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Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits. Cross-ancestry genome-wide association analyses in individuals of European and East Asian ancestry identify 11 new risk loci for intracranial aneurysms and highlight a polygenic architecture explaining a substantial fraction of disease heritability.

Intracranial aneurysms (IA) are local dilatations in cerebral arteries that predominantly affect the circle of Willis. Occurring in approximately 2–5% of adults, these weakened areas are susceptible to rupture, leading to subarachnoid hemorrhage (SAH), a type of hemorrhagic stroke. Due to its early age of onset and poor prognosis, SAH accounts for > 25% of years lost for all stroke victims under the age of 65. In this review, we describe the cerebrovascular pathology associated with intracranial aneurysms. To understand IA genetics, we summarize syndromes with elevated incidence, genome-wide association studies (GWAS), whole exome studies on IA-affected families, and recent research that established definitive roles for Thsd1 (Thrombospondin Type 1 Domain Containing Protein 1) and Sox17 (SRY-box 17) in IA using genetically engineered mouse models. Lastly, we discuss the underlying molecular mechanisms of IA, including defects in vascular endothelial and smooth muscle cells caused by dysfunction in mechanotransduction, Thsd1/FAK (Focal Adhesion Kinase) signaling, and the Transforming Growth Factor β (TGF-β) pathway. As illustrated by THSD1 research, cell adhesion may play a significant role in IA.

Intracranial aneurysms (IAs) linger as a potentially devastating clinical problem. Despite intense investigation, our understanding of the mechanisms leading to aneurysm development, progression and rupture remain incompletely defined. An accumulating body of evidence implicates inflammation as a critical contributor to aneurysm pathogenesis. Intracranial aneurysm formation and progression appear to result from endothelial dysfunction, a mounting inflammatory response, and vascular smooth muscle cell phenotypic modulation producing a pro-inflammatory phenotype. A later final common pathway appears to involve apoptosis of cellular constituents of the vessel wall. These changes result in degradation of the integrity of the vascular wall leading to aneurysmal dilation, progression and eventual rupture in certain aneurysms. Various aspects of the inflammatory response have been investigated as contributors to IA pathogenesis including leukocytes, complement, immunoglobulins, cytokines, and other humoral mediators. Furthermore, gene expression profiling of IA compared with control arteries has prominently featured differential expression of genes involved with immune response/inflammation. Preliminary data suggest that therapies targeting the inflammatory response may have efficacy in the future treatment of IA. Further investigation, however, is necessary to elucidate the precise role of inflammation in IA pathogenesis, which can be exploited to improve the prognosis of patients harboring IA.

Intracranial aneurysm (IA) is a common cerebrovascular disease in which sacral aneurysms occurring in the Wills ring region can lead to devastating subarachnoid hemorrhage. Despite advances in research, the underlying mechanisms of IA formation and rupture remain incompletely understood, hindering early diagnosis and effective treatment. This review comprehensively summarizes the current landscape of IA biomarkers, encompassing genetic markers, DNA, RNA, inflammatory molecules, oxidative stress proteins, and extracellular matrix (ECM) components. Accumulating evidence suggests that various biomarkers are associated with different stages of IA pathogenesis, including initiation, progression, and rupture. Aberrant ECM composition and remodeling have been observed in IA patients, and extracellular matrix-degrading enzymes are implicated in IA growth and rupture. Biomarker research in IA holds great potential for improving clinical outcomes. Future studies should focus on validating the existing biomarkers, identifying novel ones, and investigating their underlying mechanisms to facilitate the development of personalized preventive and therapeutic strategies for IA.

About 3% of adults have an unruptured intracranial aneurysm and this prevalence can increase to 10% in high-risk groups. Aneurysms are not congenital, but develop throughout life. New evidence has established that genetic, anatomical, inflammatory, and modifiable risk factors interact in the formation, growth, and rupture of aneurysms. Genome-wide association studies have found an association with genetic risk variants in 17 loci. Furthermore, circle of Willis variations predispose to aneurysm formation and cluster within families. These variations, plus modifiable risk factors, such as hypertension and smoking, result in haemodynamic stress and inflammatory reactions in the vessel and aneurysm wall but, in people at high risk, aneurysms can also form in the absence of hypertension or smoking. These research advances provide knowledge bases for the individualised concepts of identifying individuals who can have an aneurysm or patients with aneurysms at increased risk of rupture, and for pharmacological treatments for patients who do not require immediate preventive repair.

Background and purpose The causal association between inflammatory cytokines and the development of intracranial aneurysm (IA), unruptured IA (uIA) and subarachnoid hemorrhage (SAH) lacks clarity. Methods The summary‐level datasets for inflammatory cytokines were extracted from a genome‐wide association study of the Finnish Cardiovascular Risk in Young Adults Study and the FINRISK survey. The summary statistics datasets related to IA, uIA and SAH were obtained from the genome‐wide association study meta‐analysis of the International Stroke Genetics Consortium and FinnGen Consortium. The primary method employed for analysis was inverse variance weighting (false discovery rate), supplemented by sensitivity analyses to address pleiotropy and enhance robustness. Results In the International Stroke Genetics Consortium, 10, six and eight inflammatory cytokines exhibited a causal association with IA, uIA and SAH, respectively (false discovery rate, p < 0.05). In FinnGen datasets, macrophage Inflammatory Protein‐1 Alpha (MIP_1A), MIP_1A and interferon γ‐induced protein 10 (IP_10) were verified for IA, uIA and SAH, respectively. In the reverse Mendelian randomization analysis, the common cytokines altered by uIA and SAH were vascular endothelial growth factor (VEGF), MIP_1A, IL_9, IL_10 and IL_17, respectively. The meta‐analysis results show that MIP_1A and IP_10 could be associated with the decreased risk of IA, and MIP_1A and IP_10 were associated with the decreased risk of uIA and SAH, respectively. Notably, the levels of VEGF, MIP_1A, IL_9, IL_10 and TNF_A were increased with uIA. Comprehensive heterogeneity and pleiotropy analyses confirmed the robustness of these results. Conclusion Our study unveils a bidirectional association between inflammatory cytokines and IA, uIA and SAH. Further investigations are essential to validate their relationship and elucidate the underlying mechanisms.

Intracranial aneurysms (IAs) represent a major clinical concern due to their risk of rupture and the resulting morbidity and mortality. Both environmental and genetic factors contribute to IA susceptibility, yet the genetic causes of IA remain poorly understood. We previously identified several single nucleotide variants (SNVs) in collagen XXII ( ) in affected individuals with IA. However, the functional impact of these variants has not been determined, and it remains unclear whether and how they increase IA susceptibility. Here, we tested the functional effect of these variants in a zebrafish embryo model. Inducible overexpression of six human SNVs increased the incidence of cranial hemorrhage in zebrafish embryos, while overexpression of wild-type had no significant effect. Overexpression of DNA construct encoding COL22A1 P989L variant disrupted intracranial vascular architecture, leading to reduced vessel length, altered vascular surface parameters, and abnormal arterial patterning. Overexpression of the P989L SNV also caused pronounced vascular leakage, reduced pericyte number, and decreased expression of the tight junction proteins Claudin-5 and ZO-1. P989L SNV overexpression was also associated with increased expression of the endoplasmic reticulum stress marker . In silico modeling suggested that the P989L variant likely perturbs triple-helix formation in COL22A1, thereby causing protein misfolding and compromising its function. Together, these findings demonstrate the deleterious effects of IA-associated variants on vascular function and stability and suggest that these variants may increase the incidence of IA in humans.

Intracranial aneurysm (IA) poses significant health risks, yet the specific mRNA profiles and regulatory mechanisms distinguishing unruptured IA (UIA) from ruptured IA (RIA) remain unclear. This study aimed to elucidate these differences through comprehensive mRNA analysis. We employed RNA sequencing to compare mRNA expression patterns among control individuals, UIA patients, and RIA patients. Differential expression analysis identified triggering receptor expressed on myeloid cells 1 (TREM1) as a potential biomarker for IA occurrence and rupture, which was validated in an expanded cohort. In vitro experiments revealed that TREM1 overexpression in human umbilical vein endothelial cells (HUVECs) inhibited proliferation, angiogenesis, and migration while promoting apoptosis and inflammation. Bioinformatic predictions and subsequent chromatin immunoprecipitation assays confirmed signal transducer and activator of transcription 1 (STAT1) as a transcriptional regulator of TREM1. STAT1 overexpression in HUVECs activated the MAPK signaling pathway and mimicked the effects of TREM1 overexpression, which were reversible by TREM1 inhibition. Conversely, P38 MAPK inhibition produced opposite effects, which were negated by STAT1 overexpression. This study identifies TREM1 as a potential biomarker for IA occurrence and rupture, likely regulated by STAT1, offering new avenues for non-invasive IA intervention strategies.

Background Intracranial aneurysm (IA) is a severe cerebrovascular disease, and effective gene therapy and drug interventions for its treatment are still lacking. Oxidative stress (OS) is closely associated with the IA, but the key regulatory genes involved are still unclear. Through multiomics analysis and experimental validation, we identified two diagnostic markers for IA associated with OS. Methods In this study, we first analyzed the IA dataset GSE75436 and conducted a joint analysis of oxidative stress-related genes (ORGs). Differential analysis, functional enrichment analysis, immune infiltration, WGCNA, PPI, LASSO, and other methods were used to identify IA diagnostic markers related to OS. Next, the functions of TLR4 and ALOX5 expression in IA and their potential targeted therapeutic drugs were analyzed. We also performed single-cell sequencing of patient IA and control (superficial temporal artery, STA) tissues. 23,342 cells were captured from 2 IA and 3 STA samples obtained from our center. Cell clustering and annotation were conducted using R software to observe the distribution of TLR4 and ALOX5 expression in IAs. Finally, the expression of TLR4 and ALOX5 were validated in IA patients and in an elastase-induced mouse IA model using experiments such as WB and immunofluorescence. Results Through bioinformatics analysis, we identified 16 key ORGs associated with IA pathogenesis. Further screening revealed that ALOX5 and TLR4 were highly expressed to activate a series of inflammatory responses and reduce the production of myocytes. Methotrexate (MTX) may be a potential targeted drug. Single-cell analysis revealed a notable increase in immune cells in the IA group, with ALOX5 and TLR4 primarily localized to monocytes/macrophages. Validation through patient samples and mouse models confirmed high expression of ALOX5 and TLR4 in IAs. Conclusions Bioinformatics analysis indicated that ALOX5 and TLR4 are the most significant ORGs associated with the pathogenesis of IA. Single-cell sequencing and experiments revealed that the high expression of ALOX5 and TLR4 are closely related to IA. These two genes are promising new targets for IA therapy.

Richard Lifton and colleagues report the identification of three susceptibility loci for intracranial aneurysm. Two of the loci are new, with SNPs on chromosome 8q likely acting through SOX17 , which is required for the formation and maintenance of endothelial cells. Stroke is the world's third leading cause of death. One cause of stroke, intracranial aneurysm, affects ∼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 1 . 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 2 , 3 , 4 , 5 . Associated SNPs on 8q likely act via SOX17 , which is required for formation and maintenance of endothelial cells 6 , 7 , 8 , suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role 9 . These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.