Genome-wide association analysis identifies new candidate risk loci for familial intracranial aneurysm in the French-Canadian population

Sirui Zhou, Ziv Gan-Or, Amirthagowri Ambalavanan, Dongbing Lai, Pingxing Xie, Cynthia V. Bourassa, Stephanie Strong, Jay P. Ross, Alexandre Dionne-Laporte, Dan Spiegelman, Nicolas Dupré, Tatiana Foroud, Lan Xiong, Patrick A. Dion, Guy A. Rouleau

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Abstract

Intracranial Aneurysm (IA) is a common disease with a worldwide prevalence of 1-3%. In the French-Canadian (FC) population, where there is an important founder effect, the incidence of IA is higher and is frequently seen in families. In this study, we genotyped a cohort of 257 mostly familial FC IA patients and 1,992 FC controls using the Illumina NeuroX SNP-chip. The most strongly associated loci were tested in 34 Inuit IA families and in 32 FC IA patients and 106 FC controls that had been exome sequenced (WES). After imputation, one locus at 3p14.2 (FHIT, rs1554600, p = 4.66 × 10-9) reached a genome-wide significant level of association and a subsequent validation in Nunavik Inuit cohort further confirmed the significance of the FHIT variant association (rs780365, FBAT-O, p = 0.002839). Additionally, among the other promising loci (p < 5 × 10-6), the one at 3q13.2 (rs78125721, p = 4.77 × 10-7), which encompasses CCDC80, also showed an increased mutation burden in the WES data (CCDC80, SKAT-O, p = 0.0005). In this study, we identified two new potential IA loci in the FC population: FHIT, which is significantly associated with hypertensive IA, and CCDC80, which has potential genetic and functional relevance to IA pathogenesis, providing evidence on the additional risk loci for familial IA. We also replicated the previous IA GWAS risk locus 18q11.2, and suggested a potential locus at 8p23.1 that warrants further study.

Original languageEnglish (US)
Article number4356
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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Genome-Wide Association Study
Intracranial Aneurysm
Population
Founder Effect
Exome
Single Nucleotide Polymorphism
Genome
Mutation

ASJC Scopus subject areas

  • General

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Genome-wide association analysis identifies new candidate risk loci for familial intracranial aneurysm in the French-Canadian population. / Zhou, Sirui; Gan-Or, Ziv; Ambalavanan, Amirthagowri; Lai, Dongbing; Xie, Pingxing; Bourassa, Cynthia V.; Strong, Stephanie; Ross, Jay P.; Dionne-Laporte, Alexandre; Spiegelman, Dan; Dupré, Nicolas; Foroud, Tatiana; Xiong, Lan; Dion, Patrick A.; Rouleau, Guy A.

In: Scientific Reports, Vol. 8, No. 1, 4356, 01.12.2018.

Research output: Contribution to journalArticle

Zhou, S, Gan-Or, Z, Ambalavanan, A, Lai, D, Xie, P, Bourassa, CV, Strong, S, Ross, JP, Dionne-Laporte, A, Spiegelman, D, Dupré, N, Foroud, T, Xiong, L, Dion, PA & Rouleau, GA 2018, 'Genome-wide association analysis identifies new candidate risk loci for familial intracranial aneurysm in the French-Canadian population', Scientific Reports, vol. 8, no. 1, 4356. https://doi.org/10.1038/s41598-018-21603-7
Zhou, Sirui ; Gan-Or, Ziv ; Ambalavanan, Amirthagowri ; Lai, Dongbing ; Xie, Pingxing ; Bourassa, Cynthia V. ; Strong, Stephanie ; Ross, Jay P. ; Dionne-Laporte, Alexandre ; Spiegelman, Dan ; Dupré, Nicolas ; Foroud, Tatiana ; Xiong, Lan ; Dion, Patrick A. ; Rouleau, Guy A. / Genome-wide association analysis identifies new candidate risk loci for familial intracranial aneurysm in the French-Canadian population. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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abstract = "Intracranial Aneurysm (IA) is a common disease with a worldwide prevalence of 1-3{\%}. In the French-Canadian (FC) population, where there is an important founder effect, the incidence of IA is higher and is frequently seen in families. In this study, we genotyped a cohort of 257 mostly familial FC IA patients and 1,992 FC controls using the Illumina NeuroX SNP-chip. The most strongly associated loci were tested in 34 Inuit IA families and in 32 FC IA patients and 106 FC controls that had been exome sequenced (WES). After imputation, one locus at 3p14.2 (FHIT, rs1554600, p = 4.66 × 10-9) reached a genome-wide significant level of association and a subsequent validation in Nunavik Inuit cohort further confirmed the significance of the FHIT variant association (rs780365, FBAT-O, p = 0.002839). Additionally, among the other promising loci (p < 5 × 10-6), the one at 3q13.2 (rs78125721, p = 4.77 × 10-7), which encompasses CCDC80, also showed an increased mutation burden in the WES data (CCDC80, SKAT-O, p = 0.0005). In this study, we identified two new potential IA loci in the FC population: FHIT, which is significantly associated with hypertensive IA, and CCDC80, which has potential genetic and functional relevance to IA pathogenesis, providing evidence on the additional risk loci for familial IA. We also replicated the previous IA GWAS risk locus 18q11.2, and suggested a potential locus at 8p23.1 that warrants further study.",
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AU - Zhou, Sirui

AU - Gan-Or, Ziv

AU - Ambalavanan, Amirthagowri

AU - Lai, Dongbing

AU - Xie, Pingxing

AU - Bourassa, Cynthia V.

AU - Strong, Stephanie

AU - Ross, Jay P.

AU - Dionne-Laporte, Alexandre

AU - Spiegelman, Dan

AU - Dupré, Nicolas

AU - Foroud, Tatiana

AU - Xiong, Lan

AU - Dion, Patrick A.

AU - Rouleau, Guy A.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Intracranial Aneurysm (IA) is a common disease with a worldwide prevalence of 1-3%. In the French-Canadian (FC) population, where there is an important founder effect, the incidence of IA is higher and is frequently seen in families. In this study, we genotyped a cohort of 257 mostly familial FC IA patients and 1,992 FC controls using the Illumina NeuroX SNP-chip. The most strongly associated loci were tested in 34 Inuit IA families and in 32 FC IA patients and 106 FC controls that had been exome sequenced (WES). After imputation, one locus at 3p14.2 (FHIT, rs1554600, p = 4.66 × 10-9) reached a genome-wide significant level of association and a subsequent validation in Nunavik Inuit cohort further confirmed the significance of the FHIT variant association (rs780365, FBAT-O, p = 0.002839). Additionally, among the other promising loci (p < 5 × 10-6), the one at 3q13.2 (rs78125721, p = 4.77 × 10-7), which encompasses CCDC80, also showed an increased mutation burden in the WES data (CCDC80, SKAT-O, p = 0.0005). In this study, we identified two new potential IA loci in the FC population: FHIT, which is significantly associated with hypertensive IA, and CCDC80, which has potential genetic and functional relevance to IA pathogenesis, providing evidence on the additional risk loci for familial IA. We also replicated the previous IA GWAS risk locus 18q11.2, and suggested a potential locus at 8p23.1 that warrants further study.

AB - Intracranial Aneurysm (IA) is a common disease with a worldwide prevalence of 1-3%. In the French-Canadian (FC) population, where there is an important founder effect, the incidence of IA is higher and is frequently seen in families. In this study, we genotyped a cohort of 257 mostly familial FC IA patients and 1,992 FC controls using the Illumina NeuroX SNP-chip. The most strongly associated loci were tested in 34 Inuit IA families and in 32 FC IA patients and 106 FC controls that had been exome sequenced (WES). After imputation, one locus at 3p14.2 (FHIT, rs1554600, p = 4.66 × 10-9) reached a genome-wide significant level of association and a subsequent validation in Nunavik Inuit cohort further confirmed the significance of the FHIT variant association (rs780365, FBAT-O, p = 0.002839). Additionally, among the other promising loci (p < 5 × 10-6), the one at 3q13.2 (rs78125721, p = 4.77 × 10-7), which encompasses CCDC80, also showed an increased mutation burden in the WES data (CCDC80, SKAT-O, p = 0.0005). In this study, we identified two new potential IA loci in the FC population: FHIT, which is significantly associated with hypertensive IA, and CCDC80, which has potential genetic and functional relevance to IA pathogenesis, providing evidence on the additional risk loci for familial IA. We also replicated the previous IA GWAS risk locus 18q11.2, and suggested a potential locus at 8p23.1 that warrants further study.

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