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.
Highlights
2% of the general population has undetected intracranial aneurysms [1], only a small fraction of those will experience aneurysm rupture
To identify genetic variants associated with intracranial aneurysm (IA) in the Portuguese population, we first performed a Genome-wide association studies (GWAS) in the discovery dataset using pools of samples
To identify common genetic determinants increasing the susceptibility to IA in the Portuguese population, we conducted a multistage pool-based GWAS including a discovery phase, a technical validation step and an independent replication
Summary
2% of the general population has undetected intracranial aneurysms [1], only a small fraction of those will experience aneurysm rupture. Of those who present with subarachnoid hemorrhage, nearly 50% will die and a significant percentage is left with important neurological deficits [2]. Those patients carrying aneurysms that will never rupture should not be subjected to the risks involved with aneurysmal repair. Diagnosis before rupture and accurate biomarkers to predict the risk of rupture are of paramount importance to the IA patient’s survival and quality of life. Despite recent advances in molecular techniques, diagnosis of IA still relies solely on imaging methods and the mechanisms of IA initiation, progression, and rupture are still poorly understood
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