Genome-wide association study for intracranial aneurysm in the Japanese population identifies three candidate susceptible loci and a functional genetic variant at EDNRA

Siew Kee Low, Atsushi Takahashi, Pei Chieng Cha, Hitoshi Zembutsu, Naoyuki Kamatani, Michiaki Kubo, Yusuke Nakamura

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Abstract

Aneurysmal subarachnoid hemorrhage (aSAH) is the most serious subtype of stroke. Genetic factors have been known to play an important role in the development of intracranial aneurysm (IA), some of which further progress to subarachnoid hemorrhage (SAH). In this study, we conducted a genome-wide association study (GWAS) to identify common genetic variants that are associated with the risk of IA, using 1383 aSAH subjects and 5484 control individuals in the Japanese population. We selected 36 single-nucleotide polymorphisms (SNPs) that showed suggestive association (P < 1 × 10 -4) in the GWAS as well as additional 7 SNPs that were previously reported to be associated with IA, and further genotyped an additional set of 1048 IA cases and 7212 controls. We identified an SNP, rs6842241, near EDNRA at chromosome 4q31.22 (combined P-value = 9.58 × 10 -9; odds ratio = 1.25), which was found to be significantly associated with IA. Additionally, we successfully replicated and validated rs10757272 on CDKN2BAS at chromosome 9p21.3 (combined P-value = 1.55 × 10 -7; odds ratio = 1.21) to be significantly associated with IA as previously reported. Furthermore, we performed functional analysis with the associated genetic variants on EDNRA, and identified two alleles of rs6841581 that have different binding affinities to a nuclear protein(s). The transcriptional activity of the susceptible allele of this variant was significantly lower than the other, suggesting that this functional variant might affect the expression of EDNRA and subsequently result in the IA susceptibility. Identification of genetic variants on EDNRA is of clinical significance probably due to its role in vessel hemodynamic stress. Our findings should contribute to a better understanding of physiopathology of IA.

Original languageEnglish
Article numberdds020
Pages (from-to)2102-2110
Number of pages9
JournalHuman molecular genetics
Volume21
Issue number9
DOIs
Publication statusPublished - 01-05-2012
Externally publishedYes

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Genome-Wide Association Study
Intracranial Aneurysm
Population
Subarachnoid Hemorrhage
Single Nucleotide Polymorphism
Chromosomes
Alleles
Odds Ratio
Nuclear Proteins
Hemodynamics
Stroke

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Low, Siew Kee ; Takahashi, Atsushi ; Cha, Pei Chieng ; Zembutsu, Hitoshi ; Kamatani, Naoyuki ; Kubo, Michiaki ; Nakamura, Yusuke. / Genome-wide association study for intracranial aneurysm in the Japanese population identifies three candidate susceptible loci and a functional genetic variant at EDNRA. In: Human molecular genetics. 2012 ; Vol. 21, No. 9. pp. 2102-2110.
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abstract = "Aneurysmal subarachnoid hemorrhage (aSAH) is the most serious subtype of stroke. Genetic factors have been known to play an important role in the development of intracranial aneurysm (IA), some of which further progress to subarachnoid hemorrhage (SAH). In this study, we conducted a genome-wide association study (GWAS) to identify common genetic variants that are associated with the risk of IA, using 1383 aSAH subjects and 5484 control individuals in the Japanese population. We selected 36 single-nucleotide polymorphisms (SNPs) that showed suggestive association (P < 1 × 10 -4) in the GWAS as well as additional 7 SNPs that were previously reported to be associated with IA, and further genotyped an additional set of 1048 IA cases and 7212 controls. We identified an SNP, rs6842241, near EDNRA at chromosome 4q31.22 (combined P-value = 9.58 × 10 -9; odds ratio = 1.25), which was found to be significantly associated with IA. Additionally, we successfully replicated and validated rs10757272 on CDKN2BAS at chromosome 9p21.3 (combined P-value = 1.55 × 10 -7; odds ratio = 1.21) to be significantly associated with IA as previously reported. Furthermore, we performed functional analysis with the associated genetic variants on EDNRA, and identified two alleles of rs6841581 that have different binding affinities to a nuclear protein(s). The transcriptional activity of the susceptible allele of this variant was significantly lower than the other, suggesting that this functional variant might affect the expression of EDNRA and subsequently result in the IA susceptibility. Identification of genetic variants on EDNRA is of clinical significance probably due to its role in vessel hemodynamic stress. Our findings should contribute to a better understanding of physiopathology of IA.",
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Genome-wide association study for intracranial aneurysm in the Japanese population identifies three candidate susceptible loci and a functional genetic variant at EDNRA. / Low, Siew Kee; Takahashi, Atsushi; Cha, Pei Chieng; Zembutsu, Hitoshi; Kamatani, Naoyuki; Kubo, Michiaki; Nakamura, Yusuke.

In: Human molecular genetics, Vol. 21, No. 9, dds020, 01.05.2012, p. 2102-2110.

Research output: Contribution to journalArticle

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T1 - Genome-wide association study for intracranial aneurysm in the Japanese population identifies three candidate susceptible loci and a functional genetic variant at EDNRA

AU - Low, Siew Kee

AU - Takahashi, Atsushi

AU - Cha, Pei Chieng

AU - Zembutsu, Hitoshi

AU - Kamatani, Naoyuki

AU - Kubo, Michiaki

AU - Nakamura, Yusuke

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