Wojtarowicz J, Mogler C, Augustin I, Boutros M, Niehrs C, Augustin HG. Endothelial RSPO3 controls vascular stability and pruning through non-canonical WNT/Ca2+/NFAT signaling. Dev Cell. 2016;36:79–93.

    Article  CAS  PubMed  Google Scholar 

  32. Takeda M, Tezuka T, Kim M, Choi J, Oichi Y, Kobayashi H, Harada KH, Mizushima T, Taketani S, Koizumi A, Youssefian S. Moyamoya disease patient mutations in the RING domain of RNF213 reduce its ubiquitin ligase activity and enhance NFκB activation and apoptosis in an AAA+ domain-dependent manner. Biochem Biophys Res Commun. 2020;525:668–74.

    Article  CAS  PubMed  Google Scholar 

  33. Key J, Maletzko A, Kohli A, Gispert S, Torres-odio S, Wittig I, Heidler J, Barcena C, Otin CL, Lei Y, West AP, Christian M, Auburger G. Loss of mitochondrial ClpP , Lonp1 , and Tfam triggers transcriptional induction of Rnf213 , a susceptibility factor for moyamoya disease. Neurogenetics. 2020;187–203.

  34. Banh RS, Iorio C, Marcotte R, Xu Y, Cojocari D, Rahman AA, Pawling J, Zhang W, Sinha A, Rose CM, Isasa M, Zhang S, Wu R, Virtanen C, Hitomi T, Habu T, Sidhu SS, Koizumi A, Wilkins SE, Kislinger T, Gygi SP, Schofield CJ, Dennis JW, Wouters BG, Neel BG. PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia. Nat Cell Biol. 2016;18:803–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sugihara M, Morito D, Ainuki S, Hirano Y, Ogino K, Kitamura A, Hirata H, Nagata K. The AAA+ ATPase/ubiquitin ligase mysterin stabilizes cytoplasmic lipid droplets. J Cell Biol. 2019;218:949–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bhardwaj A, Banh RS, Zhang W, Sidhu SS, Neel BG. Moyamoya disease-associated RNF213 alleles encode dominant negative alleles that globally impair ubiquitylation. bioRxiv. 2020;2020.05.24.113795.

  37. Kobayashi H, Matsuda Y, Hitomi T, Okuda H, Shioi H, Matsuda T, Imai H, Sone M, Taura D, Harada KH, Habu T, Takagi Y, Miyamoto S, Koizumi A. Biochemical and functional characterization of RNF213 (Mysterin) R4810K, a susceptibility mutation of moyamoya disease, in Angiogenesis In Vitro and In Vivo. J Am Heart Assoc. 2015;4:1–19.

    Article  Google Scholar 

  38. Roy V, Ross JP, Pépin R, Cortez Ghio S, Brodeur A, Touzel Deschênes L, Le-Bel G, Phillips DE, Milot G, Dion PA, Guerin S, Germain L, Berthod F, Auger FA, Rouleau GA, Dupre N, Gros-Louis F. Moyamoya disease susceptibility gene RNF213 regulates endothelial barrier function. Stroke. 2022;STROKEAHA120032691.

  39. Otten EG, Werner E, Crespillo-Casado A, Boyle KB, Dharamdasani V, Pathe C, Balaji S, Randov F. Ubiquitylation of lipopolysaccharide by RNF213 during bacterial infection. Nature. 2021;594:111–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tashiro R, Niizuma K, Kasamatsu J, Okuyama Y, Rashad S, Kikuchi A, Fujimura M, Kure S, Ishii N, Tominaga T. Dysregulation of Rnf 213 gene contributes to T cell response via antigen uptake, processing, and presentation. J Cell Physiol. 2021;236:7554–64.

    Article  CAS  PubMed  Google Scholar 

  41. Kanoke A, Fujimura M, Niizuma K, Ito A, Sakata H, Sato-Maeda M, Morita-Fujimura Y, Kure S, Tominaga T. Temporal profile of the vascular anatomy evaluated by 9.4-tesla magnetic resonance angiography and histological analysis in mice with the R4859K mutation of RNF213, the susceptibility gene for moyamoya disease. Brain Res. 2015;1624:497–505.

    Article  CAS  PubMed  Google Scholar 

  42. Sonobe S, Fujimura M, Niizuma K, Nishijima Y, Ito A, Shimizu H, Kikuchi A, Arai-Ichino N, Kure S, Tominaga T. Temporal profile of the vascular anatomy evaluated by 9.4-T magnetic resonance angiography and histopathological analysis in mice lacking RNF213: A susceptibility gene for moyamoya disease. Brain Res. 2014;1552:64–71.

    Article  CAS  PubMed  Google Scholar 

  43. Morimoto T, Enmi JI, Hattori Y, Iguchi S, Saito S, Harada KH, Okuda H, Mineharu Y, Takagi Y, Youssefian S, Lida H, Miyamoto S, Ihara M, Kobayashi H, Koizumi A. Dysregulation of RNF213 promotes cerebral hypoperfusion. Sci Rep. 2018;8:1–9.

    Article  Google Scholar 

  44. Morimoto T, Mineharu Y, Ono K, Nakatochi M, Ichihara S, Kabata R, Takagi Y, Cao Y, Zhao L, Kobayashi H, Harada KH, Takenanak K, Funaki T, Yokoa M, Matsubara T, Yamaamoto K, Izawa H, Kimura T, Miyamoto S, Koizumi A. Significant association of RNF213 p.R4810K, a moyamoya susceptibility variant, with coronary artery disease. PLoS One. 2017;12:1–14.

    Article  Google Scholar 

  45. Chang SA, Song JS, Park TK, Yang JH, Kwon WC, Kim SR, Kim SM, Cha J, Jang SY, Cho YS, Kim TJ, Bang OY, Song JY, Ki CS, Kim DK. Nonsyndromic Peripheral Pulmonary Artery Stenosis Is Associated With Homozygosity of RNF213 p.Arg4810Lys Regardless of Co-occurrence of Moyamoya Disease. Chest. 2018;153:404–13.

    Article  PubMed  Google Scholar 

  46. Suzuki H, Kataoka M, Hiraide T, Aimi Y, Yamada Y, Katsumata Y, Chiba T, Kanekura K, Isobe S, Sato Y, Satoh T, Gamou S, Fukuda K, Kosaki K. Genomic comparison with supercentenarians identifies RNF213 as a risk gene for pulmonary arterial hypertension. Circ Genomic Precis Med. 2018;11:e002317.

    Article  Google Scholar 

  47. Hiraide T, Kataoka M, Suzuki H, Aimi Y, Chiba T, Isobe S, Katsumata Y, Goto S, Kanekura K, Yamada Y, Moriyama H, Kitakata H, Endo J, Yuasa S, Arai Y, Hirose N, Satoh T, Hakamata Y, Sano M, Gamou S, Kosaki K, Fukuda K. Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension. J Hear lung Transplant. 2020;39:103–12.

    Article  Google Scholar 

  48. Ishigaki K, Akiyama M, Kanai M, Takahashi A, Kawakami E, Sugishita H, Sakaue S, Matoba N, Low SK, Okada Y, Terao O, Amariuta T, Gazal S, Kochi Y, Horikoshi M, Suzuki K, Ito K, Koyama S, Ozaki K, Niida S, Sakata Y, Sakata Y, Kohno T, Shiraishi K, Momozawa Y, Hirata M, Matsuda K, Ikeda M, Iwata N, Ikegawa S, Kou I, Tanaka T, Nakagawa H, Suzuki A, Hirota T, Tamari M, Chayama K, Miki D, Mori M, Nagayama S, Daigo Y, Miki Y, Katagiri T, Ogawa O, Obara W, Ito H, Yoshida T, Imoto I, Takahasi T, Tanikawa C, Suzuki T, Sinozaki N, Minami S, Yaguchi H, Asai S, Takahashi Y, Yamaji K, Tahahashi K, Fujioka T, Takata R, Yanai H, Masumoto A, Koretsune Y, Kutsumi H, Higashiyama M, Murayama S, Minegishi N, Suzuki K, Tanno K, Shimizu A, Yamaji T, Iwasaki M, Sawada N, Uemura H, Tanaka K, Naito M, Sasaki M, Wakai K, Tsugane S, Yamamoto M, Yamamoto K, Murakami Y, Nakamura Y, Raychudhuri S, Inazawa J, Yamauchi T, Kadowaki T, Kubo M, Kamatani Y. Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases. Nat Genet. 2020;52:669–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ishigaki K, Akiyama M, Kanai M, Takahashi A. Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases. Nat Genet. 2020;52:669–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This research was supported by the Tailor-Made Medical Treatment program (the BioBank Japan Project) of the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), the Japan Agency for Medical Research and Development (AMED). Nobuhito Saito was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (21H03041). Satoru Miyawaki was supported by JSPS KAKENHI (19K09473), MSD Life Science Foundation (Public Interest Incorporated Foundation). Yukinori Okada was supported by JSPS KAKENHI (19H01021), AMED (JP20ek0109413, JP20km0405211, JP20ek0410075, and JP20gm4010006), Takeda Science Foundation, and Bioinformatics Initiative of Osaka University Graduate School of Medicine, Osaka University.

Author information

Author notes

  1. S. Dofuku and K. Sonehara contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan

    Shogo Dofuku, Satoru Miyawaki, Hideaki Imai, Hiroki Hongo, Yuki Shinya, Kenta Ohara, Yu Teranishi, Atsushi Okano, Hideaki Ono, Hirofumi Nakatomi & Nobuhito Saito

  2. Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan

    Kyuto Sonehara, Saori Sakaue, Kenichi Yamamoto, Toshihiro Kishikawa, Ken Suzuki, Jun Hirata & Yukinori Okada

  3. Department of Neurosurgery, Tokyo Shinjuku Medical Center, Tokyo, 162-8543, Japan

    Hideaki Imai

  4. Department of Neurosurgery, Kanto Neurosurgical Hospital, Kumagaya, 360-0804, Japan

    Masahiro Shimizu

  5. Department of Neurosurgery, Fuji Brain Institute and Hospital, Fujinomiya, 418-0021, Japan

    Hideaki Ono

  6. Department of Neurosurgery, Teraoka Memorial Hospital, Fukuyama, 729-3103, Japan

    Akira Teraoka

  7. Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan

    Kenichi Yamamoto

  8. Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan

    Yuichi Maeda, Takuro Nii & Atsushi Kumanogoh

  9. Laboratory of Immune Regulation, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan

    Yuichi Maeda & Takuro Nii

  10. Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan

    Toshihiro Kishikawa

  11. Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan

    Meiko Takahashi & Fumihiko Matsuda

  12. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, 108-8639, Japan

    Koichi Matsuda

  13. Laboratory of Immunopathology, World Premier International Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, 565-0871, Japan

    Atsushi Kumanogoh

  14. Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, 565-0871, Japan

    Kyuto Sonehara, Yuichi Maeda, Atsushi Kumanogoh & Yukinori Okada

  15. Laboratory of Statistical Immunology, World Premier International Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, 565-0871, Japan

    Yukinori Okada

  16. Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, 464-8681, Japan

    Toshihiro Kishikawa

  17. Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan

    Yukinori Okada

  18. Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, 230-0045, Japan

    Yukinori Okada

Authors
  1. Shogo Dofuku
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kyuto Sonehara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Satoru Miyawaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Saori Sakaue
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hideaki Imai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masahiro Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiroki Hongo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuki Shinya
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kenta Ohara
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yu Teranishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Atsushi Okano
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hideaki Ono
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hirofumi Nakatomi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Akira Teraoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Kenichi Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yuichi Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Takuro Nii
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Toshihiro Kishikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Ken Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Jun Hirata
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Meiko Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Koichi Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Atsushi Kumanogoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Fumihiko Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Yukinori Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Nobuhito Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Satoru Miyawaki, Yukinori Okada, and Nobuhito Saito supervised the study. Shogo Dofuku, Kyuto Sonehara, Satoru Miyawaki, and Yukinori Okada wrote the manuscript. Shogo Dofuku, Kyuto Sonehara, Saori Sakaue, K. Suzuki, Jun Hirata, Meiko Takahashi, and Yukinori Okada conducted data analysis. Shogo Dofuku, Satoru Miyawaki, Hideaki Imai, Masahiro Shimizu, Hiroki Hongo, Yuki Shinya, Kenta Ohara, Yu Teranishi, Atsushi Okano, Hideaki Ono, Hirofumi Nakatomi, Akira Teraoka, Kenichi Yamamoto, Yuichi Maeda, Takuro Nii, Toshihiro Kishikawa, Ken Suzuki, Koichi Matsuda, and Atsushi Kumanogoh collected the samples. Ken Suzuki, Jun Hirata, Meiko Takahashi, and Fumihiko Matsuda constructed the data. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Satoru Miyawaki.

Ethics declarations

Ethics Approval

This study was approved by the ethical committee of the University of Tokyo (approval number G10026; approval date, September 12, 2011) and adhered to the principles of the Declaration of Helsinki.

Informed Consent

All the participants provided written informed consent with documents approved by the institutional review board of each participating hospital or institution.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 706 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dofuku, S., Sonehara, K., Miyawaki, S. et al. Genome-Wide Association Study of Intracranial Artery Stenosis Followed by Phenome-Wide Association Study. Transl. Stroke Res. 14, 322–333 (2023). https://doi.org/10.1007/s12975-022-01049-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-022-01049-w

Keywords

Search

Navigation