Abstract
3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a sporadic and a familial form. Subarachnoid hemorrhage from sIA (sIA-SAH) is a devastating form of stroke. Certain rare genetic variants are enriched in the Finns, a population isolate with a small founder population and bottleneck events. As the sIA-SAH incidence in Finland is >2× increased, such variants may associate with sIA in the Finnish population. We tested 9.4 million variants for association in 760 Finnish sIA patients (enriched for familial sIA), and in 2,513 matched controls with case-control status and with the number of sIAs. The most promising loci (p<5E-6) were replicated in 858 Finnish sIA patients and 4,048 controls. The frequencies and effect sizes of the replicated variants were compared to a continental European population using 717 Dutch cases and 3,004 controls. We discovered four new high-risk loci with low frequency lead variants. Three were associated with the case-control status: 2q23.3 (MAF 2.1%, OR 1.89, p 1.42×10-9); 5q31.3 (MAF 2.7%, OR 1.66, p 3.17×10-8); 6q24.2 (MAF 2.6%, OR 1.87, p 1.87×10-11) and one with the number of sIAs: 7p22.1 (MAF 3.3%, RR 1.59, p 6.08×-9). Two of the associations (5q31.3, 6q24.2) replicated in the Dutch sample. The 7p22.1 locus was strongly differentiated; the lead variant was more frequent in Finland (4.6%) than in the Netherlands (0.3%). Additionally, we replicated a previously inconclusive locus on 2q33.1 in all samples tested (OR 1.27, p 1.87×10-12). The five loci explain 2.1% of the sIA heritability in Finland, and may relate to, but not explain, the increased incidence of sIA-SAH in Finland. This study illustrates the utility of population isolates, familial enrichment, dense genotype imputation and alternate phenotyping in search for variants associated with complex diseases.
Highlights
About 3% of the population develops saccular intracranial aneurysms during life [1,2]
Genome-wide association studies (GWAS) have been extensively used to identify common genetic variants associated with complex diseases
As common genetic variants have explained only a small fraction of the heritability of most complex diseases, there is a growing interest in the role of how low frequency and rare variants contribute to the susceptibility
Summary
About 3% of the population develops saccular intracranial aneurysms (sIAs) during life [1,2]. Genome wide association (GWA) studies have identified six definite and one probable loci with common variants associated to sIA: 4q31.23 (OR 1.22) [10,11]; 8q11.23–q12.1 (OR 1.28); 9p21.3 (OR 1.31); 10q24.32 (OR 1.29); 12q22 (OR 1.16) [10]; 13q13.1 (OR 1.20); 18q11.2 (OR 1.22) [12] (Table S5). These seven loci were estimated to explain 6.1%, 4.4% and 4.1% of the four-fold sibling recurrence risk in Finland, Europe and Japan respectively [10]. In these previous GWA studies, results on 2q33.1 locus were inconsistent: the locus was significant in the first GWAS [13], not significant in the enlarged follow-up GWAS [12], and in the third GWAS the risk allele was reversed in the Japanese replication sample [10]
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