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1.
J Am Heart Assoc ; 5(7)2016 07 14.
Article in English | MEDLINE | ID: mdl-27418160

ABSTRACT

BACKGROUND: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. METHODS AND RESULTS: We performed a mega-analysis of 1000 Genomes Project-imputed genome-wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA-, AAA-, and TAA-associated SNPs and tested these scores for association to case-control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium-score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single-nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10(-5)) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10(-3)). CONCLUSIONS: Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication.


Subject(s)
Aortic Aneurysm, Abdominal/genetics , Aortic Aneurysm, Thoracic/genetics , Intracranial Aneurysm/genetics , Aged , Case-Control Studies , Cohort Studies , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Linkage Disequilibrium , Male , Middle Aged , Odds Ratio , Polymorphism, Single Nucleotide , Risk Factors
2.
Stroke ; 45(11): 3194-9, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25256182

ABSTRACT

BACKGROUND AND PURPOSE: Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. METHODS: Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest. RESULTS: Genome-wide evidence of association was detected in the discovery sample on chromosome 9 (CDKN2BAS; rs10733376: P<1.0×10(-11)), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9, was associated with IA (rs10230207; P=4.14×10(-8)). This association replicated in the Dutch sample (P=0.01) but failed to show association in the Finnish sample (P=0.25). Meta-analysis results of the 3 cohorts reached statistical significant (P=9.91×10(-10)). CONCLUSIONS: We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9), suggesting a possible genetic link between this stroke subtype and IA.


Subject(s)
Chromosomes, Human, Pair 7/genetics , Genome-Wide Association Study/methods , Intracranial Aneurysm/genetics , Polymorphism, Single Nucleotide/genetics , White People/genetics , Adult , Aged , Cohort Studies , Female , Humans , Intracranial Aneurysm/diagnosis , Male , Middle Aged
3.
Neurology ; 83(1): 34-9, 2014 Jul 01.
Article in English | MEDLINE | ID: mdl-24879094

ABSTRACT

OBJECTIVE: We investigated whether risk alleles of single nucleotide polymorphisms associated with intracranial aneurysm (IA) are enriched in patients with familial IA, IA located at the middle cerebral artery (MCA), or IA rupture at a younger age. METHODS: In this case-only study, we calculated genetic risk scores (GRS) for 973 Dutch and 718 Finnish patients with IA by summing effect size-weighted risk allele counts of 7 single nucleotide polymorphisms associated with IAs previously identified through genome-wide association studies. We tested the GRS for association with presence of familial IA or IA at the MCA using logistic regression, and with age at time of IA rupture using linear regression. We also calculated odds ratios with 95% confidence intervals for the proportion of patients with each characteristic in the highest compared with the lowest GRS tertile. RESULTS: GRS were higher in IA at the MCA in the Dutch (p = 2.5 × 10(-4)), Finnish (p = 0.039), and combined cohort (p = 4.9 × 10(-5)). GRS were not associated with familial IA in the Dutch (p = 0.34), Finnish (p = 0.45), and combined cohort (p = 0.98), or with age at time of IA rupture in the Dutch (p = 0.28), Finnish (p = 0.86), and combined cohort (p = 0.45). In the combined cohort, odds ratios were 0.89 (0.67-1.20) for familial IA, 1.03 (0.79-1.34) for lower age, and 1.54 (1.20-1.98) for MCA aneurysms. CONCLUSIONS: Our findings suggest that genetic risk factors have a larger role in the development of IA at the MCA than at other sites, and that genetic heterogeneity should be considered in future genetic studies.


Subject(s)
Genetic Predisposition to Disease , Intracranial Aneurysm/genetics , Polymorphism, Single Nucleotide/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Cohort Studies , Female , Finland , Gene Frequency , Genetic Association Studies , Genotype , Humans , Logistic Models , Male , Middle Aged , Netherlands , Young Adult
4.
PLoS Genet ; 10(1): e1004134, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24497844

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.


Subject(s)
Genome-Wide Association Study , Intracranial Aneurysm/genetics , Stroke/genetics , Subarachnoid Hemorrhage/genetics , Chromosomes, Human, Pair 2/genetics , Europe , Finland , Gene Frequency , Genetic Predisposition to Disease , Genetic Variation , Genetics, Population , Humans , Intracranial Aneurysm/pathology , Risk Factors , Stroke/pathology , Subarachnoid Hemorrhage/pathology
5.
Blood ; 122(5): 658-65, 2013 Aug 01.
Article in English | MEDLINE | ID: mdl-23803710

ABSTRACT

Vascular bypass procedures in the central nervous system (CNS) remain technically challenging, hindered by complications and often failing to prevent adverse outcome such as stroke. Thus, there is an unmet clinical need for a safe and effective CNS revascularization. Vascular endothelial growth factors (VEGFs) are promising candidates for revascularization; however, their effects appear to be tissue-specific and their potential in the CNS has not been fully explored. To test growth factors for angiogenesis in the CNS, we characterized the effects of endothelium-specific growth factors on the brain vasculature and parenchyma. Recombinant adeno-associated virus (AAV) vectors encoding the growth factors were injected transcranially to the frontoparietal cerebrum of mice. Angiogenesis, mural cell investment, leukocyte recruitment, vascular permeability, reactive gliosis and neuronal patterning were evaluated by 3-dimensional immunofluorescence, electron microscopy, optical projection tomography, and magnetic resonance imaging. Placenta growth factor (PlGF) stimulated robust angiogenesis and arteriogenesis without significant side effects, whereas VEGF and VEGF-C incited growth of aberrant vessels, severe edema, and inflammation. VEGF-B, angiopoietin-1, angiopoietin-2, and a VEGF/angiopoietin-1 chimera had minimal effects on the brain vessels or parenchyma. Of the growth factors tested, PlGF emerged as the most efficient and safe angiogenic factor, hence making it a candidate for therapeutic CNS revascularization.


Subject(s)
Central Nervous System/blood supply , Cerebral Revascularization , Intercellular Signaling Peptides and Proteins/physiology , Pregnancy Proteins/physiology , Animals , Blood Vessels/growth & development , Blood Vessels/metabolism , Central Nervous System Neoplasms/etiology , Central Nervous System Neoplasms/genetics , Encephalitis/etiology , Encephalitis/genetics , Female , Genetic Therapy/methods , Hemangioma/etiology , Hemangioma/genetics , Intercellular Signaling Peptides and Proteins/genetics , Mice , Mice, Inbred C57BL , Neovascularization, Physiologic/genetics , Placenta Growth Factor , Pregnancy Proteins/genetics , Pregnancy Proteins/metabolism , Pregnancy Proteins/therapeutic use , Vascular Endothelial Growth Factor A/adverse effects , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor C/adverse effects , Vascular Endothelial Growth Factor C/genetics
6.
Circulation ; 127(4): 424-34, 2013 Jan 29.
Article in English | MEDLINE | ID: mdl-23357661

ABSTRACT

BACKGROUND: There is an unmet need for proangiogenic therapeutic molecules for the treatment of tissue ischemia in cardiovascular diseases. However, major inducers of angiogenesis such as vascular endothelial growth factor (VEGF/VEGF-A) have side effects that limit their therapeutic utility in vivo, especially at high concentrations. Angiopoietin-1 has been considered to be a blood vessel stabilization factor that can inhibit the intrinsic property of VEGF to promote vessel leakiness. In this study, we have designed and tested the angiogenic properties of chimeric molecules consisting of receptor-binding parts of VEGF and angiopoietin-1. We aimed at combining the activities of both factors into 1 molecule for easy delivery and expression in target tissues. METHODS AND RESULTS: The VEGF-angiopoietin-1 (VA1) chimeric protein bound to both VEGF receptor-2 and Tie2 and induced the activation of both receptors. Detailed analysis of VA1 versus VEGF revealed differences in the kinetics of VEGF receptor-2 activation and endocytosis, downstream kinase activation, and VE-cadherin internalization. The delivery of a VA1 transgene into mouse skeletal muscle led to increased blood flow and enhanced angiogenesis. VA1 was also very efficient in rescuing ischemic limb perfusion. However, VA1 induced less plasma protein leakage and myeloid inflammatory cell recruitment than VEGF. Furthermore, angioma-like structures associated with VEGF expression were not observed with VA1. CONCLUSIONS: The VEGF-angiopoietin-1 chimera is a potent angiogenic factor that triggers a novel mode of VEGF receptor-2 activation, promoting less vessel leakiness, less tissue inflammation, and better perfusion in ischemic muscle than VEGF. These properties of VA1 make it an attractive therapeutic tool.


Subject(s)
Angiopoietin-1/pharmacology , Genetic Therapy/methods , Ischemia/drug therapy , Neovascularization, Physiologic/physiology , Recombinant Fusion Proteins/pharmacology , Vascular Endothelial Growth Factor A/pharmacology , Adenoviridae/genetics , Angiopoietin-1/genetics , Angiopoietin-1/metabolism , Animals , Capillary Permeability/physiology , Cell Line, Tumor , Disease Models, Animal , Female , HEK293 Cells , Hindlimb/blood supply , Human Umbilical Vein Endothelial Cells , Humans , Ischemia/genetics , Leukemia, Myeloid , Mice , Mice, Inbred Strains , Muscle, Skeletal/blood supply , Receptor Protein-Tyrosine Kinases/metabolism , Receptor, TIE-2 , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Signal Transduction/physiology , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-1/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism
7.
PLoS Genet ; 8(3): e1002563, 2012.
Article in English | MEDLINE | ID: mdl-22438818

ABSTRACT

Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, the pathomechanisms of most remain elusive. Studying the genetics of risk factors predisposing to disease is an attractive approach to identify targets for functional studies. Intracranial aneurysms (IA) are rupture-prone pouches at cerebral artery branching sites. IA is a complex disease for which GWAS have identified five loci with strong association and a further 14 loci with suggestive association. To decipher potential underlying disease mechanisms, we tested whether there are IA loci that convey their effect through elevating blood pressure (BP), a strong risk factor of IA. We performed a meta-analysis of four population-based Finnish cohorts (n(FIN)  =  11 266) not selected for IA, to assess the association of previously identified IA candidate loci (n  =  19) with BP. We defined systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure as quantitative outcome variables. The most significant result was further tested for association in the ICBP-GWAS cohort of 200 000 individuals. We found that the suggestive IA locus at 5q23.2 in PRDM6 was significantly associated with SBP in individuals of European descent (p(FIN)  =  3.01E-05, p(ICBP-GWAS)  =  0.0007, p(ALL)  =  8.13E-07). The risk allele of IA was associated with higher SBP. PRDM6 encodes a protein predominantly expressed in vascular smooth muscle cells. Our study connects a complex disease (IA) locus with a common risk factor for the disease (SBP). We hypothesize that common variants in PRDM6 can contribute to altered vascular wall structure, hence increasing SBP and predisposing to IA. True positive associations often fail to reach genome-wide significance in GWAS. Our findings show that analysis of traditional risk factors as intermediate phenotypes is an effective tool for deciphering hidden heritability. Further, we demonstrate that common disease loci identified in a population isolate may bear wider significance.


Subject(s)
Blood Pressure , Genome-Wide Association Study , Intracranial Aneurysm/genetics , Zinc Fingers/genetics , Adult , Blood Pressure/genetics , Chromosomes, Human, Pair 5/genetics , Cohort Studies , Female , Finland , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Muscle Proteins/genetics , Myocytes, Smooth Muscle/metabolism , Polymorphism, Single Nucleotide , Risk Factors , Transcription Factors/genetics
8.
Proc Natl Acad Sci U S A ; 108(49): 19707-12, 2011 Dec 06.
Article in English | MEDLINE | ID: mdl-22106312

ABSTRACT

The pathogenesis of intracranial aneurysm (IA) formation and rupture is complex, with significant contribution from genetic factors. We previously reported genome-wide association studies based on European discovery and Japanese replication cohorts of 5,891 cases and 14,181 controls that identified five disease-related loci. These studies were based on testing replication of genomic regions that contained SNPs with posterior probability of association (PPA) greater than 0.5 in the discovery cohort. To identify additional IA risk loci, we pursued 14 loci with PPAs in the discovery cohort between 0.1 and 0.5. Twenty-five SNPs from these loci were genotyped using two independent Japanese cohorts, and the results from discovery and replication cohorts were combined by meta-analysis. The results demonstrated significant association of IA with rs6841581 on chromosome 4q31.23, immediately 5' of the endothelin receptor type A with P = 2.2 × 10(-8) [odds ratio (OR) = 1.22, PPA = 0.986]. We also observed substantially increased evidence of association for two other regions on chromosomes 12q22 (OR = 1.16, P = 1.1 × 10(-7), PPA = 0.934) and 20p12.1 (OR = 1.20, P = 6.9 × 10(-7), PPA = 0.728). Although endothelin signaling has been hypothesized to play a role in various cardiovascular disorders for over two decades, our results are unique in providing genetic evidence for a significant association with IA and suggest that manipulation of the endothelin pathway may have important implications for the prevention and treatment of IA.


Subject(s)
Chromosomes, Human, Pair 4/genetics , Genetic Predisposition to Disease/genetics , Intracranial Aneurysm/genetics , Polymorphism, Single Nucleotide , Receptor, Endothelin A/genetics , Cohort Studies , Gene Frequency , Genome-Wide Association Study/methods , Genotype , Humans , Odds Ratio , Risk Factors
9.
Nat Genet ; 42(5): 420-5, 2010 May.
Article in English | MEDLINE | ID: mdl-20364137

ABSTRACT

Saccular intracranial aneurysms are balloon-like dilations of the intracranial arterial wall; their hemorrhage commonly results in severe neurologic impairment and death. We report a second genome-wide association study with discovery and replication cohorts from Europe and Japan comprising 5,891 cases and 14,181 controls with approximately 832,000 genotyped and imputed SNPs across discovery cohorts. We identified three new loci showing strong evidence for association with intracranial aneurysms in the combined dataset, including intervals near RBBP8 on 18q11.2 (odds ratio (OR) = 1.22, P = 1.1 x 10(-12)), STARD13-KL on 13q13.1 (OR = 1.20, P = 2.5 x 10(-9)) and a gene-rich region on 10q24.32 (OR = 1.29, P = 1.2 x 10(-9)). We also confirmed prior associations near SOX17 (8q11.23-q12.1; OR = 1.28, P = 1.3 x 10(-12)) and CDKN2A-CDKN2B (9p21.3; OR = 1.31, P = 1.5 x 10(-22)). It is noteworthy that several putative risk genes play a role in cell-cycle progression, potentially affecting the proliferation and senescence of progenitor-cell populations that are responsible for vascular formation and repair.


Subject(s)
Genome-Wide Association Study , Intracranial Aneurysm/genetics , Cell Cycle , Cell Proliferation , Cohort Studies , Europe , Female , Genotype , Hemorrhage/genetics , Humans , Japan , Male , Models, Genetic , Odds Ratio , Polymorphism, Single Nucleotide
10.
Neurosurgery ; 65(1): 39-52; discussion 52-3, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19574824

ABSTRACT

OBJECTIVE: The lateral supraorbital approach for safely and completely removing olfactory groove meningiomas was assessed. METHODS: Between September 1997 and June 2008, a total of 656 meningiomas were operated on by the senior author (JH) at the Department of Neurosurgery, Helsinki University Central Hospital; 66 were olfactory meningiomas. We retrospectively analyze the clinical data, radiological findings, surgical treatment, histology, and outcome of all the olfactory groove meningioma patients and discuss the operative techniques used. RESULTS: Sixty-six patients were operated on by the lateral supraorbital approach. The median preoperative Karnofsky Performance Scale score was 80 (range, 40-100). Three patients were redo cases in which the primary operation had been performed elsewhere. Seemingly complete tumor removal was achieved in 60 patients (91%); there was no surgical mortality. Postoperatively, 6 patients (9%) had cerebrospinal fluid leakage, 5 (8%) had new visual deficits, 4 (6%) had wound infections, 4 (6%) had cotton granulomas, and 1 (2%) had a postoperative hematoma. The median Karnofsky score at discharge was 80 (range, 40-100). Six patients had recurrent tumors; 3 underwent reoperations after an average of 21 months (range, 1-41 months); 1 was treated with radiosurgery, and 2 were only followed. During the median follow-up time of 45 months (range, 2-128 months), there were 4 recurrences (6%) diagnosed on average 32 months (range, 17-59 months) after surgery. CONCLUSION: The lateral supraorbital approach can be used safely for olfactory groove meningiomas of all sizes with no mortality and relatively low morbidity. Surgical results and tumor recurrence with this fast and simple approach are similar to those obtained with more extensive, complex, and time-consuming approaches.


Subject(s)
Frontal Bone/surgery , Meningeal Neoplasms/pathology , Meningeal Neoplasms/surgery , Meningioma/pathology , Meningioma/surgery , Neurosurgical Procedures/methods , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Magnetic Resonance Imaging/methods , Male , Meningeal Neoplasms/mortality , Meningioma/mortality , Middle Aged , Postoperative Complications , Retrospective Studies , Statistics, Nonparametric , Treatment Outcome
11.
Hum Mol Genet ; 18(15): 2912-21, 2009 Aug 01.
Article in English | MEDLINE | ID: mdl-19454485

ABSTRACT

Population isolates, such as Finland, have proved beneficial in mapping rare causative genetic variants due to a limited number of founders resulting in reduced genetic heterogeneity and extensive linkage disequilibrium (LD). We have here used this special opportunity to identify rare alleles in autism by genealogically tracing 20 autism families into one extended pedigree with verified genealogical links reaching back to the 17th century. In this unique pedigree, we performed a dense microsatellite marker genome-wide scan of linkage and LD and followed initial findings with extensive fine-mapping. We identified a putative autism susceptibility locus at 19p13.3 and obtained further evidence for previously identified loci at 1q23 and 15q11-q13. Most promising candidate genes were TLE2 and TLE6 clustered at 19p13 and ATP1A2 at 1q23.


Subject(s)
Autistic Disorder/genetics , Genome-Wide Association Study , Linkage Disequilibrium , Pedigree , Chromosomes, Human, Pair 1/genetics , Chromosomes, Human, Pair 15/genetics , Chromosomes, Human, Pair 19/genetics , Female , Finland , Humans , Male , Microsatellite Repeats , White People/genetics
12.
Nat Genet ; 40(12): 1472-7, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18997786

ABSTRACT

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.


Subject(s)
Genetic Predisposition to Disease , Intracranial Aneurysm/genetics , Asian People/genetics , Chromosomes, Human, Pair 2/genetics , Chromosomes, Human, Pair 8/genetics , Chromosomes, Human, Pair 9/genetics , Genome-Wide Association Study , Humans , Intracranial Aneurysm/epidemiology , Intracranial Aneurysm/pathology , Polymorphism, Single Nucleotide , White People/genetics
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