title: Genetic Variants Underlying Risk of Intracranial Aneurysms: Insights from a GWAS in Portugal.
abstract: Subarachnoid hemorrhage (SAH) is a life-threatening event that most frequently leads to severe disability and death. Its most frequent cause is the rupture of a saccular intracranial aneurysm (IA), which is a blood vessel dilation caused by disease or weakening of the vessel wall. Although the genetic contribution to IA is well established, to date no single gene has been unequivocally identified as responsible for IA formation or rupture. We aimed to identify IA susceptibility genes in the Portuguese population through a pool-based multistage genome-wide association study. Replicate pools were allelotyped in triplicate in a discovery dataset (100 IA cases and 92 gender-matched controls) using the Affymetrix Human SNP Array 6.0. Top SNPs (absolute value of the relative allele score difference between cases and controls |RASdiff|≥13.0%) were selected for technical validation by individual genotyping in the discovery dataset. From the 101 SNPs successfully genotyped, 99 SNPs were nominally associated with IA. Replication of technically validated SNPs was conducted in an independent replication dataset (100 Portuguese IA cases and 407 controls). rs4667622 (between UBR3 and MYO3B), rs6599001 (between SCN11A and WDR48), rs3932338 (214 kilobases downstream of PRDM9), and rs10943471 (96 kilobases upstream of HTR1B) were associated with IA (unadjusted allelic chi-square tests) in the datasets tested (discovery: 6.84E-04≤P≤1.92E-02, replication: 2.66E-04≤P≤2.28E-02, and combined datasets: 6.05E-05≤P≤5.50E-04). Additionally, we confirmed the known association with IA of rs1333040 at the 9p21.3 genomic region, thus validating our dataset. These novel findings in the Portuguese population warrant further replication in additional independent studies, and provide additional candidates to more comprehensively understand IA etiopathogenesis.
authors.affiliation: Instituto Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Abrantes
authors.affiliation: Serviço de Neurocirurgia, Hospital de Santa Maria, Lisboa, Portugal.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Santos
authors.affiliation: Instituto Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Sousa
authors.affiliation: Instituto Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Joana M
authors.initials: JM
authors.lastname: Xavier
authors.affiliation: Instituto Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Vânia
authors.initials: V
authors.lastname: Francisco
authors.affiliation: Instituto Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Tiago
authors.initials: T
authors.lastname: Krug
authors.affiliation: Instituto Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Sobral
authors.affiliation: Instituto Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Mafalda
authors.initials: M
authors.lastname: Matos
authors.affiliation: Instituto Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Madalena
authors.initials: M
authors.lastname: Martins
authors.affiliation: Centro de Estudos de Doenças Crónicas (CEDOC), Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: António
authors.initials: A
authors.lastname: Jacinto
authors.affiliation: Serviço de Neurocirurgia, Hospital de Santa Maria, Lisboa, Portugal.
authors.forename: Domingos
authors.initials: D
authors.lastname: Coiteiro
authors.affiliation: Instituto Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Sofia A
authors.initials: SA
authors.lastname: Oliveira
mesh_terms: D004247:DNA / Q000235:genetics; D030541:Databases, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D002532:Intracranial Aneurysm / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011174:Portugal; D015203:Reproducibility of Results; D012307:Risk Factors
chemical_list: D004247:DNA