Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors

Bakker, Mark K; Spek, Rick A. A. van der; Rheenen, Wouter van; Morel, Sandrine; Bourcier, Romain; Hostettler, Isabel C.; Alg, Varinder S; Eijk, Kristel R. van; Koido, Masaru; Akiyama, Masato; Terao, Chikashi; Matsuda, Koichi; Walters, Robin G.; Lin, Kuang; Li, Liming; Millwood, Iona Y.; Chen, Zhengming; Rouleau, Guy A.; Zhou, Sirui; Rannikmäe, Kristiina; Sudlow, Cathie; Houlden, Henry; Berg, Leonard H van den; Dina, Christian; Naggara, Olivier; Gentric, Jean-Christophe; Shotar, Eimad; Eugène, François; Desal, Hubert; Winsvold, Bendik S.; Børte, Sigrid; Johnsen, Marianne Bakke; Brumpton, Ben; Sandvei, Marie Søfteland; Willer, Cristen J.; Hveem, Kristian; Zwart, John Anker; Verschuren, W M Monique; Friedrich, Christoph M.; Hirsch, Sven; Schilling, Sabine; Dauvillier, Jérôme; Martin, Olivier; Jones, Gregory T.; Bown, Matthew J.; Ko, Nerissa; Kim, Helen; Coleman, Jonathan R. I.; Breen, Gerome; Zaroff, Jonathan G.; Klijn, Catharina J.M.; Malik, Rainer; Dichgans, Martin; Sargurupremraj, Muralidharan; Tatlısumak, Turgut; Amouyel, Philippe; Debette, Stéphanie; Rinkel, Gabriël J.E.; Worrall, Bradford B.; Pera, Joanna; Słowik, Agnieszka; Gaál-Paavola, Emília; Niemelä, Mika; Jääskeläinen, Juha E.; Fraunberg, Mikael von und zu; Lindgren, Antti; Broderick, Joseph P.; Werring, David J.; Woo, Daniel; Redon, Richard; Bijlenga, Philippe; Kamatani, Yoichiro; Veldink, Jan H.; Ruigrok, Ynte M.

doi:10.1038/s41588-020-00725-7

Cited by 184 publications

(191 citation statements)

References 85 publications

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“…Therefore, the timely identification of IAs with a higher risk of rupture and the implementation of intervention measures to prevent the progression from UIAs to RIAs are of great significance. Many studies have found that genetic factors play an important role in the rupture of UIAs ( Bourcier et al, 2018 ; Bakker et al, 2020 ; Yanagisawa et al, 2020 ). In this study, bioinformatics analysis was conducted to explore the underlying mechanisms based on transcriptional profiles.…”

Section: Discussionmentioning

confidence: 99%

“…Intracranial aneurysms (IAs) are abnormal bumps that occur in an arterial wall, and they are an important cause of spontaneous subarachnoid hemorrhage (SAH) ( Macdonald and Schweizer, 2017 ). In the past few years, high blood pressure, smoking, atherosclerosis, and other factors have been shown to cause the occurrence and development of IAs ( Bakker et al, 2020 ; Ogilvy et al, 2020 ). However, the molecular mechanisms of the formation and rupture of IAs remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Integrated Transcriptional Profiling Analysis and Immune-Related Risk Model Construction for Intracranial Aneurysm Rupture

et al. 2021

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Intracranial aneurysms (IAs) may cause lethal subarachnoid hemorrhage upon rupture, but the molecular mechanisms are poorly understood. The aims of this study were to analyze the transcriptional profiles to explore the functions and regulatory networks of differentially expressed genes (DEGs) in IA rupture by bioinformatics methods and to identify the underlying mechanisms. In this study, 1,471 DEGs were obtained, of which 619 were upregulated and 852 were downregulated. Gene enrichment analysis showed that the DEGs were mainly enriched in the inflammatory response, immune response, neutrophil chemotaxis, and macrophage differentiation. Related pathways include the regulation of actin cytoskeleton, leukocyte transendothelial migration, nuclear factor κB signaling pathway, Toll-like receptor signaling pathway, tumor necrosis factor signaling pathway, and chemokine signaling pathway. The enrichment analysis of 20 hub genes, subnetworks, and significant enrichment modules of weighted gene coexpression network analysis showed that the inflammatory response and immune response had a causal relationship with the rupture of unruptured IAs (UIAs). Next, the CIBERSORT method was used to analyze immune cell infiltration into ruptured IAs (RIAs) and UIAs. Macrophage infiltration into RIAs increased significantly compared with that into UIAs. The result of principal component analysis revealed that there was a difference between RIAs and UIAs in immune cell infiltration. A 4-gene immune-related risk model for IA rupture (IRMIR), containing CXCR4, CXCL3, CX3CL1, and CXCL16, was established using the glmnet package in R software. The receiver operating characteristic value revealed that the model represented an excellent clinical situation for potential application. Enzyme-linked immunosorbent assay was performed and showed that the concentrations of CXCR4 and CXCL3 in serum from RIA patients were significantly higher than those in serum from UIA patients. Finally, a competing endogenous RNA network was constructed to provide a potential explanation for the mechanism of immune cell infiltration into IAs. Our findings highlighted the importance of immune cell infiltration into RIAs, providing a direction for further research.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Integrated Transcriptional Profiling Analysis and Immune-Related Risk Model Construction for Intracranial Aneurysm Rupture

et al. 2021

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“…Risk factors for aneurysmal rupture are female sex, age, black ethnicity, smoking, and an aneurysm size ≥7 mm in diameter [5,7]. Antiepileptic drugs and sex hormones have been shown to be associated with the formation of IAs [8]. In addition, the formation of IAs has been linked to genetic factors that promote smoking and high blood pressure, suggesting the overlap of genetic and environmental factors [8].…”

Section: Etiologymentioning

confidence: 99%

“…Antiepileptic drugs and sex hormones have been shown to be associated with the formation of IAs [8]. In addition, the formation of IAs has been linked to genetic factors that promote smoking and high blood pressure, suggesting the overlap of genetic and environmental factors [8]. These give proof for epidemiologically identified risk factors.…”

Section: Etiologymentioning

confidence: 99%

Endovascular Treatment of Intracranial Aneurysms

Adamou

Alexandrou

Roth

et al. 2021

Life

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Traditionally, surgical clipping was the only available treatment modality for intracranial aneurysms. However, in the last few decades, the endovascular therapy of intracranial aneurysms (IAs) has seen a tremendous evolution and development. From coiling to flow diversion and flow disruptor devices, endovascular treatment modalities have increased in number and received broader indications throughout the years. In this review article, the treatment modalities for the endovascular management of IAs are presented, emphasizing newer devices and technologies.

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“…The increasing number of elderly people with good functional capacity has led to an increase in the number of elderly patients treated at intensive care units (ICU) [1,11]. As a vascular disorder with lifelong modifiable risk factors [2,18], subarachnoid hemorrhage (SAH) has been shown to reach its peak incidence at 70-75 years of age [17]. Therefore, the number of elderly patients with SAH treated at neuro-ICUs is increasing.…”

Section: Introductionmentioning

confidence: 99%

Neurointensive care results and risk factors for unfavorable outcome in aneurysmatic SAH: a comparison of two age groups

et al. 2021

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Background The mean age of actively treated subarachnoid hemorrhage (SAH) patients is increasing. We aimed to compare outcomes and prognostic factors between older and younger SAH patients. Methods A retrospective single-center analysis of aneurysmal SAH patients admitted to a neuro-ICU during 2014–2019. We defined older patients as ≥70 years and younger patients as <70 years. For every older patient, we identified three younger patients with the same World Federation of Neurological Surgeons (WFNS) grade. We only included patients receiving active aneurysm treatment. Favorable functional outcome, defined as a Glasgow Outcome Scale (GOS) of 4–5 at 12 months, was our primary outcome. We used logistic regression to compare prognostic factors between the groups. Results Ninety-five (85%) of 112 older patients and 317 (94%) of 336 younger patients received aneurysm treatment. Of the younger patients, 91% with a good-grade SAH (WFNS I-III) had a favorable outcome compared to 52% in the older good-grade SAH group. In poor-grade patients (WFNS IV-V), favorable outcome was seen in 51% of younger patients, compared to 24% of older patients. Acute hydrocephalus and intracerebral hemorrhage were associated with unfavorable outcome in the younger (OR 4.7, 95% CI 2.6–8.4, and OR 3.7, 95% CI 2.1–6.4), but not in the older patients (OR 1.8, 95% CI 0.8–4.2, and OR 1.3, 95% CI 0.5–3.1, respectively). Conclusions In actively treated SAH patients, age was a major determinant of outcome. Factors reflecting increases in intracranial pressure associated with outcome only among younger patients.

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Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors

Cited by 184 publications

References 85 publications

Integrated Transcriptional Profiling Analysis and Immune-Related Risk Model Construction for Intracranial Aneurysm Rupture

Integrated Transcriptional Profiling Analysis and Immune-Related Risk Model Construction for Intracranial Aneurysm Rupture

Endovascular Treatment of Intracranial Aneurysms

Neurointensive care results and risk factors for unfavorable outcome in aneurysmatic SAH: a comparison of two age groups

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