Susceptibility loci for intracranial aneurysm in European and Japanese populations

Department of Neurosurgery, Neurobiology, Yale Center for Human Genetics and Genomics, Yale University School of Medicine, New Haven, CT 06510, USA.
Nature Genetics (Impact Factor: 29.35). 01/2009; 40(12):1472-7. DOI: 10.1038/ng.240
Source: PubMed


Stroke is the world's third leading cause of death. One cause of stroke, intracranial aneurysm, affects approximately 2% of the population and accounts for 500,000 hemorrhagic strokes annually in mid-life (median age 50), most often resulting in death or severe neurological impairment. The pathogenesis of intracranial aneurysm is unknown, and because catastrophic hemorrhage is commonly the first sign of disease, early identification is essential. We carried out a multistage genome-wide association study (GWAS) of Finnish, Dutch and Japanese cohorts including over 2,100 intracranial aneurysm cases and 8,000 controls. Genome-wide genotyping of the European cohorts and replication studies in the Japanese cohort identified common SNPs on chromosomes 2q, 8q and 9p that show significant association with intracranial aneurysm with odds ratios 1.24-1.36. The loci on 2q and 8q are new, whereas the 9p locus was previously found to be associated with arterial diseases, including intracranial aneurysm. Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells, suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role. These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.

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Available from: Atsushi Tajima
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    • "Type 2 diabetes and sIA disease are complex traits with genomic components. The 9p21.3 locus associates with both diseases (6,7,30,31) but not in the same linkage disequilibrium block. To our knowledge, other shared susceptibility loci have not been found, suggesting that type 2 diabetes and sIA disease do not share genomic predisposition. "
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    ABSTRACT: OBJECTIVE Type 2 diabetes is a risk factor for other forms of stroke, but its association with subarachnoid hemorrhage (SAH) from ruptured saccular intracranial aneurysm (sIA) has remained unclear.RESEARCH DESIGN AND METHODS Kuopio Intracranial Aneurysm Database ( includes all ruptured and unruptured sIA cases from a defined catchment population in eastern Finland since 1980. We compared the age-adjusted incidences of type 2 diabetes in 1,058 ruptured and 484 unruptured sIA patients during 1994-2008, using the national registry of prescribed medicine purchases.RESULTSOf the 1,058 ruptured sIA patients, 43% were males and 57% females, with a median age at rupture of 51 and 56 years, respectively. From 1994 to 2008 or until death, 9% had been prescribed antidiabetes medication (ADM) with a median starting age of 58 years for males and 66 years for females. Of the 484 unruptured sIA patients, 44% were males and 56% females, with a median age at the diagnosis of 53 and 55 years, respectively, and 9% had used ADM, with a median starting age of 61 years for males and 66 years for females. The incidence of type 2 diabetes was highest in the age-group 60-70 years, with no significant differences between the ruptured and unruptured sIA patients.CONCLUSIONS Our study suggests that type 2 diabetes does not increase the risk of rupture of sIA, which is by far the most frequent cause of nontraumatic SAH.
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    • "PANOGA combines nominally significant evidence of genetic association with current knowledge of protein-protein interaction (PPI) networks and functional information of selected SNPs. Here, we applied PANOGA on two IA GWAS separately: i) Finnish, Dutch (European, EU) population of 1701 cases and 7409 control cohorts [39], [41], ii) Japanese (JP) population of 1069 cases and 904 controls [40]. Even though there were not so many common disease predisposing SNPs and commonly targeted genes between these two populations, the identification of 7 common pathways in the top 10 pathways demonstrated the relevance of our pathway-oriented approach. "
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    ABSTRACT: The identification of significant individual factors causing complex diseases is challenging in genome-wide association studies (GWAS) since each factor has only a modest effect on the disease development mechanism. In this study, we hypothesize that the biological pathways that are targeted by these individual factors show higher conservation within and across populations. To test this hypothesis, we searched for the disease related pathways on two intracranial aneurysm GWAS in European and Japanese case-control cohorts. Even though there were a few significantly conserved SNPs within and between populations, seven of the top ten affected pathways were found significant in both populations. The probability of random occurrence of such an event is 2.44E-36. We therefore claim that even though each individual has a unique combination of factors involved in the mechanism of disease development, most targeted pathways that need to be altered by these factors are, for the most part, the same. These pathways can serve as disease markers. Individuals, for example, can be scanned for factors affecting the genes in marker pathways. Hence, individual factors of disease development can be determined; and this knowledge can be exploited for drug development and personalized therapeutic applications. Here, we discuss the potential avenues of pathway markers in medicine and their translation to preventive and individualized health care.
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    • "Stroke-related genetic loci have recently been identified implementing genome-wide association (GWA) studies [9,10]. Further, genetic variants related to other stroke etiologies, such as aneurysms [11,12] and diabetes [13], have also been reported. "
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    ABSTRACT: To understand how stroke risk factors mechanistically contribute to stroke, the genetic components regulating each risk factor need to be integrated and evaluated with respect to biological function and through pathway-based algorithms. This resource will provide information to researchers studying the molecular and genetic causes of stroke in terms of genomic variants, genes, and pathways. Reported genetic variants, gene structure, phenotypes, and literature information regarding stroke were collected and extracted from publicly available databases describing variants, genome, proteome, functional annotation, and disease subtypes. Stroke related candidate pathways and etiologic genes that participate significantly in risk were analyzed in terms of canonical pathways in public biological pathway databases. These efforts resulted in a relational database of genetic signals of cerebral stroke, SigCS base, which implements an effective web retrieval system. The current version of SigCS base documents 1943 non-redundant genes with 11472 genetic variants and 165 non-redundant pathways. The web retrieval system of SigCS base consists of two principal search flows, including: 1) a gene-based variant search using gene table browsing or a keyword search, and, 2) a pathway-based variant search using pathway table browsing. SigCS base is freely accessible at SigCS base is an effective tool that can assist researchers in the identification of the genetic factors associated with stroke by utilizing existing literature information, selecting candidate genes and variants for experimental studies, and examining the pathways that contribute to the pathophysiological mechanisms of stroke.
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