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

Sci Rep. 2018 Mar 12;8(1):4356. doi: 10.1038/s41598-018-21603-7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Anhydride Hydrolases / genetics*
  • Adult
  • Aged
  • Canada
  • Cohort Studies
  • Extracellular Matrix Proteins
  • Female
  • Founder Effect
  • Genetic Loci*
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Glycoproteins / genetics*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intracranial Aneurysm / genetics*
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Proteins / genetics*
  • Polymorphism, Single Nucleotide

Substances

  • CCDC80 protein, human
  • Extracellular Matrix Proteins
  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • Neoplasm Proteins
  • fragile histidine triad protein
  • Acid Anhydride Hydrolases

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