{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:45:50Z","timestamp":1789983950535,"version":"4.0.1"},"reference-count":52,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2019,2,25]],"date-time":"2019-02-25T00:00:00Z","timestamp":1551052800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science, Information and Communication Technologies and Future Planning of the Korea Government","award":["2017M3A9E8033223"],"award-info":[{"award-number":["2017M3A9E8033223"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Genome-wide association studies found genetic variations with modulatory effects for intracranial aneurysm (IA) formations in European and Japanese populations. We aimed to identify the susceptibility of single nucleotide polymorphisms (SNPs) to IA in a Korean population consisting of 250 patients, and 294 controls using the Asian-specific Axiom Precision Medicine Research Array. Twenty-nine SNPs reached a genome-wide significance threshold (5 \u00d7 10\u22128). The rs371331393 SNP, with a stop-gain function of ARHGAP32 (11q24.3), showed the most significant association with the risk of IA (OR = 43.57, 95% CI: 21.84\u201386.95; p = 9.3 \u00d7 10\u221227). Eight out of 29 SNPs\u2014GBA (rs75822236), TCF24 (rs112859779), OLFML2A (rs79134766), ARHGAP32 (rs371331393), CD163L1 (rs138525217), CUL4A (rs74115822), LOC102724084 (rs75861150), and LRRC3 (rs116969723)\u2014demonstrated sufficient statistical power greater than or equal to 0.8. Two previously reported SNPs, rs700651 (BOLL, 2q33.1) and rs6841581 (EDNRA, 4q31.22), were validated in our GWAS (Genome-wide association study). In a subsequent analysis, three SNPs showed a significant difference in expressions: the rs6741819 (RNF144A, 2p25.1) was down-regulated in the adrenal gland tissue (p = 1.5 \u00d7 10\u22126), the rs1052270 (TMOD1. 9q22.33) was up-regulated in the testis tissue (p = 8.6 \u00d7 10\u221210), and rs6841581 (EDNRA, 4q31.22) was up-regulated in both the esophagus (p = 5.2 \u00d7 10\u221212) and skin tissues (1.2 \u00d7 10\u22126). Our GWAS showed novel candidate genes with Korean-specific variations in IA formations. Large population based studies are thus warranted.<\/jats:p>","DOI":"10.3390\/jcm8020275","type":"journal-article","created":{"date-parts":[[2019,2,25]],"date-time":"2019-02-25T03:06:52Z","timestamp":1551064012000},"page":"275","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Genomic Variations in Susceptibility to Intracranial Aneurysm in the Korean Population"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7789-686X","authenticated-orcid":false,"given":"Eun Pyo","family":"Hong","sequence":"first","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Institute of New Frontier Stroke Research, Hallym University College of Medicine, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bong Jun","family":"Kim","sequence":"additional","affiliation":[{"name":"Institute of New Frontier Stroke Research, Hallym University College of Medicine, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1511-2596","authenticated-orcid":false,"given":"Steve S.","family":"Cho","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4883-7224","authenticated-orcid":false,"given":"Jin Seo","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Hallym University College of Medicine, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyuk Jai","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Hallym University College of Medicine, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1130-9754","authenticated-orcid":false,"given":"Suk Hyung","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Hallym University College of Medicine, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Pyeong","family":"Jeon","sequence":"additional","affiliation":[{"name":"Institute of New Frontier Stroke Research, Hallym University College of Medicine, Chuncheon 24252, Korea"},{"name":"Department of Neurosurgery, Hallym University College of Medicine, Chuncheon 24252, Korea"},{"name":"Genetic and Research, Chuncheon 25252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/S1474-4422(11)70109-0","article-title":"Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: A systematic review and meta-analysis","volume":"10","author":"Vlak","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1159\/000103118","article-title":"Description of quality of life and its predictors in patients with aneurysmal subarachnoid hemorrhage","volume":"24","author":"Katati","year":"2007","journal-title":"Cerebrovasc Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1227\/01.NEU.0000249270.18698.BB","article-title":"Genetics of intracranial aneurysms","volume":"60","author":"Nahed","year":"2007","journal-title":"Neurosurgery"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/j.ejrad.2012.12.026","article-title":"Epidemiology and genetics of intracranial aneurysms","volume":"82","author":"Caranci","year":"2013","journal-title":"Eur. J. Radiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1086\/323614","article-title":"Genomewide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7q11","volume":"69","author":"Onda","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Olson, J.M., Vongpunsawad, S., Kuivaniemi, H., Ronkainen, A., Hernesniemi, J., Ryynanen, M., Kim, L.L., and Tromp, G. (2002). Search for intracranial aneurysm susceptibility gene(s) using Finnish families. BMC Med. Genet., 3.","DOI":"10.1186\/1471-2350-3-7"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1086\/426953","article-title":"Mapping a Mendelian form of intracranial aneurysm to 1p34.3-p36.13","volume":"76","author":"Nahed","year":"2005","journal-title":"Am. J. Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3727","DOI":"10.1161\/01.CIR.0000143077.23367.18","article-title":"Genome-wide scan for Japanese familial intracranial aneurysms: linkage to several chromosomal regions","volume":"110","author":"Yamada","year":"2004","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1038\/ng.240","article-title":"Susceptibility loci for intracranial aneurysm in European and Japanese populations","volume":"40","author":"Bilguvar","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/jhg.2010.82","article-title":"Genome-wide association study to identify genetic variants present in Japanese patients harboring intracranial aneurysms","volume":"55","author":"Akiyama","year":"2010","journal-title":"J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/ng.563","article-title":"Genome-wide association study of intracranial aneurysm identifies three new risk loci","volume":"42","author":"Yasuno","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2102","DOI":"10.1093\/hmg\/dds020","article-title":"Genome-wide association study for intracranial aneurysm in the Japanese population identifies three candidate susceptible loci and a functional genetic variant at EDNRA","volume":"21","author":"Low","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2154","DOI":"10.1212\/WNL.0b013e318295d751","article-title":"Genetic risk factors for intracranial aneurysms: A meta-analysis in more than 116,000 individuals","volume":"80","author":"Alg","year":"2013","journal-title":"Neurology"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Huang, T., Shu, Y., and Cai, Y.D. (2015). Genetic differences among ethnic groups. BMC Genomics, 16.","DOI":"10.1186\/s12864-015-2328-0"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2586","DOI":"10.1093\/eurheartj\/ehx213","article-title":"Korean atrial fibrillation network genome-wide association study for early-onset atrial fibrillation identifies novel susceptibility loci","volume":"38","author":"Lee","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"467","DOI":"10.3340\/jkns.2017.0505.006","article-title":"Endovascular Treatment with Intravenous Thrombolysis versus Endovascular Treatment Alone for Acute Anterior Circulation Stroke: A Meta-Analysis of Observational Studies","volume":"61","author":"Kim","year":"2018","journal-title":"J. Korean Neurosurg. Soc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.3349\/ymj.2017.58.5.1006","article-title":"A Novel Association between Lysyl Oxidase Gene Polymorphism and Intracranial Aneurysm in Koreans","volume":"58","author":"Hong","year":"2017","journal-title":"Yonsei Med. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e823","DOI":"10.1016\/j.wneu.2017.11.108","article-title":"Association of SOX17 Gene Polymorphisms and Intracranial Aneurysm: A Case-Control Study and Meta-Analysis","volume":"110","author":"Hong","year":"2018","journal-title":"World Neurosurg."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13742-015-0047-8","article-title":"Second-generation PLINK: Rising to the challenge of larger and richer datasets","volume":"4","author":"Chang","year":"2015","journal-title":"Gigascience"},{"key":"ref_20","unstructured":"GTEx Consortium (2015). Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans. Science, 348, 648\u2013660."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1093\/bioinformatics\/btq419","article-title":"LocusZoom: Regional visualization of genome-wide association scan results","volume":"26","author":"Pruim","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"P3","DOI":"10.1186\/gb-2003-4-5-p3","article-title":"DAVID: Database for Annotation, Visualization, and Integrated Discovery","volume":"4","author":"Dennis","year":"2003","journal-title":"Genome Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"D447","DOI":"10.1093\/nar\/gku1003","article-title":"STRING v10: Protein-protein interaction networks, integrated over the tree of life","volume":"4","author":"Szklarczyk","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4161\/sgtp.28846","article-title":"Involvement of Rho GTPases and their regulators in the pathogenesis of hypertension","volume":"5","author":"Loirand","year":"2014","journal-title":"Small GTPases"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2910","DOI":"10.1038\/ncomms3910","article-title":"The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension","volume":"4","author":"Bai","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1016\/S0090-3019(00)00244-5","article-title":"Intracranial aneurysms and arterial hypertension: A review and hypothesis","volume":"53","author":"Inci","year":"2000","journal-title":"Surg. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1136\/jnnp-2017-317348","article-title":"Features of GBA-associated Parkinson\u2019s disease at presentation in the UK Tracking Parkinson\u2019s study","volume":"89","author":"Malek","year":"2018","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1212\/WNL.0000000000001315","article-title":"Differential effects of severe vs mild GBA mutations on Parkinson disease","volume":"84","author":"Amshalom","year":"2015","journal-title":"Neurology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e153","DOI":"10.1038\/emm.2014.128","article-title":"Loss of glucocerebrosidase 1 activity causes lysosomal dysfunction and alpha-synuclein aggregation","volume":"47","author":"Bae","year":"2015","journal-title":"Exp. Mol. Med."},{"key":"ref_30","first-page":"2117","article-title":"The role of autophagic and lysosomal pathways in ischemic brain injury","volume":"23","author":"Gu","year":"2013","journal-title":"Neural Regen. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9147","DOI":"10.1158\/0008-5472.CAN-07-5127","article-title":"Lysosomal cathepsin B participates in the podosome-mediated extracellular matrix degradation and invasion via secreted lysosomes in v-Src fibroblasts","volume":"68","author":"Tu","year":"2008","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1182\/blood-2015-07-659185","article-title":"Misshapen\/NIK-related kinase (MINK1) is involved in platelet function, hemostasis, and thrombus formation","volume":"127","author":"Yue","year":"2016","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"041005","DOI":"10.1115\/1.4029580","article-title":"Mechanical platelet activation potential in abdominal aortic aneurysms","volume":"137","author":"Hansen","year":"2015","journal-title":"J. Biomech. Eng."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"20140403","DOI":"10.1098\/rsif.2014.0403","article-title":"Synergy between shear-induced migration and secondary flows on red blood cells transport in arteries: considerations on oxygen transport","volume":"11","author":"Biasetti","year":"2014","journal-title":"J. R. Soc. Interface."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1007\/s11357-017-9995-5","article-title":"Connective tissue growth factor (CTGF) in age-related vascular pathologies","volume":"39","author":"Ungvari","year":"2017","journal-title":"Geroscience"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1161\/STROKEAHA.108.540245","article-title":"Sequencing of TGF-beta pathway genes in familial cases of intracranial aneurysm","volume":"40","author":"Pannu","year":"2009","journal-title":"Stroke"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6","DOI":"10.3389\/fcell.2014.00006","article-title":"Olfactomedin proteins: Central players in development and disease","volume":"2","author":"Anholt","year":"2014","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1042\/BJ20050120","article-title":"Identification and characterization of photomedins: Novel olfactomedin-domain-containing proteins with chondroitin sulphate-E-binding activity","volume":"389","author":"Furutani","year":"2005","journal-title":"Biochem. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1007\/s12035-009-8076-x","article-title":"Olfactomedin domain-containing proteins: Possible mechanisms of action and functions in normal development and pathology","volume":"40","author":"Tomarev","year":"2009","journal-title":"Mol. Neurobiol."},{"key":"ref_40","first-page":"167","article-title":"Endothelial injury preceding intracranial aneurysm formation in rabbits","volume":"63","author":"Li","year":"2014","journal-title":"West Indian Med. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/ni.2670","article-title":"The scavenger receptor SCARF1 mediates the clearance of apoptotic cells and prevents autoimmunity","volume":"14","author":"Pendergraft","year":"2013","journal-title":"Nat. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1007\/s00011-018-1154-7","article-title":"SCARF1: A multifaceted, yet largely understudied, scavenger receptor","volume":"67","author":"Patten","year":"2018","journal-title":"Inflamm. Res."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"HUGO Pan-Asian SNP Consortium, Abdulla, M.A., Ahmed, I., Assawamakin, A., Bhak, J., Brahmachari, S.K., Calacal, G.C., Chaurasia, A., Chen, C.H., and Chen, J. (2009). Indian Genome Variation Consortium. Mapping human genetic diversity in Asia. Science, 326, 1541\u20131545.","DOI":"10.1126\/science.1177074"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"454","DOI":"10.3109\/00207454.2013.763803","article-title":"Association of polymorphisms in the elastin gene with sporadic ruptured intracranial aneurysms and unruptured intracranial aneurysms in Chinese patients","volume":"123","author":"Yang","year":"2013","journal-title":"Int. J. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.1111\/j.1476-5381.1995.tb15093.x","article-title":"Endothelin ETA receptor expression in human cerebrovascular smooth muscle cells","volume":"116","author":"Yu","year":"1995","journal-title":"Br. J. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2971","DOI":"10.1161\/01.STR.31.12.2971","article-title":"Endothelin-1 in subarachnoid hemorrhage: An acute-phase reactant produced by cerebrospinal fluid leukocytes","volume":"31","author":"Fassbender","year":"2000","journal-title":"Stroke"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1093\/hmg\/11.18.2147","article-title":"Zeta-sarcoglycan, a novel component of the sarcoglycan complex, is reduced in muscular dystrophy","volume":"11","author":"Wheeler","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1038\/mp.2015.218","article-title":"Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer\u2019s disease with OSBPL6, PTPRG, and PDCL3","volume":"21","author":"Herold","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"ref_49","first-page":"14","article-title":"Incidences of unruptured intracranial aneurysms and subarachnoid hemorrhage: Results of a statewide study","volume":"7","author":"Asaithambi","year":"2014","journal-title":"J. Vasc. Interv. Neurol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1161\/STROKEAHA.112.673806","article-title":"Exploring the age of intracranial aneurysms using carbon birth dating: Preliminary results","volume":"44","author":"Etminan","year":"2013","journal-title":"Stroke"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1177\/1479164118780799","article-title":"Diabetes mellitus and abdominal aortic aneurysms: A review of the mechanisms underlying the negative relationship","volume":"15","author":"Dattani","year":"2018","journal-title":"Diab. Vasc. Dis. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"117","DOI":"10.5808\/GI.2012.10.2.117","article-title":"Sample size and statistical power calculation in genetic association studies","volume":"10","author":"Hong","year":"2012","journal-title":"Genomics Inform."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/2\/275\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:34:30Z","timestamp":1760186070000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/2\/275"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,25]]},"references-count":52,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2019,2]]}},"alternative-id":["jcm8020275"],"URL":"https:\/\/doi.org\/10.3390\/jcm8020275","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,25]]}}}